Vol 35, No.

3, 2013
Medicographia
116
A Ser vier publication

Emotions and depression

E DITORIAL
259 Emotions and depression
motions et dpression
G. M. Goodwin, United Kingdom

T HEMED ARTICLES
265 Emotion and trauma
B. Cyrulnik, France

271 Gender/sex differences in emotions

G. Einstein, J. Downar, S. H. Kennedy, Canada

281 A look into emotions with neuroimaging

G. Northoff, Canada

287 From sadness to depressed mood and from anhedonia

to positive mood and well-being
K. Demyttenaere, Belgium

292 Pleasure and depression: anhedonia as a core feature

M. Di Giannantonio, Italy

299 Anxiety symptoms in depression: clinical and conceptual considerations

D. J. Stein, South Africa

304 Antidepressants and emotions: therapeutics and iatrogenic effects

H. J. Mller, F. Seemller, Germany

Contents continued on next page

Vol 35, No. 3, 2013
Medicographia
116
A Ser vier publication

C ONTROVERSIAL QUESTION
311 Do you take positive emotions into account while treating depressive
patients?
A. S. Avedisova, Russia - M. Bauer, Germany - K. Bazaid, Saudi Arabia -
R. Evsegneev, Belarus - V. Gentil, Brazil - D. Marazziti, Italy - J. Marques-
Teixeira, Portugal - Y. M. Mok, Singapore - M. Nasreldin, Egypt -
E. T. Oral, Turkey - M. A. Rangel, Mexico - M. Rufer, Switzerland -
A. B. Singh, Australia - M. H. Tyal, Morocco - A. M. Zain, Malaysia

VALDOXAN
327 Valdoxans unique profile of antidepressant efficacy at the core of
depression
C. Muoz, France

I NTERVIEW
334 Treating emotions in depression: clinical experience
P. A. Schmidt do Prado-Lima, Brazil

F OCUS
337 Assessment of emotion
C. Harmer, United Kingdom

U PDATE
344 Neurobiology and neuropharmacology of emotion
P. Fossati, France

A TOUCH OF V IENNA
350 Medical developments in the 19th century: the Vienna Clinical School
I. Percebois, France

362 Emoticons in marble and bronze: Messerschmidts intriguing

character heads
P. Poullali, France
 EDITORIAL
Mindless formulations of
psychopharmacology have tradi-
tionally left outemotion. We
should restore emotional experi-
ence to primacy, because we now
appreciate that one effect of sero-
tonergic antidepressants is to
blunt the emotions. This was first
recognized in relation to sexual in-
terest and performance. It is also
seen in automatic processing of
expressive faces. It suggests that
some antidepressants may treat
depression at the expense of nor-
mal emotion, while others like ago-
melatine may not.
Guy M. GOODWIN, FMedSci
University of Oxford
Department of Psychiatry
Warneford Hospital
Oxford, UK
Address for correspondence:
Guy M. Goodwin, University of
Oxford Department of Psychiatry,
Warneford Hospital,
Oxford OX3 7JX, UK
(e-mail: guy.goodwin@psych.ox.ac.uk))
Medicographia. 2013;35:259-264
www.medicographia.com
Emotions and depression Goodwin
Emotions and depression
by G. M. Goodwin, United Kingdom
motion and depression are words that go together very naturally in ordinary
E language. It would be unexceptional to say that major depression is a dis-
order of the emotions. But while the definition of depression is operationalized
and agreed, the definition of emotion has been, and is, surprisingly controver-
sial. A recent review effectively suggested that it had come to mean anything one
wants it to.1 The present volume certainly illustrates the pleomorphic character of
the idea of emotion from infant development through neuroscience to psycho-pathol-
ogy. It may be worth grounding the concept in its historical description and how
I see it emerging in contemporary clinical controversies relevant to the treatment
of depression.
In Western philosophical thought, it has been commonplace to oppose emotion and
reason, and much argument about their respective value, primacy, and importance
has followed. The science of emotion is a recent development. A convenient start-
ing point to illustrate how the problem of understanding emotion can be framed is
the well-known work of William James.2 In 1884, he addressed the question of where
in the brain or body emotion should be located. The topographical representation of
sensation and movement in different parts of the brain was newly recognized in the
cerebral cortex. James wrote as follows:
My thesisis that the bodily changes follow directly the perception of the exciting fact
and that our feeling of the same changesis the emotion. Common sense says we
lose our fortune are sorry and weep, we see a bear, are frightened and run, we are in-
cited by a rival, are angry and strike. The hypothesis here to be defended says that this
order of sequence is incorrect.[T]he more rational statement is that we feel sorry be-
cause we cry, angry because we strike, afraid because we tremble and not that we cry,
strike or tremble because we are sorry, angry or fearful as the case may be.
James was stating a hypothesis that runs highly counterintuitive to common un-
derstanding. However, most importantly, the question what is emotion? was now
open to experiment and such a theory was open to falsification. Science was taking
over from philosophy. It soon became clear that emotional responses were repre-
sented in the brain and James theory was partly refuted by experiments on deaffer-
ented or decerebrated animals by Cannon and Bard.3 The identification of emotion-
al experience with specialized brain structures started with Cannon, and an association
was made with the limbic circuit (originally proposed by Papez), including the hip-
pocampus, the ipsilateral mammillary body, the anterior nucleus of the thalamus,
the cingulate cortex, the parahippocampal gyrus, and the entorhinal cortex.4 The
prefrontal cortex, septum, and amygdala are also now included in the so-called lim-
MEDICOGRAPHIA, Vol 35, No. 3, 2013 259
EDITORIAL
bic system. Modern neuroimaging has confirmed and extend-
ed our understanding of the functional connections of these
structures, which show correlated activity at rest in the default-
mode network and during emotional processing of various
kinds.5 It is a useful hypothesis that emotion is an emergent
property of synchronous activity in these brain areas. Neuro-
science has thus affirmed and confirmed the engagement of
brain with the mind in relation to emotion. This has important,
often forgotten, value in trying to understand the complex men-
tal and physical presentations of mood disorder.
If the emotions were secondary to reason, as in we lose our
fortune are sorry and weep, then emotions become a simple
function of mind. The tendency to divorce thinking and feel-
ing from the body has been attractively phrased Descartes
error in the book of the same name by Antonio Damasio.6
Dualism is deeply embedded in our language and therefore
in nonreflective thought. The very term mental illness imme-
diately poses the problem. Can there be a disease of a brain-
less mind? How can one then imagine a physical treatment
having value? Psychiatry has been deeply scarred by those of
its practitioners who have insisted on a meaning for the mind
necessarily separate from the body/brain. Damasio was influ-
ential in promoting the view that parts of the human brain are
specialized for the representation, and therefore the experi-
ence, of emotion, and in a partial reinstatement of James the-
ories, via the somatic marker hypothesis (which will not be de-
scribed in detail here). If some areas of the limbic cortex and
related structures are ablated, then human beings become
literally unable to experience emotion normally. This has a
purely subjective dimension, but also a much more interest-
ing consequence. This was long described informally as per-
sonality change. The original famous example, to which Da-
masio returned, was Phineas Gage, who sustained bilateral
damage to his mesial frontal cortex when a tamping iron ex-
ploded through the front of his head in a railway construc-
tion accident.7 Gages problem was described as a loss of his
moral sense: he was no longer Gage in the words of con-
temporaries.
Modern neuroscience has clarified what impact ablation of
the emotional sense actually has. It reduces the capacity of
any individual to make decisions which involve value choices.
The individual with a lesion of the mesial frontal cortex is cog-
nitively intact: asked what they would do in simple morally
valenced situations they will give a conventional correct reply.
However, asked to make real decisions, it turns out they have
lost the capacity to assess risk. They will make choices that
promise large rewards, irrespective of whether they also carry
a risk of large losses. They are apparently no longer able to
balance prospective rewards and punishments. Risky choice
is now seen to require emotional processes, if a person is to
pursue adaptive strategies.8 The automatic emotional under-
pinning of human choice has spawned the new discipline of
neuroeconomics.
260 MEDICOGRAPHIA, Vol 35, No. 3, 2013
The centrality of emotion in cognition frequently omits the dis-
cussion of pathological emotion. This is regrettable because
psychiatric disorder usually represents experience on a con-
tinuum with normality. Its very extremes offer potential ways
of testing hypotheses generated in mainstream normal psy-
chology. This disjunction between the neuroscience of health
and the traditions of psychiatry (and clinical psychology) has
been unhelpful. Hence, we have been relatively slow to see
neuroscience as offering key translational opportunities to
understand and treat mental disorders better. This has now
changed as several contributions in this volume will illustrate.
Nevertheless, clinical practice bears unmistakable scars from
its past. In relation to the understanding of emotion and cog-
nition in mood disorder, the most unhelpful factor has been
the polarization between psychological and drug treatment.
The most influential contemporary psychological approach to
mood disorder has been the cognitive theory originally devel-
oped by Beck in the 1970s,9 and relatively little modified since.
Beck was exasperated by psychoanalysis and its passive ac-
ceptance of poor outcomes for patients in endless therapy.
He listened to what patients told him about their conscious
experience of depression and was struck by the distorted
way in which they thought. He rejected the interpretations
of the unconscious popular at the time and suggested instead
that low mood is maintained by negative beliefs, thoughts, and
reflections. He developed a therapy designed to reverse these
conscious emotional biases. It involved both a Socratic cri-
tique of the patients faulty thinking and behavioral change.
Cognitive behavior therapy (CBT) has acquired very wide ac-
ceptance since. Unlike psychoanalysis, CBT lends itself to clin-
ical trials, although the methodology of comparing the active
treatment with a waiting-list control or treatment as usual is
often poor, and together with publication bias has inflated es-
timates of its efficacy.10 Until quite recently, it has failed to en-
gage with neuroscience.
For clinical psychologists, cognitive formulations have become
pervasive. Abnormal beliefs or ways of thinking provide an ex-
planation for why optimistic or depressive interpretations might
arise when emotional events are experienced. This view of
mood disorder and emotion lends itself to an exclusively men-
talistic way of thinking. In other words, mental illness is thought
of as not physical, just in the way that Descartes formulated
the split between body and mind. Thus, although beliefs clear-
ly are a product of brain function, any brain-based explana-
tion drawing on cognitive formulations would be too complex
to be of use in understanding mental disease. Because these
formulations follow a folk psychology tradition, they receive
easy acceptance from a general public who use Cartesian lan-
guage in everyday life. More importantly, emotion fits easily into
cognitive formulations and in a sense has been appropriated
by mentalistic or brainless formulations of depression.
Emotions and depression Goodwin

For psychiatrists, their most challenging patients are those
for whom psychological treatment is not possible because,
and honoring William James, the body is so evident in their
presentations. There is the slowness of movement, thought,
and action that characterizes the retardation of severe depres-
sion. This has always looked like an integrated impact of mood
on the motor system. The arousal of anxiety argues for a sim-
ilar overlap in brain representations of the autonomic nervous
system and anxiety. Thus, the phenomena of severe depres-
sion argue for the potential power of brain abnormalities to
condition experience through automatic rather than conscious
cognitive mechanisms. If such effects have a substrate in
those parts of the brain subserving emotional processing,
then it is there that we should look for the actions of effec-
tive physical treatments. Electroconvulsive therapy, antide-
pressants, and ketamine have all been discovered largely by
serendipity. Yet how they work has been the best clue we have
to the neurobiology of mood disorder and its treatment. This
relationship has motivated the whole field of psychopharma-
References
1. Izard CE. The many meanings/aspects of emotion: definitions, functions, ac-
tivation, and regulation. Emot Rev. 2010;2(4):363-370.
2. James W. The physical bases of emotion. 1894. (Reprinted from Psychol Rev.
1894;1:516-529). Psychol Rev. 1994;101(2):205-210.
3. Cannon WB. The James-Lange theory of emotions: a critical examination and
an alternative theory. By Walter B. Cannon, 1927. (Reprinted from Am J Psychol.
1927;39:106-124). Am J Psychol. 1987;100(3-4):567-586.
4. Papez JW. A proposed mechanism of emotion. 1937. (Reprinted from Arch Neu-
rol Psychiatry. 1937;38:725-743). J Neuropsychiatry Clin Neurosci. 1995;7(1):
103-112.
5. Grimm S, Boesiger P, Beck J, et al. Altered negative BOLD responses in the
default-mode network during emotion processing in depressed subjects. Neu-
ropsychopharmacology. 2009;34(4):932-843.
6. Damasio A. Descartes Error: Emotion, Reason and the Human Brain. London,
UK: Putnam Publishing; 1994:285.
7. Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of
Phineas Gage: clues about the brain from the skull of a famous patient. Science.
Keywords: antidepressant; emotion; major depression; neuroscience; treatment
Emotions and depression Goodwin
EDITORIAL
cology. It can provide models of drug action at the levels of re-
ceptor, cell, and brain system. Unfortunately, what the mind-
less formulations of psychopharmacology have traditionally
left out is emotion. We should restore emotional experience to
primacy, because we now appreciate that one effect of sero-
tonergic antidepressants is to blunt the emotions. This was
first recognized in relation to sexual interest and performance.11
It is also seen in automatic processing of expressive faces.12
It suggests that some antidepressants may treat depression
at the expense of normal emotion,13 while others like agomel-
atine may not.
What is important for the future is that the parallel paths to
treatment provided by cognitive mechanisms on the one hand
and biological on the other do not use mutually exclusive lan-
guage and ideas. The neuroscience of the emotions can unite
the mental and physical traditions in our understanding of
mood disorder. The present volume will illustrate how this is
happening. I
1994;264(5162):1102-1105.
8. Bechara A, Damasio H, Damasio AR. Emotion, decision making and the or-
bitofrontal cortex. Cereb Cortex. 2000;10(3):295-307.
9. Rush AJ, Khatami M, Beck AT. Cognitive and behavior-therapy in chronic de-
pression. Behav Ther. 1975;6(3):398-404.
10. Cuijpers P, Smit F, Bohlmeijer E, Hollon SD, Andersson G. Efficacy of cogni-
tive-behavioural therapy and other psychological treatments for adult depres-
sion: meta-analytic study of publication bias. Br J Psychiatry. 2010;196(3):173-
178.
11. Opbroek A, Delgado PL, Laukes C, et al. Emotional blunting associated with
SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? Int
J Neuropsychopharmacol. 2002;5(2):147-151.
12. Harmer CJ, Mackay CE, Reid CB, Cowen PJ, Goodwin GM. Antidepressant
drug treatment modifies the neural processing of nonconscious threat cues.
Biol Psychiatry. 2006;59(9):816-820.
13. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin
reuptake inhibitors: qualitative study. Br J Psychiatry. 2009;195(3):211-217.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 261
 DITORIAL

Il est malheureux que les for-

mulations de la psychopharmaco-
logie excluant lesprit aient
gnralement comme effet dli-
miner les motions. Cest bien
pourquoi il faut redonner lexp-
rience motionnelle toute son im-
motions et dpression
portance, car nous savons dsor-
mais que les antidpresseurs
srotoninergiques ont notamment
comme effet dmousser les mo-
tions. Ceci suggre que certains
antidpresseurs traitent la dpres-
sion aux dpens des motions nor-
males, tandis que dautres, comme
lagomlatine, sont libres deffets
de ce type.
p a r G . M . G o o d w i n , G ra n d e - B re t a g n e

L
es termes motion et dpression vont trs naturellement ensemble
dans le langage ordinaire, et rien de plus banal que de dire que la dpression
majeure est un trouble des motions. Toutefois, alors que la dfinition de la
dpression est standardise et valide, celle de lmotion a toujours t et,
de faon surprenante, reste controverse. Une rcente revue de la littrature a ef-
fectivement suggr que ce terme en tait venu dire tout et nimporte quoi 1. Le
prsent numro de Medicographia illustre tout fait la nature plomorphe de lide
dmotion, que ce soit dans le contexte du dveloppement du nourrisson, celui de
la psychopathologie ou celui des neurosciences. Il peut donc tre utile de dfinir le
concept dmotion dans le cadre de sa description historique, et dobserver com-
ment il a surgi au milieu des controverses cliniques contemporaines concernant le
traitement de la dpression.

La philosophie occidentale a frquemment oppos lmotion la raison, et un grand

nombre darguments sur la valeur, la prdominance et limportance respectives de
ces deux termes ont t avancs. La science de lmotion est de dveloppement
rcent. Les travaux bien connus de William James constituent un point de dpart pra-
tique pour illustrer comment le problme de la comprhension des motions peut
tre dlimit 2. En 1884, alors que la reprsentation topographique des sensations
et des mouvements dans diffrentes parties du cerveau venait dtre tablie dans le
cortex crbral, cet auteur sest demand o, dans le cerveau ou dans lorganisme,
les motions taient localises. Citons William James :
Selon mon hypothse les changements corporels sont directement conscutifs
la perception dun stimulus et cest notre sensation de ces mmes changements qui
constitue lmotion. Le sens commun nous fait dire que si nous perdons notre fortune
nous sommes tristes et nous pleurons, si nous voyons un ours, nous sommes effrays
et nous nous mettons courir, si nous sommes provoqus par un rival, nous sommes
en colre et nous attaquons. Lhypothse dfendue ici considre que cet ordre s-
quentiel est incorrect et quil est en fait plus rationnel de dire que nous nous sentons
tristes parce que nous pleurons, en colre parce que nous attaquons, effrays parce
que nous tremblons et non que nous pleurons, attaquons ou tremblons parce que nous
sommes respectivement tristes, en colre ou apeurs, selon le cas.

Lhypothse nonce par William James allait totalement contre-courant du bon

sens habituel. Mais lessentiel tait que la question Quest-ce que lmotion ?
tait dsormais ouverte lexprimentation et donc quune thorie de ce type pou-
vait tre soumise rfutation (au sens de Karl Popper). La science avait pris le pas
sur la philosophie. Il est toutefois rapidement apparu que les rponses motionnelles

262 MEDICOGRAPHIA, Vol 35, No. 3, 2013 motions et dpression Goodwin


taient reprsentes dans le cerveau, et la thorie de James
fut partiellement rfute par des exprimentations menes
par Cannon et Bard sur des animaux dsaffrents ou dc-
rbrs 3. Cannon fut le premier mettre en rapport lexprience
motionnelle avec des structures crbrales spcialises, et
cest Papez lorigine qui dcrivit limplication du circuit lim-
bique, constitu par lhippocampe, le corps mamillaire homo-
latral, le noyau antrieur du thalamus, le cortex cingulaire, la
circonvolution parahippocampique temporale et le cortex en-
torhinal 4. On inclut dsormais sous lappellation de systme
limbique galement le cortex prfrontal, le septum et les amyg-
dales. La neuro-imagerie moderne a confirm et approfondi
notre comprhension des connexions fonctionnelles entre ces
structures, qui montrent une activit corrle au repos dans
le rseau crbral du mode par dfaut ainsi quau cours de
diffrents types de traitement motionnel ( emotional process-
ing ) 5. Une hypothse utile postule que lmotion est une
proprit mergente de lactivit synchrone de ces zones c-
rbrales. Les neurosciences ont par consquent affirm et
confirm le rle initiateur du cerveau par rapport lesprit dans
la gense de lmotion. Il sagit dune notion dun grand int-
rt, bien que souvent nglige, dans la comprhension des
tableaux mentaux et physiques complexes prsents par les
troubles de lhumeur.
Si les motions sont secondaires par rapport la raison, se-
lon le schma nous perdons notre fortune, nous sommes
tristes et nous pleurons , alors les motions se rduisent
une simple fonction de lesprit. La tendance affirmer le di-
vorce entre la pense et les sensations corporelles a t juste
titre dsigne par le terme d erreur de Descartes , selon le
titre ponyme du livre dAntonio Damasio.6 Le dualisme est
profondment ancr dans notre langage et par consquent
dans notre pense non rflexive. Le terme mme de mala-
die mentale souligne immdiatement le problme : la mala-
die dun esprit sans cerveau peut-elle exister ? Comment
alors imaginer quun traitement physique ait la moindre va-
leur ? La psychiatrie porte encore les cicatrices infliges par
ceux de ses praticiens qui ont insist pour affirmer lesprit
comme tant ncessairement spar du corps et du cerveau.
Antonio Damasio joua un rle influent dans la dfense de
lopinion selon laquelle certaines parties du cerveau humain
sont spcialises dans la reprsentation, et donc lexprience
de lmotion. De mme, il fut lorigine de la rhabilitation
partielle des thories de William James, par lintermdiaire de
lhypothse du marqueur somatique (qui ne sera pas dcrite
en dtail ici). Si certaines aires du cortex limbique et des struc-
tures apparentes sont supprimes, alors les tres humains
deviennent tout fait incapables de ressentir normalement
les motions. Ceci entrane des effets purement subjectifs,
mais a galement une consquence extrmement intres-
sante, longtemps dcrite familirement comme un change-
ment de personnalit . Lexemple fondateur clbre rapport
par Antonio Damasio est celui de Phineas Gage, victime de
motions et dpression Goodwin
DITORIAL
lsions bilatrales du cortex frontal msial lorsque, la suite
dune explosion sur un chantier de construction de voie de
chemin de fer, une barre mine lui traversa le crne de part
en part 7. Les symptmes de Gage furent dcrits comme une
perte du sens moral. Ce nest plus Gage disaient de lui ceux
qui le connaissaient.
Les neurosciences modernes ont pu prciser les cons-
quences de lablation du sens motionnel. Cette dernire
rduit la capacit prendre des dcisions comportant des
choix de valeurs. Certes, les fonctions cognitives demeurent
intactes : si on demande une personne prsentant une l-
sion du cortex frontal msial ce quelle ferait dans des situa-
tions moralement simples, elle donnera une rponse tout
fait classique et correcte. En revanche, si on lui demande de
prendre de vritables dcisions, la perte de la capacit va-
luer les risques sera manifeste. Une telle personne fera des
choix qui promettent des bnfices importants, alors mme
que le risque de pertes est lev. De mme il semble quil y
ait incapacit mettre en balance les ventuels bnfices et
sanctions dans une situation donne. On sait maintenant quun
choix risqu ncessite des processus motionnels adquats
pour rendre possible ladoption de stratgies dadaptation 8.
La composante sous-jacente automatique de lmotion dans
les dcisions humaines est ainsi lorigine de la naissance
dune nouvelle discipline, la neuro-conomie.
Le caractre central de lmotion dans la cognition fait souvent
passer aux oubliettes lvocation de lmotion pathologique.
Cela est regrettable, car les troubles psychiatriques constituent
une exprience situe gnralement sur un continuum avec
la normalit, et dont les extrmes reprsentent un moyen po-
tentiel de tester des hypothses issues de la psychologie nor-
male classique. Cette divergence entre les points de vue des
neurosciences de ltat normal et ceux des diverses traditions
de la psychiatrie (et de la psychologie clinique) a t domma-
geable. Nous avons ainsi t relativement lents compren-
dre que les neurosciences offraient des possibilits transla-
tionnelles essentielles susceptibles de favoriser une meilleure
comprhension et un traitement plus efficace des troubles
mentaux. Cette situation a dsormais chang, comme le d-
montrent plusieurs articles de ce numro. La pratique clinique
nen porte pas moins la marque patente de son histoire. En
particulier, eu gard la comprhension de lmotion et de la
cognition dans les troubles de lhumeur, llment le plus n-
gatif a t les querelles de clocher entre psychothrapie et
traitement mdicamenteux.
Lapproche psychologique contemporaine des troubles de
lhumeur ayant eu le plus dinfluence est la thorie cognitive
dveloppe initialement par Beck dans les annes 1970 9, et
qui a t relativement peu modifie depuis. Beck tait exas-
pr par la psychanalyse et son acceptation passive de r-
sultats mdiocres obtenus chez des patients soumis dinter-
minables thrapies. coutant ce que les patients lui disaient
MEDICOGRAPHIA, Vol 35, No. 3, 2013 263
DITORIAL
sur leur exprience consciente de la dpression, if fut frapp
par leur manire dforme de penser. Il rejeta les interpr-
tations relevant de linconscient ayant cours lpoque, et
avana au contraire que lhumeur dpressive tait entretenue
par des croyances, des penses et des rflexions ngatives.
Pour inverser ces biais motionnels conscients, il dveloppa
une modalit thrapeutique reposant sur une approche so-
cratique des penses errones du patient et un changement
comportemental. Cette thrapie comportementale et cogni-
tive (TCC) a t largement accepte depuis. Contrairement
la psychanalyse, la TCC peut se prter des tudes cliniques,
bien que la mthodologie permettant de comparer le traite-
ment actif des contrles placs sur une liste dattente ou
au traitement habituel soit souvent insuffisante. Ceci, et le
fait que la TCC ait bnfici de biais de publication, expliquent
que lefficacit de cette modalit thrapeutique ait t sures-
time 10. Cest pourquoi, jusqu une priode trs rcente, la
confrontation entre la TCC et les neurosciences na pas pu
avoir lieu.
Pour les psychologues cliniciens, les formulations cognitives
sont devenues omniprsentes. Des croyances ou des ma-
nires de penses anormales fournissent une explication sur
la raison pour laquelle des interprtations optimistes ou d-
pressives peuvent survenir lorsque des vnements motion-
nels sont vcus par le patient. Cette approche des troubles
de lhumeur et de lmotion favorise un mode de pense de
type exclusivement mentaliste. En dautres termes, les ma-
ladies mentales sont considres comme indpendantes du
physique, exactement de la mme manire que Descartes
avait formul la sparation entre le corps et lesprit. Aussi, bien
quil soit clair que les croyances sont un produit de la fonction
crbrale, toute explication base sur le cerveau et invoquant
des formulations cognitives serait trop complexe pour per-
mettre de comprendre la maladie mentale. Dans la mesure o
ces formulations sont le reflet de reprsentations psycholo-
giques populaires dites naves , elles sont facilement ac-
ceptes par le grand public, qui utilise un langage cartsien
dans la vie quotidienne. Plus important encore, lmotion se
prte facilement aux formulations cognitives et, dans le cadre
de la dpression, les formulations mentalistes ou excluant le
cerveau se les sont pour ainsi dire appropries.
Pour les psychiatres, les patients les plus difficiles traiter sont
ceux chez qui la psychothrapie nest pas possible, car leur ta-
bleau clinique, (donnant ainsi raison William James), contient
de manire trop vidente une participation du corps, tmoin
264 MEDICOGRAPHIA, Vol 35, No. 3, 2013
la lenteur des mouvements, de la pense et de laction carac-
tristiques du ralentissement psychomoteur de la dpres-
sion. Ce phnomne a toujours t considr comme un r-
sultant dun impact intgr de lhumeur sur le systme moteur.
La survenue dune anxit plaide pour un chevauchement si-
milaire des reprsentations crbrales du systme nerveux
autonome et de lanxit. Par consquent, les phnomnes
lis la dpression svre sont en faveur de la capacit po-
tentielle des anomalies crbrales conditionner lexprience
par lintermdiaire de mcanismes automatiques, plutt que
par des mcanismes cognitifs conscients. Si ces phnomnes
ont pour origine les diffrentes zones du cerveau impliques
dans le traitement motionnel, ce sont ces zones quil faut
scruter la recherche des actions des thrapeutiques mdi-
camenteuses ou physiques dployes. Les effets des lectro-
chocs, des antidpresseurs et de la ktamine ont t dcou-
verts largement par hasard. Et pourtant cest bien leur mode
daction qui a fourni les meilleures pistes pour la comprhen-
sion de la neurobiologie des troubles de lhumeur et de leur
traitement. Cest ce contexte qui a fait merger et continue
inspirer le domaine de la psychopharmacologie grce la-
quelle sont fournis des modles daction mdicamenteuse au
niveau des rcepteurs, des cellules et des systmes crbraux.
Il est malheureux que les formulations de la psychopharma-
cologie excluant lesprit aient gnralement comme effet
dliminer les motions. Cest bien pourquoi il faut redonner
lexprience motionnelle toute son importance, car nous
savons dsormais que les antidpresseurs srotoninergiques
ont notamment comme effet dmousser les motions. Ce
phnomne a t observ pour la premire fois en relation
avec la libido et les performances sexuelles 11. Il a galement
t mis en vidence au cours du traitement neuronal automa-
tique des visages expressifs ressentis comme menaants 12.
Ceci suggre que certains antidpresseurs traitent la dpres-
sion aux dpens des motions normales 13, tandis que dau-
tres, comme lagomlatine, sont libres deffets de ce type.
Ce qui est essentiel pour lavenir est que les thrapeutiques
issues des voies parallles que sont les mcanismes cog-
nitifs dune part et les mcanismes biologiques dautre part
vitent dutiliser un langage et des ides mutuellement exclu-
sifs. La neuroscience des motions a ainsi vocation unifier
les approches mentaliste et physique de notre comprhen-
sion des troubles de lhumeur. Cette unification est en route,
et cest ce que ce numro de Medicographia sattache d-
montrer. I
motions et dpression Goodwin

A baby that experiences trau-
matic fright before it has learned
to speak is unable to master or re-
work its representation of the trau-
ma. It seeks support from an ex-
ternal secure base to relieve the
emotion caused by the terrifying
experience. When that figure is ab-
sent or dysfunctional, the infant is
insecure and loses the ability to
learn emotional control. More cru-
cially still, the event inscribes amyg-
dala hyperactivity into its brain,
triggering emotional panic at the
slightest subsequent event.
Boris CYRULNIK, MD
Director of Teaching
University of Toulon
FRANCE
Address for correspondence:
Boris Cyrulnik, Villa Beau Rivage,
317 corniche Michel Pacha,
83500 La Seyne sur Mer
(e-mail : cyrulnik.boris@orange.fr)
www.medicographia.com
Emotion and trauma Cyrulnik
E MOTI O N S AND DEPRESSION
Emotion and trauma
b y B . C y r u l n i k , Fra n c e
W
ithout emotion, there can be no memory. An event needs to arouse
neurological circuits that leave a memory potential like a scar in
brain tissue (William James) or rather like a path carved out of the
neuronal undergrowth. Everyday experience teaches us that what is a major
event for one person may only be a minor incident for another. Thus trauma
is defined not by the event in itself, but by its psychological impact. Memory
is a heterogeneous system made up of neurology, affectivity, verbality, and
cultural narratives. The biological component of emotion is physically deter-
mined by the functioning of a neuronal circuitry that mediates events and
chemical compounds. Feeling is an emotion triggered by the representation
of remembered images or individual and collective narratives. Healthy mem-
ory evolves, reworked over a lifetime, while traumatic memory stays fixed, but
can be reworked employing targeted techniques.
Medicographia. 2013;35:265-270 (see French abstract on page 270)
memory is said to be traumatic when a past event causing an emotional
A shock at the time is followed by a sustained aftershock of altered self-repre-
sentation. Healthy memory is a heterogeneous system made up of neurobi-
ology, interpersonal relationships, and collective narratives reworked over a lifetime.
Traumatic memory, on the other hand, remains fixed on the recollection of misfor-
tune and ceases to incorporate incoming self-representational data. Unable to re-
work the memory, the victim endures psychic agony as a prisoner of the past. Differ-
ing radically from an ordeal that a person confronts and overcomes before moving
on, trauma fixes the mind on the memory of perpetually recurrent misfortune. Psy-
choanalysis likens traumatic memory to a break-in by a foreign body that plays hav-
oc with the psychic apparatus. Neither internal conflict nor Oedipal neurosis,1 trau-
matic memory is the fear of death paralyzing the machinery of the mind.
Without emotion, there can be no memory. An event needs to arouse neurological
circuits that leave a memory potential like a scar in brain tissue2 (William James) or
rather like a path carved out of the neuronal undergrowth.3 Everyday experience
teaches us that what is a major event for one person may only be a minor incident
for another. Thus trauma is defined not by the event in itself, but by its psycholog-
ical impact.4 This becomes easier to understand if we differentiate between emo-
tion, caused by a cerebral stimulus or ingestion of a substance, and feeling, defined
as emotion triggered by mental representation (a scenario made up of images and
words).
MEDICOGRAPHIA, Vol 35, No. 3, 2013 265
E MOT I O N S AND DEPRESSION
Emotion
Emotion is regulated primarily by a neuronal substrate. The
orbitofrontal cortex plays an important role in emotivity: with
its connections to the amygdala and anterior cingulate cor-
tex, it modulates the affective connotation of events. When
prefrontal inhibition is impaired by disease or accident, the un-
leashed amygdala overstimulates the anterior cingulate lim-
bic circuit. In such cases, the slightest event triggers uncon-
trollable emotion that spreads to the hypothalamus, midbrain,
and brainstem nuclei: the motor expression of emotion be-
comes uncontrollable.5
Figure 1. Attachment figure: the secure external base will be in-
ternalized in the infants memory.
Toronto Star/Andrew Francis Wallace/Getty Images.
A baby that experiences traumatic fright before it has learned
to speak is unable to master or rework its representation of
the trauma. It seeks support from an external secure base to
relieve the emotion caused by the terrifying experience. When
the attachment figure is present, the infant huddles close (Fi-
gure 1). But when that figure is absent or dysfunctional (dead,
sick, or abused by partner, past, or community), the infant is
insecure and loses the ability to learn emotional control. More
crucially still, the event inscribes amygdala hyperactivity into
its brain, triggering emotional panic at the slightest subse-
quent event. The infants pain threshold tumbles so that it be-
comes frightened and hurt by anything: it perceives the slight-
266 MEDICOGRAPHIA, Vol 35, No. 3, 2013
est facial expression of annoyance or impending remonstrance
from an adult as an aggression equivalent (Figure 2).6,7 When
a childs developmental niche becomes so impoverished as
to descend into sensory deprivation, the dendritic spines fail
to establish connections. Neuroimaging shows atrophy8 while
the overworked amygdala becomes hypertrophic.9
Feeling
A child may be particularly given to emotion even when the
affective component of its developmental niche is stable and
well structured. Such emotivity is genetically determined, en-
coded in all mammals by a group of genes that undersynthe-
size a synaptic serotonin transporter protein.10 Fifteen percent
of all mammals come into the world deprived of the natural
emotional tranquility conferred by serotonin. If misfortune hap-
pens to strike, these 15% of minor serotonin transporters are
seriously wounded. Faced by the slightest event, such children
seek to downplay its emotional potential by self-centered be-
havior such as gaze aversion, rocking, twirling, and nail-biting.
When emotion overwhelms them (as readily happens), it trig-
gers autoaggressive behavior. Frightened by any relationship,
they have never learned to direct toward others the interac-
tive rituals that make for peaceful coexistence. The paradox-
ical result is that autoaggressive behavior has a tranquilizing
effect.
Regardless of whether they are genetically hypersensitive or
have amygdala hypertrophy induced by early deprivation, such
children experience the frustration inevitably encountered in
any game or conflictual situation as a source of violent stress.
Any encounter triggers outward- and/or inward-directed ag-
gression. Every emotional alert takes long to die down. For-
ever on standby, the hypothalamic-pituitary-adrenal axis in-
creases mean circulating cortisol levels. The limbic cells that
are supersensitive to cortisone swell in response, the ion chan-
nels open and let in potassium. The Na+/K+ gradient is reversed,
causing such hyperosmolarity that the cell bursts. This process
accounts for the limbic atrophy seen in depressed patients11
who progress from hypersensitivity to the slightest event to
memory disturbance and affective indifference (Figure 3).12
Imprinting
During normal development, the same deprivation has differ-
ent effects depending on when it occurs. It leaves its imprint on
every human being who needs other people in order to com-
plete his or her development. A sensory figure featuring at a
sensitive moment in a childs development becomes a key ob-
ject that the child perceives over and above any other. From
that point onwards a circuit is traced in its implicit memory,
attaching the child to the familiar figure. Whether mother, fa-
ther, peer, or place, this attachment figure makes the child feel
secure and gives it the strength to explore its world with pleas-
ure. Without such a figure, the child panics, runs in all direc-
tions, suffers emotional diarrhea, becomes accident-prone and
is unable to process information correctly (Figure 4).13
Emotion and trauma Cyrulnik
 E MOTI O N S AND DEPRESSION

Memory no longer retains an imprint once

blunted emotion prevents an object or event
from standing out in a childs experience. In
a world without emotion, everything is the
same, there are no value judgments, no event
Amygdala is worth inscribing in memory, and no figure
response
stands out for potential attachment.
cACC
s carrier
Genetic determinants create a predisposition
rACC
rather than determine an ineluctable fate. Mi-
vmPFC l/l
genotype
nor serotonin transporters who live in a re-
assuring environment soon develop enough
Amygdala
self-confidence and affective stability to be-
gin exploring with pleasure. Conversely, major
serotonin transporters living in longstanding
isolation acquire an emotional vulnerability
that subjects them to their impulses and the
Figure 2. Interaction with an environmental factor: facial expressions. stimuli of others. This may account for the
Abbreviations: cACC, caudal anterior cingulate cortex; rACC, rostral anterior cingulate cortex; emotional storms in borderline states. Having
vmPFC, ventromedial prefrontal cortex.
After reference 7: Hamann. Nature Neurosci. 2005;8(6)701-703. 2005, Nature Publishing Group.
suffered a torrent of early childhood traumas,
the prefrontal lobes in such individuals fail to
Failed imprinting may be due as much to the childs environ- acquire the ability to inhibit emotion. Stimuli are too intermit-
ment as to its development. A deprived niche (a dead or de- tent to develop the frontolimbic connections that could con-
pressed mother, conjugal violence, or underprivilege14) leaves trol the expression of emotion.16 A distorted interactional spi-
no reassuring imprint in a childs biological memory. Similarly, ral then becomes established in which such children, who are
genetic disease causing a deficiency of acetylcholine, endo- incapable of controlling their impulses, sabotage the emotion-
genous opioids or oxytocin undermines the biological basis al reactions of those around them, thus jeopardizing their af-
for imprinting.15 Drugs may have the same effect: -blockers, fective relationships with their attachment figures.17
certain antidepressants and interferon (in 50% of prescrip-
tions) make the body indifferent to contextual information. The insecurity of a child whose sensory niche has been de-
prived by parental misfortune (death, disease, marital break-
down, underprivilege) leads it to perceive its world as an un-
ending series of alarms. The resulting prefrontal hypotrophy

A B

Significance
4.2 3.0

3.8 2.5

3.4 2.0

3.1 1.5 C
2.7 1.0

2.3 0.5

1.9 0.0

Figure 3. Limbic atrophy.

Dynamic evaluation of genetic vulnerability factors in depression, according to
presence or absence of s allele. Structural, correlated, and functional high-reso-
lution MRI (1 mm3) in more than 100 subjects. Cingular atrophy is evidenced in
s allele carriers. This determinant of emotivity is not a determinant of resilience.
After reference 12: Pezawas et al. Nature Neurosci. 2005;8(6):828-834. 2005,
Nature Publishing Group.
Figure 4. Attachment figure and imprinting.
A and B: In the presence of the attachment/imprinting object the duckling feels
secure and is able to learn how its environment works. C: In the absence of
the attachment/imprinting object, the duckling panics and fails to learn anything.
This leads to a propensity for accidents, emotional diarrhea, and immunodepres-
sion, as all new information is experienced as traumatic.

Emotion and trauma Cyrulnik MEDICOGRAPHIA, Vol 35, No. 3, 2013 267
E MOT I O N S AND DEPRESSION
and limbic atrophy subject the child to its environmental stim-
uli since it is unable either to plan ahead or use its memory.
Everything and anything frightens the child and triggers re-
actions of fight or flight.
Erosion of the soul
Once stress has been so overwhelming as to have consumed
the capacity to respond, the physiological reactions of the
burned-out amygdala induce a state of psychic numbness.
An amygdala rendered dysfunctional by physiological burn-
out or head injury leads to anhedonia. Nothing excites such
individuals anymore. They lose all taste for life.
Amygdala response is what determines whether an item of
information is stored in memory. An alert amygdala ensures
that some facts will become memory events. A numbed or
lesioned amygdala, on the other hand, lets nothing through
to memory. Thus the soldiers who took propranolol during the
Iraq War in 1991 avoided the hypermnesia of posttraumatic
stress syndrome, but conversely experienced enormous gaps
in memory.18
Anhedoniathe inability to enjoy lifewas described in the
19th century in melancholics, neurasthenics, and those with
early dementia. The following variants were identified:
N Reactive anhedonia in subjects who once enjoyed life, but
eventually experienced erosion of the soul after a trauma or
cascade of painful events.
N Anhedonia as a personality trait reflecting a hyporeactive
amygdala, in a subject whose life since childhood had been
deprived, bleak, and led at slow pace in social isolation.
Prospective studies speak of chronic depression and psy-
chotic tendencies.19 These traits are common among risk tak-
ers who depend on strong stimuli to feel alive. Other instances
include the astonishing anesthesia of psychotics capable of
walking on a broken leg, remaining upright with peritonitis, or
slicing into their forearms with no change in facial expression.
Evidence suggests that such agenesis of the amygdala is due
to the numbing of amygdala reactivity by opioid hypersecretion
in response to early interactions in the first few months of life.20
Victims of the prefrontal leukotomies practiced between 1935
and 1960 or patients with crude lobotomies caused by head
injuries were found to have lost the ability to inhibit their be-
havioral or mental responses. Having lost the neurologic sub-
strate required for the representation of time (memory and an-
ticipation), such patients become incapable of imagining the
effect that their words or acts could have (later) in the mind
of someone else. Incapable of empathy, they give free rein to
their impulses, as is seen after lobotomy, in frontotemporal
dementia, sexual deviation, and in children under 4 who have
yet to develop a theory of mind. As prisoners of the here and
now, incapable of combining representation of the past with
that of the future, they are unable to give meaning to what they
268 MEDICOGRAPHIA, Vol 35, No. 3, 2013
perceive. They become detached from an existence that no
longer holds meaning for them, switching between overre-
action and indifference, depending on the stimuli emanating
from those around them. When people are busy around them,
they can become agitated; but when things calm down again,
they become immobile, bereft of either internal language or
emotion.
Empathy
Patients whose amygdala has been destroyed by lobotomy
become totally indifferent. If you ask them to lay their hand on
the table and you then pretend to strike it with a hammer, they
do not even flinch, since they do not anticipate feeling pain.
They remain stone-faced and devoid of empathy in front of
any manifestation of pain or suffering in another person. Yet
paradoxically they can be hurt by their own indifference of af-
fect. Lobotomized patients often say: I miss the time when
I felt pain and suffering. I at least felt alive. Does this mean
that pain and suffering are part of the human condition and
that they help us develop the empathy that enables everyone
to live together? The minor frustrations that are inevitable in
daily life (eg, a delayed feed or temporary absence of its moth-
er for an infant, a physical malaise or a relationship issue) cause
minor levels of discomfort or distress that train us in empathy.
Child survivors of natural disasters, war, or serious illness show
an astonishing acceleration of emotional maturity.21
Affective anesthesia thus has a variety of causes:
N Dysfunctional frontolimbic circuitry due to early deprivation
of environmental stimuli leading to amygdala burnout.
N Erosion of the soul caused by a cascade of insidious trau-
ma such as underprivilege or an unwelcoming environment
(soul-destroying work, harassment, racism).
N Ingestion of amygdala-numbing substances such as pro-
pranolol, -blockers, or certain psychotropic agents.
N Lobotomy due to head injury.22
Recent neuroimaging data confirm the time-honored neuro-
logic concept of the complementarity of opposites between
pleasure and pain.23 Dopaminergic and opioid systems pref-
erentially stimulate the ventral segmental area of the brain-
stem.24 But excessive stimulation of the inferior longitudinal
fasciculus (pleasure area) eventually stimulates the lateral
spinothalamic fasciculus (pain area), and vice versa. We see
this pair of opposites at work in attachment behavior: an in-
fant moves away from its secure attachment figure and ex-
plores its environment until it experiences fright, at which
point it scuttles back to huddle deliciously close to its moth-
er. An infant that experiences neither fright nor frustration is
numbed by the absence of stimuli and neither mentalizes nor
develops an attachment figure.25 Perhaps, when poets write
that magic consists of transforming pain by endowing it with
inordinate nobility (nothing makes us greater than great pain
the most beautiful songs are the most despairing24), they are
simply giving voice to this combination of contrary emotions.
Emotion and trauma Cyrulnik

Figure 5. Memory of a psychologically traumatic syndrome.
Images of a terrifying event tend to become pervasive within the subjects men-
tal life, whereas the precise memory of the traumatic event tends to fade.
Man aiming gun. Micha Klootwijk/123RF.
Reworking emotion
It is thus possible to rework the pain in a feeling by ennobling
it or transforming it into poetry. In doing so we become au-
thor-actors in the representation of our life stories.26
The memory of a psychologically traumatic syndrome is con-
straining and painful: an image of terror takes over our thoughts,
seeps into our mental lives, and constantly recurs, haunting
us in particular in nightmares (Figure 5). The memory of a ter-
rifying event is said to ease over time, but it is more accurate
to say that time gives the victim an opportunity to develop
the relationships that will help rework the memory so that he
or she is no longer its victim. Emotion is transformed by meet-
ing someone with whom one can share a narrative. Words
have to be found in which to address the person we trust.
Healthy memory adjusts its representation of the past to cur-
rent circumstances: 73 14-year-old boys answered a 28-point
questionnaire describing how they perceived their current sit-
uation: Is religion helpful to you?, What do you enjoy most?,
Is the discipline you receive upsetting to you? Thirty-four
years later, the investigators recontacted 67 of the ex-ado-
lescents, now aged 48, and re-asked the same questions: the
answers were astonishingly different. Twenty-eight percent of
the 14-year-olds had replied that they enjoyed school and
homework least; this figure jumped to 58% at age 48. One
adolescent in four considered that he enjoyed peer relation-
ships most, a proportion that expanded to one in two of the
48-year-olds. Eight adolescents in ten (82%) were upset by
the corporal punishment they received, whereas at age 48 the
Emotion and trauma Cyrulnik
E MOTI O N S AND DEPRESSION
upset was remembered by only about a third (28%).27 The
emotion we experience at the time is different from the emo-
tion we remember. It is in the present that we become drunk
on the Baudelaires wine of memory and the reconstituted
past. Reworking of the emotion associated with memory is
thus the general rule. Predictably, the memory associated with
the least reworked emotion is the memory of horror.
Three factors combine to keep a memory intact and accurate
or allow it to fade into haziness:
N Time of occurrence of the traumatizing experience. Pre-
verbal terror leaves a trace in biological memory, but no mem-
ory. The persons concerned do not know why they have been
made sensitive to this type of event: they have source amne-
sia. Later in life, they may become able to find images and/or
words to represent the source event or situation that has giv-
en the particular taste to their world, but it will not necessar-
ily be factually accurate (false allegations of rape, impressions
of persecution, mistaken identity). If terror strikes when a per-
son is depressed or has been made vulnerable by previous
trauma, there is a high probability of the image of the terrify-
ing event becoming part of a psychologically traumatic syn-
drome, comprising a fascination with the aggressor who is
recalled in hyper-real focus, while the setting in which the ag-
gression occurred remains hazy.28
N The emotion of horror. We do not need to experience hor-
ror in order to strengthen our memory of horrific images. Peo-
ple only have to be shown one series of horrific images and
another of attractive images. A month later, they clearly re-
member the horrific images, but retain only vague recollec-
tions of the attractive photographs.29 Horror has a fascination
that fixes memory, whereas pleasure has a relaxing effect that
traces in memory a readiness for well-being that is devoid of
individual images.30
N The power of words. The words that accompany photo-
graphs have a strongly reworking effect on memory. When hor-
rific photographs are shown with an accompanying commen-
tary that gives meaning to the horror involved (the making of
a hero, a noble sacrifice, or dramatic fiction), the horror of the
memory will be largely blurred. But if attractive photographs
are shown with an uplifting commentary, the attractive mem-
ory becomes clearer.
Even written words are involved in the reworking of memory.
When the written words trawl a painful past for the details of
an atrocity in order to commit them to paper, the mental work
required can concentrate the mind to a degree approximat-
ing to psychological trauma syndrome. Primo Levi dwelled
on Auschwitz to the point of suicide, while Jorge Semprn
described his drafts on his experience of Buchenwald as hav-
ing bled for 20 years. Conversely, when victims write on trau-
ma to give others the pleasure of understanding or to create
a work of art (novel, film, art, or poetry), they rework the rep-
resentation of what they have suffered.31 In restoring the past
by the wine of remembrance, collective narratives play a ma-
MEDICOGRAPHIA, Vol 35, No. 3, 2013 269
E MOT I O N S AND DEPRESSION

jor role in attenuating or exacerbating a traumatic memory.32 Conclusion

When traumatized parents are sustained by the cultural nar-
ratives that surround them, they give their children the im-
pression of emerging victorious. But when the cultural con-
text isolates, aggresses, or despises them, the unresolved
trauma suffered by the parents destabilizes the children.
Whether triggered by an affectively and/or socially deprived
environment, organic lesion, or enveloping narrative, emotion
is what gives taste to the world we perceive. It is by shaping
the environment that shapes us that we enjoy a measure of
freedom. I

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Into Human Knowledge Structures. Hillsdale, NJ, USA: Lawrence Erlbaum As-
sociates Inc; 1977.
27. Offer D, Kaiz M, Howard KI, Bennett ES. The altering of reported experiences.
J Am Acad Child Adolesc Psychiatry. 2000;39(6):735-742.
28. Hever F, Reisberg D. Emotion, arousal and memory for detail. In: Christianson SA,
ed. The Handbook of Emotion and Memory: Research and Theory. Hillsdale,
NJ, USA: Lawrence Erlbaum Associates Inc; 1992;151-180.
29. Walker WR, Vogl RJ, Thompson CP. Autobiographical memory: unpleasant-
ness fades faster than pleasantness over time. Applied Cognitive Psychology.
1997;11(5):399-413.
30. Schacter DL. The Seven Sins of Memory: How the Mind Forgets and Remem-
bers. Boston, USA: Houghton Mifflin; 2001.
31. Pennebaker JW. Writing about emotional experiences as a therapeutic process.
Psychol Sci. 1997;8(3):162-166.
32. Rim B, Christophe V. How individual emotional episodes feed collective mem-
ory. In: Pennebaker JW, Paez D, Rim B, eds. Collective Memory of Political
Events. Mahwah, NJ, USA: Lawrence Erlbaum Associates Inc; 1997;131-146.

Keywords: affective relationships; cultural narratives; neurological circuits; sensory deprivation

MOTIONS ET TRAUMATISMES
Sans motion, pas de mmoire. Il faut un vnement pour veiller les circuits neurologiques qui tracent dans le
cerveau une aptitude mnsique, comme une cicatrice dans le tissu crbral (William James) ou plutt comme, le
frayage dun chemin dans la brousse des neurones. Dans la vie quotidienne, on constate que, ce qui est un v-
nement majeur pour lun, nest quun incident mineur pour lautre. Ce qui fait trauma ce nest donc pas le rel de
laccident, cest leffet psychique quil produit. Le phnomne mnsique est un systme htrogne, compos par
de neurologie, daffectivit, de verbalit et de rcits culturels. La composante biologique de lmotion est matrielle-
ment dtermine par le fonctionnement neuronal circuit par les vnements et les substances. Le sentiment est une
motion provoque par une reprsentation dimages mnsiques ou de rcits individuels et collectifs. La mmoire saine
volutive se remanie avec lhistoire du sujet. La mmoire traumatique fige, peut intentionnellement tre remanie.

270 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Emotion and trauma Cyrulnik

Both society (gender) and bi-
ology (sex) are equal determinants
of emotion. Of the three categories
of drive required for survival, im-
portant differences in males and
females exist in agonistic and re-
productive drives which influence
emotional circuitry across core
limbic structures: amygdala, hypo-
thalamus, and hippocampus. The
challenge for the future is to deter-
mine when a sex/gender difference
makes a difference.
L
Sidney H. KENNEDY 1,2
MD, FRCPC
Gillian EINSTEIN,3 PhD
Jonathan DOWNAR,1,2 MD
PhD, FRCPC
1
Department of Psychiatry
University Health Network
2
Institute of Medical Sciences
University of Toronto
3 son as feminine and not masculine2 and there is a strong current of thinking that
Department of Psychology
Dalla Lana School of Public Health
University of Toronto
Toronto, Ontario, CANADA
Address for correspondence:
Sidney H. Kennedy, Department
of Psychiatry, University of Toronto,
University Health Network,
200 Elizabeth Street, Toronto, ON,
Canada M5G 2C4
(e-mail: Sidney.kennedy@uhn.ca)
www.medicographia.com
Gender/sex differences in emotions Kennedy and others
E MOTI O N S AND DEPRESSION
Gender/sex differences
in emotions
b y G . E i n s t e i n , J . D o w n a r,
a n d S . H . Ke n n e d y, C a n a d a
B
iological sex differences begin in utero and continue to develop through-
out life, based on biology and experience. The concept of gender re-
quires disentangling biological (sex) and social (gender) constructs as
well as considering the role that hormones and genes play in establishing
emotional differences, especially those due to the sexual differentiation of the
fetus and the reproductive cycle. Increasingly sophisticated functional neu-
roimaging techniques highlight what is known about brain sex differences,
and its influence on different expressions of emotions. There is also limited
evidence of difference in symptoms of depression between men and women,
and conflicting reports about differential antidepressant response in men and
women with major depressive disorder.
Medicographia. 2013;35:271-280 (see French abstract on page 280)
ince the mid-20th century, women have been viewed as the expressive ex-
S
perts and men the instrumental experts.1 Emotional competencies are so em-
bedded in our popular notions of what it is to be female or male, that tests of
gender role identification use emotion items as key components to identify a per-
females have greater access to their emotions.3 However, while much of the pop-
ular imagination continues to maintain this divide between male and female emo-
tions, the scientific literature has moved toward an understanding that there is a
filigreed intertwining of biological, social, and interpretive dimensions that influences
an individuals emotional repertoire, leading to individual differences being greater
than differences between sexes. These potential differences have implications when
it comes to the etiopathology and treatment of psychiatric disorders, such as ma-
jor depressive disorder (MDD), which include aberrant emotional function as a key
component of the illness.
Sex and gender
Sex is indicative of the biological characteristics of the organism, while gender
refers to the social situation of that phenotypewhether a person is interpreted by
themselves and others as male or female. Gender operates at many levelsthe
personal, social, and institutional.4 One may have the biological characteristics of a
male (XY), but want to be part of the gendered world of a female (XX). Ones gen-
dered experience of being treated as male affects ones biology to conform more
closely to what is considered maleness. These experiences will shape neural cir-
cuits that will, in turn, mediate ones actions and perceptions of the world.5
MEDICOGRAPHIA, Vol 35, No. 3, 2013 271
E MOT I O N S AND DEPRESSION
Sexual differentiation
The first step toward establishing sex differences occurs in
the developing embryo. If the fetus is XY, there is a region
on the short arm of the Y-chromosome, containing the gene
SRY, that when switched on leads the indifferent gonad to de-
velop into the testes. The testes begin to produce androgens
in the sixth week of gestation and this has repercussions for
each body system, including the nervous system. It is well un-
derstood from rodent studies that estrogen via testosterone
synthesis early in development sets the neural circuitry in the
XY brain on a course that differentiates it from female neural
circuitry, especially in the areas of the brain that mediate sex-
ual reproduction.6 Since the XX fetus does not have SRY, the
indifferent gonad follows a developmental path toward be-
coming ovaries which do not secrete appreciable estrogen
until much later in development and so with respect to brain
development, the male brain sees testosterone and estrogen
early and often, while the female brain develops essentially in
their absence. The production of follicle-stimulating hormone
(FSH) is thought to play a key role in the development of the
ovaries. Both androgens and estrogens will affect neural cir-
cuits throughout life and are essentially growth factors caus-
ing dendrites and axons to grow7 as well as synapses and
neural connections to form.8
Hormonal and social effects on sex differences
in emotion
N Hormones during reproductive cycle
The cyclic release of hormones in the ovarian cycle and the
menstrual cycle has been viewed as sources of mood differ-
ences between females and males. It has not gone unnoticed
that some neuropsychiatric disorders seem to be in synchrony
with phases of the ovarian cycle and are so named: premen-
strual dysphoric disorder (PMDD; low estrogen), catemenial
epilepsy (high estrogen), and menstrual migraine (low estro-
gen). However, these conditions are very rare. While the preva-
lence of PMDD has been estimated to occur in 3% to 9% of
the adult female population, a recent community study re-
ported 1.3%,9-11 Since mood disorders are nearly twice as
prevalent in females as in males,12,13 a discrepancy that begins
at puberty and dissipates following menopause,14 it has been
difficult to move away from hormonal explanations for womens
moods as opposed to mens, with the late luteal or premen-
strual phase perceived as a time of increased irritability and
negativity, leading to the broader lay concept of premenstru-
al syndrome (PMS15,16).
Attempts to correlate female gonadal hormones with womens
mood in both women with PMDD and women without disor-
ders have been largely inconclusive. Studies on the effects of
exogenous hormone administration on mood in menopausal
women also reveal contradictory results; estrogen administra-
tion has been shown to reduce, increase, or have no signifi-
cant effect on negative mood: Studies conducted, however,
have overwhelmingly refuted the presumption that gonadal
272 MEDICOGRAPHIA, Vol 35, No. 3, 2013
steroid levels are abnormal in women with PMDD.17 In stud-
ies of randomly recruited, non-help-seeking women, who were
blinded to the purpose of the study, no correspondence was
observed either between menstrual phase18,19 or ovarian ste-
roids and either negative or positive mood.19 Rather it was psy-
chosocial factorsstress and physical healththat were most
highly correlated with mood (Figure 1).19 Thus, despite reports
of a link between menstrual phase and self-reported mood,
a direct relationship between ovarian hormones and mood is
not well established (for review, see reference 20).
N Hormones and life changes during pregnancy and
postpartum
Much has been written about the moods of women during
pregnancy and delivery, especially with respect to depression
and anxiety.21 The postpartum period is seen as a particularly
vulnerable time for women, especially if there is prior depres-
sion or psychosis.22 What is not known is how much of post-
partum mood depends on hormonal fluctuations and how
much depends on the enormity of the undertaking of parent-
hood, societal expectations, and sleep deprivation. Robinson
and Stewart23 suggest that the postpartum period is a time
when family roles are reevaluated, often becoming more tra-
ditional with women taking on the greater load of household
and childcare responsibilities. Changing roles and sleep dep-
rivation may be strong drivers for mood shifts. These can be
seen as affecting men as well; consequently, men may also
be vulnerable to paternal postpartum depression, with rates
ranging from 10.4%-25.6%.24 Thus, in the period when women
most commonly suffer postpartum depression, significant
numbers of men do as well. Since many studies show that
children are affected by depression in fathers as well as moth-
ers,25 this is an important, but as yet understudied aspect of
mens moods.
N Sex differences in emotion behavior
From a behavioral perspective, at least one approach has
served to delineate emotions so the permutations and com-
SELECTED ABBREVIATIONS AND ACRONYMS
ACC anterior cingulate cortex
CRESCEND Clinical RESearch CENter for Depression
CYP cytochrome P450
DBS deep brain stimulation
fMRI functional magnetic resonance imaging
MAOI monoamine oxidase inhibitor
MDD major depressive disorder
NCS National Comorbidity Survey
PMDD premenstrual dysphoric disorder
rTMS repetitive transcranial magnetic stimulation
SNRI serotonin-norepinephrine reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
vmPFC ventromedial prefrontal cortex
Gender/sex differences in emotions Kennedy and others
 E MOTI O N S AND DEPRESSION

15 A 15 B 15 C

10 10 10

5 5 5
**
t-statistics

0 0 0

*
5 5 5

10 10 10

15 15 15
Same day Positive mood Same day Negative mood 1 Day prior irritability

E1G PdG Social support Stress Physical health

Figure 1. Linear mixed models of mood items with t-statistics of mood variables.
All models include measures of E1G, PdG, weekly social support, and subjective stress and physical health (*P<0.05, **P<0.01, P<0.0001). (A) Model of com-
posite positive mood with E1G and PdG measured the same day. Composite positive mood is the average of happiness, confidence, enjoyment, energy, feeling of
being on top of things, and motivation. Only perceived stress and physical health contributed significantly to the model (P<0.0001). (B) Model of composite negative
mood with E1G and PdG measured the same day. Composite negative mood is the average of irritability, sadness, anxiety, and difficulty coping. Only perceived stress
and physical health contributed significantly to the model (P<0.0001). (C) Model of irritability with E1G and PdG measured 1 day prior. PdG (P=0.0048), stress
(P<0.0001), and physical health (P=0.0120) contributed significantly to the model.
Abbreviations: E1G, estrone glucuronide; PdG, pregnanediol-3 glucuronide.
After reference 19: Schwartz et al. Horm Behav. 2012;62(4):448-454. 2012, Elsevier Inc.

binations can be viewed as mixed and matched by the sex-
es.26,27 This framework addresses: (i) overt actions; (ii) subjec-
tive reports, and (iii) physiological responses. When emotion
is deconstructed into these components, studies that only
focus on sex differences do not account for the complexity
of emotional processes.28 With respect to overt actions, while
men and women both report feeling sadness at the same lev-
els, women tend to display overt signs of sadness while men
tend to withdraw. However, this difference in behavioral reper-
toire may be situational, with women believing that they should
verbally express their emotion while men do not. Both feel
more expressive when talking with a woman.
In the case of alexithymia, a personality construct that is char-
acterized by impoverishment of imagination, poor capacity
for symbolic thought, and inability to experience and describe
feelings,29 neither subjective reports nor physiological response
differs between the sexes. Numerous studies have failed to
find a reliable sex difference.30-32 In subjective reports, men and
women report experiencing anger with equal intensity and fre-
quency.2 Physiological responses reveal that men tend to make
evident more responses than women; however, with regard
to fear, for example, there are no specific fear-related differ-
ences in autonomic response between females and males.28
Work on emotional regulation also belies the traditional stereo-
types. Emotion regulation as defined by Nolen-Hoeksema and
Aldao33 consists of many types of coping: adaptive (eg, ac-
tive coping, positive reappraisal) and maladaptive (eg, avoid-
ance and self-blame). Interestingly, women reported using self-
blame as a strategy more than men only in studies in which
women appraised the stressor as more severe than men did,
suggesting that sex differences might actually be in the do-
main of stressor appraisal. Additionally, women reported us-
ing a wider range of strategies than men, including rumination,
reappraisal, active coping (or problem solving), acceptance,
and social support. Importantly, this sex difference was sig-
nificant, even when self-reported depressive symptoms were
controlled for, suggesting that this difference in coping strate-
gies is not simply a reflection of womens greater tendency
toward depressive symptoms. There were sex differences
in rumination, suppression, and social support seeking that
were not moderated by stressor appraisal and these are more
strongly related to depressive symptoms than adaptive strate-
gies (Table I, page 274).33
Emotional regulation strategies vary with age in older women,
but not so in men; use of acceptance did not decrease with
age for women. Older men made the fewest reports of reap-
praisal, active coping, and acceptance. This suggests that
men may find it harder than women to assume a positive, ef-
ficacious, or accepting attitude toward problems that arise in
older age. Lack of acceptance, active coping, or reappraisal
was not associated with depressive symptoms in the oldest
age group as they were with the younger adults.33 When tak-
en together, these studies and others suggest that individual
variation in emotion and its expression depend more on the

Gender/sex differences in emotions Kennedy and others MEDICOGRAPHIA, Vol 35, No. 3, 2013 273
E MOT I O N S AND DEPRESSION
Women
Young adults Middle-aged adults Older adults
Depressive symptoms 5.50 (0.27) 4.94 (0.26)
Rumination 2.04 (0.02) 1.90 (0.02)
Suppression 1.95 (0.04) 1.97 (0.04)
Reappraisal 2.85 (0.05) 2.81 (0.05)
Active coping 2.91 (0.05) 2.93 (0.05)
Acceptance 3.02 (0.05) 3.22 (0.05)
Social support 3.05 (0.06) 3.03 (0.05)
Notes: Means for emotion regulation strategies are adjusted for depressive symptom scores: numbers in parentheses are standard deviations for depressive
symptoms and standard errors for emotion regulation strategies.
Table I. Descriptive statistics for all variables by gender and age.
After reference 33: Nolen-Hoeksema and Aldao. Pers Individ Dif. 2011;51:704-708. 2011, Elsevier Ltd.
nature of the emotional stimulus, mental health status, con-
text, age, and the response format. This complex pattern of
findings is best accounted for by acknowledging that both
society (gender) and biology (sex) are equal determinants of
emotion: emphasizing sex differences in emotionality imposes
a framework on the patient that might burden psychotherapy
with stereotypes.
Neural effects on sex differences in emotion
How, and why, might emotions differ across sex? An adap-
tationist perspective affirms that the bodys individual or-
gans serve several functions. Although there is an overlap in
critical survival functions across sex, there are also important
distinctions among several organ systems, namely, reproduc-
tive, endocrine, cardiovascular, digestive, and the central nerv-
ous system.
Three categories of drive are required for survival of any or-
ganism: homeostatic (maintaining key internal parameters
in safe ranges), agonistic (self-preserving behaviors against
hostile conspecifics or predators, and self-advancing behav-
iors against prey or rivals), and reproductive (finding suitable
mates, birthing, nurturing, and defending young). For at least
the latter two categories of drive, important differences ex-
ist between the males and females in nearly every species,
including humans. These differences are reflected in the emo-
tional circuitry of the brain, most notably in the so-called core
limbic structures: the amygdala, hypothalamus, and hippo-
campus.
The emerging field of affective neuroscience has made rap-
id progress in delineating the neural substrates of emotion.34
The core limbic structures are essential for the generation of
integrated emotional states such as fear, anger, or sadness.
Other, more caudal, regions of the neuraxis, such as the brain-
stem, the periaqueductal gray, and ventrolateral medulla co-
ordinate the outward expression of emotional states, while
274 MEDICOGRAPHIA, Vol 35, No. 3, 2013
Men
Young adults Middle-aged adults Older adults
4.10 (0.33) 4.29 (0.28) 4.24 (0.27) 3.60 (0.37)
1.65 (0.03) 1.98 (0.03) 1.85 (0.02) 1.58 (0.03)
2.31 (0.05) 2.03 (0.04) 2.03 (0.04) 2.09 (0.06)
2.67 (0.07) 2.70 (0.06) 2.57 (0.05) 2.22 (0.07)
2.65 (0.07) 3.01 (0.05) 2.84 (0.05) 2.32 (0.07)
3.14 (0.06) 3.04 (0.05) 3.07 (0.05) 2.76 (0.06)
2.65 (0.07) 2.78 (0.06) 2.66 (0.06) 2.24 (0.08)
peripheral autonomic pathways generate visceral responses
and provide interceptive input about the inner state of the
body. Rostrally, the limbic sensory cortex in the insula inte-
grates this input into the feel of emotions, while the limbic
motor cortex of the anterior cingulate cortex (ACC) and ven-
tromedial prefrontal cortex (vmPFC) generate appropriate so-
matic markers or visceral feelings to guide complex behavior
and decision-making. The ventral striatum and limbic nuclei
of the thalamus provide key outputs from core limbic struc-
tures to cortex, essential for weaving the survival functions of
emotion into everyday perception and action. Finally, a net-
work of prefrontal regions including the dorsomedial, ventro-
lateral, ventromedial, and frontopolar cortices are critical for
the process of reappraisal: adjusting emotional states based
on cognition and context.35
All of these structures show varying degrees of sexual di-
morphism. Structurally, total brain volume is approximately
10% higher in males,36 while the gray-white matter ratio is sim-
ilar in both females and males.37 Voxel-based morphometry
(VBM) studies have shown subtly larger gray matter volume
in the amygdala, hippocampus, and parahippocampal cortex
in males, as well as increased white matter volume in the an-
terior temporal lobes, which connect densely to the amyg-
dala.38 Females have slightly larger gray matter volumes in the
ventrolateral and lateral orbitofrontal cortex,37 which play crit-
ical roles in reappraisal of emotional stimuli,39 as well as in the
superior temporal sulcus (STS), which plays a critical role in
social cue perception.40
Functional imaging positron emission tomography (PET) stud-
ies have shown slightly higher metabolic activity in the male
anterior temporal lobe as well as in the amygdala, hippocam-
pus, and orbitofrontal cortex, consistent with volumetric find-
ings. Females have shown lower activity in posterior and mid-
cingulate regions.41 However, there is considerable variability
in results among studies, with some studies showing opposite
Gender/sex differences in emotions Kennedy and others
 E MOTI O N S AND DEPRESSION

effects in the same regions,42-44 and some smaller studies find
no significant differences in resting metabolic activity between
males and females.45,46 Functional magnetic resonance im-
aging (fMRI) studies have found no sex differences in the func-
tional connectivity of resting-state networks for the default
mode of introspection and self-reflection, the executive con-
trol network engaged during cognitive tasks, or the salience
network activated by potentially relevant events in the sen-
sory environment.47
well as in decision-making, akin to those of the famous case
of Phineas Gage. Left-sided lesions produced mild or no im-
pairment.55 In contrast, among women, it was lesions of the
left vmPFC that led to profound social and emotional im-
pairment, while right vmPFC lesions were relatively benign.56
The same type of sex difference has been observed for the
amygdala, with social and emotional deficits arising from right-
sided, but not left-sided, lesions in men and left-sided, but
not right-sided, lesions in women.57

N Sex differences in hemispheric asymmetries in

emotion pathways
In a majority of studies to date, sex differences in raw struc-
A
tural and functional neuroanatomy are consistently identified,
but they are subtle in magnitude. A major exception is a well-
replicated sex difference: asymmetry of emotional functions
across the two hemispheres of the brain (Figure 2). For exam-
ple, on resting-state fMRI, the left amygdala shows marked-
ly stronger and more widespread functional connectivity to
the rest of the brain in women; conversely, the right amyg-
dala shows stronger connectivity to the rest of the brain in
men.48 During emotional provocation, there is a three-way in-
teraction between sex, hemisphere, and emotional valence. B
In women, negative stimuli activate the left amygdala, hip-
pocampus, hypothalamus, vmPFC, and ACC,49 while in men,
it is positive emotional stimuli that activate a left-sided net-
work of limbic structures (including amygdala, orbitofrontal cor-
tex, uncus, and temporal pole). Likewise, males show greater
activation of the right amygdala in response to sad faces.50
Subjective sadness is correlated with right amygdala activa- C
tion in males, but not females.51

Sex differences in asymmetry are also apparent in studies of

emotional memory. Men watching emotional slides or film clips
show strongly lateralized right, but not left amygdala activa-
tion which is associated with enhanced memory of the emo-
tionally arousing scenes. Women demonstrate left, but not
right amygdala activation associated with better memory for
the emotional scenes.52,53
Sex differences in limbic activity are also apparent during more
complex emotion-driven prosocial behavior. For example,
the anterior insula activates not only during pain, but also em-
pathetically, when witnessing others in pain.54 In women, this
empathetic response is reduced if the other person had pre-
viously acted unfairly in a social exchange. However, in men
witnessing unfair individuals in pain, the empathetic insular
response is abolished entirely. Additionally, in these men, the
reward circuitry of the left ventral striatum was also activat-
ed asymmetrically. No such vengeful response was seen in
women, in either hemisphere.
Lesion studies confirm sex differences in functional asymme-
try of limbic regions. Among men, right vmPFC lesion caused
profound impairments in social and emotional functioning as
Figure 2. Gender-dependent hemispheric asymmetries in emo-
tion regulation pathways.
(A) In females, the left, but not the right, amygdala shows strong resting-state
connectivity to a widespread network of ventral prefrontal, temporal, and parahip-
pocampal regions. In males, the reverse is true. (B) The left amygdala is activated
by negative emotional stimuli in females, but by positive emotional stimuli in males.
(C) Major deficits in social, emotional, and decision-making functions arise from
left-hemisphere lesions of the amygdala or ventromedial prefrontal cortex in fe-
males, but from right-hemisphere lesions of these structures in males.
Sex differences in MDD symptom presentation
The case for sex differences in psychiatric illnesses has at-
tracted increasing attention in recent years.58 Beginning in ado-
lescence, women have a twofold greater risk for MDD com-
pared with men.59 Although men and women report similar
depressive symptoms,60 women are more likely to recall their
symptoms and also experience a greater number of recurring
depressive episodes.61 Classically, atypical (reversed) neu-
rovegetative symptoms are more prevalent in women com-

Gender/sex differences in emotions Kennedy and others MEDICOGRAPHIA, Vol 35, No. 3, 2013 275
E MOT I O N S AND DEPRESSION
pared with men.62 Evidence to support higher rates of atyp-
ical depression in women is derived from studies of twins
and sibling pairs.
An evaluation of more than 200 opposite-sex dizygotic twin
pairs who met lifetime criteria for MDD showed that fatigue,
hypersomnia, and psychomotor retardation were more preva-
lent in females, while insomnia and agitation were more like-
ly to occur in males.63 The authors suggested that both sex
and gender played a role in differential recall as well as hor-
monal and sociocultural variables.
In an assessment of 94 female twin pairs, Kendler and col-
leagues identified severe typical and atypical depression response
groups. The severe typical group was characterized by co-
morbid anxiety and panic symptoms, greater functional im-
pairment, and a longer episode duration, while the atypical
group reported increased eating, hypersomnia, and more fre-
quent, but shorter episodes. Interestingly, neither neuroticism
nor anxiety symptoms were prevalent in the atypical group.
However, the absence of male comparison twins limits any
conclusions about apparent sex differences in depressive
symptoms. This finding was supported by results from a Cana-
dian community epidemiology study which examined the
symptom presentation of recurrent depressive episodes in
over 650 cases. The authors reported persistent atypical pres-
entation in only 11% of cases, while the majority were either
typical or did not firmly belong in either category. In both
typical and atypical groups, women represented 77% and
75% of the sample, respectively.64
Using a different technique, Moskvina and colleagues65 com-
pared symptom presentation in more than 400 sibling pairs
who met criteria for MDD across European centers. They con-
firmed a higher frequency of atypical symptoms (fatigue, in-
creased appetite, weight gain, and hypersomnia) in women,
who also had higher rates of tearfulness, pathological guilt,
morning severity, and loss of reactivity. Female siblings also
reported an earlier age of onset and prolonged episode length
compared with male siblings. There was also a significant cor-
relation in symptom profiles between female sibling pairs, but
not between male sibling pairs or in male-female sibling pairs.
While most studies captured data from white samples, Lai,66
examined male-female differences in 146 Taiwanese patients:
women had greater frequency of sleep disturbance (time to
onset and total sleep time), somatic complaints (chest pain,
headaches, and appetite loss), as well as sadness and nerv-
ousness. Women were also more likely than men to report a
reduction in sexual interest, function, and overall satisfaction.
In the largest clinical cohort to date of depressed patients par-
ticipating in a treatment study, 63% were women and they re-
ported greater severity of depressive symptoms, comorbidity
of anxiety disorders, binge eating, and somatoform disorders
as well as hypersomnia and rejection sensitivity, but less sui-
276 MEDICOGRAPHIA, Vol 35, No. 3, 2013
cidal ideation compared with men.67 Men reported a greater
number of depressive episodes as well as alcohol and sub-
stance use.67
In contrast, Silverstein and colleagues68 found that in both the
National Comorbidity Survey (NCS14) and the Zurich study,69
pure depression was comparable in frequency between men
and women, while anxious somatic depression was twice as
frequent in women. These authors concluded that atypical
depressive symptoms did not contribute to male-female dif-
ferences.
Sex differences in antidepressant treatment
The presence of differing symptom distributions and poten-
tial depressive subtypes in men and women suggests that
response to antidepressant treatment may also display sex
differences.70 However, publications in this area provide con-
trasting results (Table II).70-85
N Response to tricyclic antidepressants and monoamine
oxidase inhibitors
Reports from the preselective serotonin reuptake inhibitor
(SSRI) era suggest that men have higher response rates than
women to tricyclic antidepressants (TCAs).86-88 A subsequent
publication by Quitkin in 200270 used retrospective data to
analyze differences in treatment response to TCAs by cate-
gorizing participants according to age (<50 years of age and
>50 years of age) and sex. A survival analysis indicated that
there was no difference in TCA treatment response between
older men and older women. However, older women had su-
perior response rates to TCAs when compared with younger
women. These results were also replicated in a study by Grigo-
riadis and colleagues who found that older women respond-
ed more favorably to the TCA desipramine than younger wom-
en with response rates of 62% and 34%, respectively.84
Quitkin and colleagues70 also evaluated sex differences in re-
sponse to monoamine oxidase inhibitor (MAOI) therapies. While
there was no difference in antidepressant response between
older men and older women, there was a difference in re-
sponse rates between sexes which was accounted for by
younger women having a superior response to MAOIs com-
pared with younger men.70 These findings contrast with re-
sults from a large naturalistic study which concluded that men
and women were equally likely to respond to SSRI, TCA, MAOI,
and serotonin norepinephrine reuptake inhibitor (SNRI) anti-
depressants.77
N Response to SSRIs and SNRIs
In a study of chronic depression involving 235 men and 400
women, Kornstein and colleagues71 identified sex differences
in antidepressant response to sertraline and imipramine. There
was a statistically significant interaction between sex and treat-
ment, with women having a more favorable response to ser-
Gender/sex differences in emotions Kennedy and others
 E MOTI O N S AND DEPRESSION

traline than imipramine (57% vs 46%), while men were more
likely to respond to imipramine than sertraline (62% vs 45%).
Moreover, compared with men, women had a greater likeli-
hood of achieving remission over the 12-week treatment pe-
riod. The inferior response to imipramine compared with ser-
traline in premenopausal women was attributed to higher
attrition among younger women who received the TCA.71
Using data from the 9-year, multicenter, prospective trial
CRESCEND (the Clinical RESearch CENter for Depression),
based in South Korea, Yang and colleagues85 found that wom-
en were more likely to respond to SSRIs,70,71 supporting pre-
vious findings that atypical symptoms are more prevalent in
women and respond better to SSRIs.89 There were no sig-
nificant differences in response rates between sexes when

Author, Year Treatment Study type n Findings

Kornstein et al,71 2000 Sertraline, imipramine 12-Week double-blind trial 635 Women had a superior response to
sertraline, men to imipramine

Martenyi et al,72 2001 Fluoxetine, maprotiline 6-Week double-blind trial 105 Women were more responsive to fluoxe-
tine than maprotiline; no difference in men

Entsuah et al,73 2001 Venlafaxine, SSRIs 8 Double-blind, active con- 2045 No sex differences
trolled, randomized trials
(4 were placebo controlled)

Quitkin et al,70 2002 TCAs, MAOIs, fluoxetine 8 Placebo-controlled trials 1746 Older women had a more favorable response
and 1 open-label study to TCAs than younger women; women had
a statistically superior response to MAOIs

Parker et al,74 2003 TCA, SSRI 1 Retrospective study 346 No sex differences
1 Prospective study 162

Hildebrandt et al,75 2003 TCA, SSRI, MAOI 3 Double-blind, randomized 292 No sex differences
controlled trials

Grigoriadis et al,76 2003 SSRI, nefazodone, or 8-Week double-blind study 201 Younger compared with older women were
venlafaxine more responsive to serotonergic anti-
depressants

Scheibe et al,77 2003 TCAs, SSRIs, SNRIs, MAOIs, Retrospective study 385 No sex differences
RIMAs

Wohlfarth et al,78 2004 TCAs 30 Randomized, placebo 3886 No sex differences

controlled trials

Cassano et al,79 2004 Fluoxetine 8-Week open-label study 320 No sex differences

Khan et al,80 2005 SSRIs, SNRIs 15 Randomized placebo- 323 Women responded better to SSRIs and
controlled trials SNRIs than men

Kornstein et al,81 2006 Duloxetine 7 Randomized, double-blind, 896 No sex differences in antidepressant re-
placebo controlled trials sponse, but women on duloxetine com-
pared with placebo had a significant
reduction in pain severity

Grigoriadis et al,82 2007 TCAs, SSRIs, SNRIs 8-Week, open-label, flexible- 205 Men responded more favorably to SSRIs
dose trial and venlafaxine than women

Young et al,83 2009 Citalopram 12- to14-Week, open-label, 2876 Women were significantly more likely to
flexible dose study achieve remission than men during
citalopram treatment

Grigoriadis et al,84 2010 Desimpramine 8-Week, double-blind, flexible- 113 No sex differences; older women showed
dose study; women only better response to desimpramine than
younger women (trend)

Yang et al,85 2011 SSRIs, newer dual anti- 12-Week naturalistic cohort 723 Women were significantly more likely to
depressants, other anti- study respond to SSRIs than men
depressants

Table II. Sex- and age-related differences in antidepressant treatment response.

Abbreviations: MAOI, monoamine oxidase inhibitor; RIMA, reversible inhibitor of monoamine oxidase A; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI,
selective serotonin reuptake.
Updated from reference 82: Grigoriadis et al. J Clin Psychopharmacol. 2007;27(1):95-98. 2007, Lippincott Williams & Wilkins.

Gender/sex differences in emotions Kennedy and others MEDICOGRAPHIA, Vol 35, No. 3, 2013 277
E MOT I O N S AND DEPRESSION
data from seven randomized double-blind, placebo-controlled
trials of duloxetine were pooled. On the other hand, compared
with men, duloxetine-treated women showed a greater re-
duction in overall pain severity scores.81
N Other medications
Data are limited on sex differences in response rates to new-
er antidepressants and augmentation therapies for depres-
sion. Recent evidence suggests that agomelatine, which is a
novel melatonergic antidepressant with good tolerability has
equal efficacy in men and women.90
N Limitations
Gonadal hormones, specifically estrogen, which is a substrate
for cytochrome P450 (CYP) 3A4 and CYP1A2 as well as an
inhibitor of CYP1A2, may impact antidepressant metabolism
by enhancing response to SSRIs or inhibiting response to
TCAs.91 However, failure to demonstrate differences may also
relate to methodological limitations in published studies. Not
all studies stratified their samples according to the hormonal
status of women (pre/perimenopausal vs postmenopausal);
several studies were underpowered due to small sample size.70
N Neurostimulation therapies
Sex differences may also be relevant in response to anatom-
ically targeted device therapies such as repetitive transcra-
nial magnetic stimulation (rTMS)92 and deep brain stimulation
(DBS). Given the differential roles of left- and right-hemisphere
limbic structures in negative emotions in men and women,
tailoring the parameters of rTMS according to the sex of the
patient could potentially improve antidepressant efficacy. In
DBS for MDD, electrodes are typically implanted bilaterally in
the subgenual cingulum, an area of the vmPFC that is dense-
ly connected with the amygdala. Stimulation is typically bilat-
eral. Although DBS is effective in many refractory depression
cases, approximately one-third still do not respond to treat-
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Keywords: antidepressants; emotion; gender differences; major depressive disorder (MDD); neurobiology; neuroimaging;
sex differences; symptom presentation; treatment response

DIFFRENCES MOTIONNELLES SELON LE SEXE ET LE GENRE

Les diffrences sexuelles biologiques commencent in utero et se dveloppent tout au long de la vie en fonction des
processus biologiques et de lexprience. Le concept de genre ncessite de sparer les constructions biologiques
(sexe) et sociales (genre) et de sintresser au rle jou par les hormones et les gnes dans la mise en place des dif-
frences motionnelles, et plus particulirement de celles qui sont dues la diffrenciation sexuelle du ftus et au
cycle reproductif. Des techniques de neuro-imagerie fonctionnelles de plus en plus sophistiques mettent en vi-
dence les diffrences sexuelles crbrales et leur influence sur les diffrentes expressions des motions. Il existe
peu de preuves dmontrant des diffrences de symptmes entre les hommes et les femmes dans la dpression
et les donnes sur les diffrences de rponse aux antidpresseurs selon le sexe dans la dpression majeure sont
contradictoires.

280 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Gender/sex differences in emotions Kennedy and others

No one particular region has
abnormal activity in depression;
rather, there is an imbalance in ac-
tivity between regions. Hence, the
whole network is altered, appar-
ently undergoing changes that im-
balance and shift the neural ac-
tivity distribution across different
regions. How that works in detail,
though, remains unclear. This sug-
gests that in depression, rather
than alteration of one particular
emotion, all emotions are altered
in an abnormal way.
Georg NORTHOFF,
MD, PhD, FRCPC
Research Unit Director
Mind, Brain Imaging, and
Neuroethics
Canada Research Chair
University of Ottawa
The Michael Smith Chair
ELJB-CIHR, Royal Ottawa
Health Care Group
CANADA
Address for correspondence:
Georg Northoff, University of Ottawa
Institute of Mental Health Research,
1145 Carling Avenue, Room 6435,
Ottawa, ON K1Z 7K4, Canada
(e-mail: georg.northoff@theroyal.ca)
(personal website:
http://www.imhr.ca/research/mind-
neuroethics-e.cfm)
www.medicographia.com
Emotions and the brain Northoff
E MOTI O N S AND DEPRESSION
A look into emotions
with neuroimaging
b y G . N o r t h of f, C a n a d a
E
motions are fundamental to our life and are largely altered in many psy-
chiatric disorders, such as depression. Recent imaging studies investi-
gated various types of emotions, such as anger, fear, sadness, disgust,
and happiness, aiming to localize them in specific regions of the brain. These
studies reveal that many regionsincluding the amygdala, insula, ventro- and
dorsolateral prefrontal cortex, ventro- and dorsomedial prefrontal cortex, peri-
aqueductal gray, and anterior cingulate cortexare implicated in various
types of emotions, suggesting that emotions are mediated by different neu-
ral networks rather than specific regions. Complicating matters further, the
brains spontaneous or intrinsic activity, eg, resting-state activity, is also closely
related to emotion processing. Recent studies demonstrate that the level of
resting-state activity may be modulated by preceding emotions, suggesting
that these emotions are somehow encoded in a yet unclear way into the neu-
ral patterns of the brains intrinsic activity. Thus, the neural activity we observe
when experiencing emotions may be the result of the integration of extrinsic
stimuli and intrinsic activity. This is highly relevant in depression, where the
brains intrinsic activity is abnormally imbalanced, with resting-state hyper-
activity in medial regions and resting-state hypoactivity in lateral regions.
Medicographia. 2013;35:281-286 (see French abstract on page 286)
Emotions and the regions of the brain
number of imaging studies using functional magnetic resonance imaging
A have been conducted over the last 10 years both in healthy and depressed
subjects. Focusing on the main findings in the main regions of the brain in
healthy subjects and the implications for depression, this general overview of the
numerous imaging studies on emotion will first take a brief look at the methodol-
ogy involved.
N Emotion paradigms
Imaging studies on emotion apply different kinds of paradigms. The bulk of the stud-
ies use visual stimulation. Subjects view emotional pictureseg, faces that are sad,
happy, angry, etcor they watch videos of emotional scenes. Other studies apply
auditory stimulation as well, using emotional tones, for example. In the study design,
it is also important to consider the task associated with the respective emotional
stimulus. Subjects may be asked to merely perceive the emotional stimuli without
much self-involvement. Alternatively, they may be required to imagine themselves
in that particular scene and to experience the respective emotion.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 281
E MOT I O N S AND DEPRESSION
Besides mere perception and actual experience of emotion-
al stimuli, other studies require a judgment to be made, where
subjects have to judge the emotional stimulus as positive or
negative, for example, either during or immediately following
its presentation. Finally, subjects may be asked to recall and
retrieve specific emotional experiences from their own life.
This introduces a strong memory component into the design.
These so-called task-related effects are important to consid-
er since they may confound and mix with the neural effects
related to the emotional stimulus effect, the stimulus-related
effects. For instance, it has been shown that task-related ef-
fects like judgment are associated with the lateral prefrontal
cortex, while mere perception and actual experience of the
same emotional stimulus yield neural activity in the medial pre-
frontal cortex. Hence, we have to distinguish between task-
and stimulus-related effects.
N Brain regions involved in processing emotion
Various regions of the brain are implicated in emotion process-
ing (see meta-analyses1-3). One core region is the amygdala,
a subcortical region that lies anterior to the hippocampus.
The amygdala has been shown to be involved in emotion pro-
cessing in both animal and human studies, and has therefore
often been considered the emotion region of the brain. More
specifically, emotions yielding activity changes in the amyg-
dala include fear, disgust, and anger, ie, negative emotions.
Another subcortical region especially implicated in the pro-
cessing of fear is the periaqueductal gray (PAG). The PAG is
a convergence, or node station, for the confluence of intero-
ceptive stimuli from the body, exteroceptive sensory stimuli
from the sensory modalities, and motor stimuli for generating
movement and action. This makes it perfectly suitable to be
involved in emotion. Fear and anger have been especially as-
sociated with neural activity in the PAG.
The hippocampus, lying posterior to the amygdala, has also
been implicated in emotion processing. The entorhinal cor-
tex, especially, as part of the hippocampal complex has been
shown to be recruited during disgust, sadness, anger, and fear.
This is important as the hippocampus is a central focus in de-
pression, in the context of stress and cortisol-related changes
as an important part of the pathophysiology. How the stress-
related hippocampal changes in depression are related to the
abnormal emotion processing in this and other regions, how-
ever, remains unclear.
Another region centrally implicated in emotion processing is
the insula. The insula lies on the outer surface of the brain and,
like the amygdala, receives both interoceptive, eg, vegetative,
input from the body and exteroceptive input from the various
sensory modalities. Such convergence seems to make the
insula an ideal candidate for emotion processing since emo-
tions are supposed to result from the integration between in-
teroceptive and exteroceptive stimuli. One emotion prominent-
ly shown to consistently activate the insula is disgust. Several
282 MEDICOGRAPHIA, Vol 35, No. 3, 2013
studies on disgust have been conducted and demonstrated
strong insula involvement. This has often led to the assump-
tion that the insula may be specific to the processing of dis-
gust. However, the insula has been shown to be implicated in
other emotions as well, such as anger and fear, in the same
way that disgust also recruits other regions like the occipital
cortex, the amygdala, and the lateral prefrontal cortex.
Another region involved in emotion processing is the orbito-
frontal cortex, to which the insula sends many projections.
As are the insula and the amygdala, the orbitofrontal cortex
too has been associated with different emotions. Most promi-
nent among them is anger, but fear and disgust also seem
to recruit this region. The orbitofrontal cortex is closely relat-
ed to the medial prefrontal cortex, which includes the ventro-
and dorsomedial prefrontal cortex (vmPFC and dmPFC, re-
spectively). The vmPFC and dmPFC have both been asso-
ciated with sadness, fear, and happiness. The dmPFC may
be particularly involved in reflection upon the emotional ex-
perience, as for instance during evaluation or judgment, while
the vmPFC may be more involved in the experience or per-
ception of the emotion itself.
Turning laterally, we encounter the dorso- and ventrolateral
prefrontal cortex (dlPFC and vlPFC, respectively). Both re-
gions have been associated with emotion processing in gen-
eral. Negative emotions may be more associated with the left
vlPFC and dlPFC, while positive emotions are supposed to
involve the right side. Moreover, the dlPFC, especially, has
been associated with more cognitive aspects of emotion pro-
cessing, such as cognitive control, executive attention, and
evaluation/judgment of emotions. The vlPFC is especially re-
cruited when showing emotional faces, possibly related to the
involvement of this region in face processing, particularly where
ones own face is concerned.
Closely related is the cingulate cortex. The cingulate cortex
comprises the sub/pregenual and supragenual anterior cin-
gulate cortex (PACC and SACC, respectively) and the pos-
terior cingulate cortex (PCC). The PACC has been associat-
ed with sadness in particular, but also with other emotions like
anger and disgust. The PACC receives direct interoceptive
SELECTED ABBREVIATIONS AND ACRONYMS
dlPFC dorsolateral prefrontal cortex
DMN default-mode network
dmPFC dorsomedial prefrontal cortex
PACC sub/pregenual anterior cingulate cortex
PAG periaqueductal gray
PCC posterior cingulate cortex
SACC supragenual anterior cingulate cortex
vlPFC ventrolateral prefrontal cortex
vmPFC ventromedial prefrontal cortex
Emotions and the brain Northoff

and exteroceptive input from the insula and amygdala, while
the SACC interacts with the lateral prefrontal cortex. Corre-
spondingly, the SACC is often associated with the cognitive
control of and executive attention to emotions in general. Fi-
nally, the PCC, lying posterior, is closely connected to the hip-
pocampal complex and is therefore involved in memory pro-
cessing, especially the retrieval of episodic or autobiographical
memories. The PCC has also been implicated in a range of
emotions, including anger, fear, and sadness.
Other regions implicated in emotion processing include the
visual, or occipital, cortex and the temporal cortex. While pre-
dominantly accounting for visual processing, the occipital cor-
tex has often been demonstrated to show heightened activ-
ity during different emotions, especially negative ones such as
fear, anxiety, sadness, and disgust. This cannot be due to the
type of stimuli since the purely visual processing aspects are
usually cancelled out by comparing visual emotional stimuli
with visual nonemotional stimuli. Hence, it seems that an emo-
tional component enhances neural activity in the occipital cor-
tex during visual processing. The occipital cortex is strongly
implicated, especially in studies that require subjects to imag-
ine specific emotions, possibly related to the fact that imagery
is often visual. Moreover, emotional pictures often also elicit
strong activity changes in the occipital cortex, as distinguished
from films or faces, for instance.
N Emotions are mediated by neural networks rather than
specific regions of the brain
What do these findings tell us about the relationship between
emotion and the brain? Confusing as these findings are, they
indicate that one particular emotion is not associated with one
or two particular regions in the brain. For instance, almost all
studies demonstrate that specific emotions, such as disgust,
fear, and anger, do not recruit one particular region, but many
as indicated above. As each emotion recruits multiple regions,
emotions seem to be mediated by neural networks rather than
specific regions. One may thus want to speak of a network-
rather than a region-based approach to emotion.
N Brain regions are associated with specific processes
rather than specific emotions
Moreover, there is no region that is involved only in one par-
ticular emotion. Instead, each region seems to be implicated
in several emotions. The same region may make different con-
tributions to the different emotions whose processing it me-
diates. What exactly these contributions are, though, we cur-
rently do not know. Thus, it cannot be said that one regions
neural activity and processing is specified for a particular emo-
tion, or more generally put, a specific emotional content. In-
stead, the regions seem to mediate specific processes, with
these processes being implicated in different emotions and
their respective contents. One may thus want to speak of a
process-based rather than content-based approach to the
regions.
Emotions and the brain Northoff
E MOTI O N S AND DEPRESSION
N What is the relevance to depression?
One may now raise the question as to why and how all that
is relevant to depression. The various forms of depression,
such as major depressive disorder or bipolar depression, show
changes in almost all of these regions. For instance, studies
in major depressive disorder demonstrated abnormal activ-
ity during emotional stimulation in the PACC, SACC, insula,
dlPFC, and vlPFC. These regions are also implicated in bipo-
lar depression, though possibly in different ways. What the
findings suggest is that no one particular region has abnor-
mal activity in depression; rather, there is an imbalance in ac-
tivity between regions. Hence, the whole network is altered,
apparently undergoing changes that imbalance and shift the
neural activity distribution across different regions. How that
works in detail, though, remains unclear.
This suggests that in depression, rather than alteration of one
particular emotion, all emotions are altered in an abnormal way.
The neural network seems to be imbalanced, which in turn
may lead to abnormal processing of the various emotional
contents. As mentioned above, however, we do not under-
stand the exact neural processes mediated by the various re-
gions and neural networks, making it difficult to determine the
exact pathophysiological mechanisms in depression.
Emotions and the brains intrinsic activity
This overview has thus far focused mainly on neural activity
related to particular stimuli, eg, emotional stimuli. This is de-
scribed as stimulus-induced activity that describes how stim-
uli extrinsic to the brain, eg, from the environment (or the body),
yield neural activity changes in the brain. Such extrinsic stim-
ulus-induced activity originating from stimuli outside the brain
must be distinguished from neural activity originating from
the brain itself and thus intrinsic to it. Such intrinsic activity is
often described as spontaneous activity or in an operational-
ized form as resting-state activity signaling the absence of
specific extrinsic stimuli.
N Historical extrinsic view and intrinsic view of the brain
While the notion of intrinsic activity in the brain has been around
for almost 100 years, it has recently come to the foreground
again, especially in brain imaging. What is the brain and how
does it operate? This was already the subject of controver-
sial discussion in the early days of neuroscience at the be-
ginning of the 20th century. One view of the brain, favored by
the British neurologist Sir Charles Sherrington (1857-1952),
assumed the brain and the spinal cord to be primarily reflex-
ive. Reflexive means that the brain reacts in predefined and
automatic ways to stimuli. Thus, the stimuli from outside the
brain, originating extrinsically in either the body or environment,
are assumed to determine completely and exclusively the sub-
sequent neural activity. The resulting stimulus-induced activity,
more generally any neural activity in the brain, is consecutively
traced back to the extrinsic stimuli. This may be considered an
extrinsic view of the brain (Figure 1A, page 284). For every
MEDICOGRAPHIA, Vol 35, No. 3, 2013 283
E MOT I O N S AND DEPRESSION

Figure 1. Two views of the brain: the brains

neural activity as purely determined by
extrinsic stimuli (A) and by both the brains A Extrinsic view of the brain
intrinsic activity and the extrinsic stimuli Input only from outside the brain (the environment, as extrinsic input)
from the environment (B).
The image on the left in both figures represents
stimuli from the environment, while the brain in blue in
the middle represents the brain. The purple line in the
brain in (B) symbolizes the brains intrinsic activity
its resting-state activitythat as such remains
independent of any extrinsic stimuli from the environ-
ment. The bar diagram on the far right on both
panels stands for the neural activity we observe once
the person and his/ her brain encounter the stimuli
from the environment.
(A) In the case of a purely extrinsic view of the brain,
the observed stimulus-induced activity is exclusively Stimulus-induced activity: result
and completely determined by the stimulus itself; the of stimulus-stimulus interaction
brain is passive and functions more or less like an au-
tomatic and reflex-like machine. Any neural activity in Brain itself has no say in what happens in the brain!
the brain can be traced back to stimuli and their inter-
actions with each other, ie, stimulus-stimulus interac-
tion. The brain itself has thus no say in what happens B Intrinsic view of the brain
in the brain. (B) This is different once one assumes Input from the brain itself (intrinsic input) and from the environment (extrinsic input)
intrinsic activity in the brain itself, ie, resting state.
In this case, the observed stimulus-induced activity
results from the interaction between brain and stimuli
amounting to rest-stimulus interaction. The brain itself Intrinsic (resting state) activity
thus has a say in what happens in the brain during its
encounter with extrinsic stimuli from the environment.
Colosseum. SuperStock/Corbis. Neural code
Blue brain. Courtesy of Joseph McNally
Photography/National Geographic.

view there is an opposing view, however.

An alternative view was already suggest-
ed by one of Sherringtons students, Tho-
Stimulus-induced activity: result
mas Graham Brown. In contrast to his of rest-stimulus interaction
teacher, he suggested that the brains
activity, ie, in the spinal cord and brain Brain itself has a strong say in what happens in the brain!
stem, is not primarily driven by extrinsic
stimuli from outside the brain, ie, the body
and environment. Instead, the spinal cord and brain stem N Present status: extrinsic vs intrinsic view
show spontaneous activity originating intrinsically within them- Following this rather abbreviated history of neuroscience, lets
selves. Other subsequent neuroscientists such as Karl Lash- look at the present. The dichotomy between intrinsic and ex-
ley, Kurt Goldstein, and Wolfgang Koehler followed Browns trinsic views of the brain is still just as controversial and has
line of thought and assumed the brain to show intrinsic ac- most recently resurfaced, especially in functional brain imag-
tivity. This may be considered an intrinsic view of the brain. ing (see examples4,5). Lets start with the extrinsic view.

N Stimulus-induced activity: interaction between intrinsic
activity and extrinsic stimulus
The assumption of intrinsic activity generated inside the brain
itself has major implications for how we conceive stimulus-
induced activity. What we as observers describe as stimu-
lus-induced activity and usually associate with the stimulus
itself must then be regarded as the hybrid result of a specif-
ic interaction between the brains intrinsic activity and the
extrinsic stimulus.
Stimulus-induced activity and any neural activity in the brain
must consecutively be traced back to a double input that orig-
inates in both the brains intrinsic activity and the bodys and
the environments extrinsic stimuli (Figure 1B).
Many domains of neuroscience, ranging from cellular over re-
gional to behavioral, rely on experimental application of spe-
cific stimuli and tasks to probe neural activity. By comparing
different stimuli and tasks, the resulting differences in neural
activity are associated with the respective stimuli or tasks. Con-
sequently, the experimental requirements may prime and draw
us toward the extrinsic view. The extrinsic view has been pre-
dominant in behaviorism which, according to authors like Jaak
Panksepp,6 finds its continuation in the cognitive neuroscience
of our days.
However, the extrinsic view of the brain has recently been chal-
lenged again on several grounds. Even in the resting state,
ie, in the absence of any (specific) extrinsic stimuli, the brain

284 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Emotions and the brain Northoff

shows a rather high degree of metabolism, consuming, for
instance, about 20% of the bodys overall energy budget
(and oxygen fraction).4,5,7-9
Using functional imaging, this high metabolism has been es-
pecially observed in a particular set of regionsthe default-
mode network (DMN)which includes various anterior and
posterior cortical midline structures as well as the bilateral
posterior parietal cortex.4,5,9-11 The high degree of metabolism
is indicative of continuously ongoing high levels of neural ac-
tivity even in the absence of (specific) extrinsic stimuli, ie, in the
resting state of the DMN. However, other regions outside the
DMN also show spontaneous neural activity, independent of
any extrinsic stimuli. This has been demonstrated in the au-
ditory and visual cortex, thalamus, hippocampus, olfactory
cortex, cortical midline regions, prefrontal cortex, motor cor-
tex, and other subcortical regions, such as the brain stem and
midbrain.8,9 The metabolic and neuronal signs of intrinsic ac-
tivity are further complemented by behavioral evidence; spon-
taneous behavior, such as seeking or behavioral activation,
can be observed even in the absence of extrinsic stimuli.6
Which view holdsthe intrinsic or the extrinsic one? Rather
than choosing one view and dismissing the other, the brain
itself may force us to reconcile both views. Any neural activ-
ity in the brain may be assumed to result from the interaction
between the brains intrinsic activity and the extrinsic stimuli
from the body and environment. In place of intrinsic and ex-
trinsic views, we may need to investigate how intrinsic activ-
ity and extrinsic stimuli interact with each other in order to un-
derstand the brains neural activity.
N Relevance to processing of emotions
Why is all that relevant for the neural processing of emotions?
Its relevant because emotions may result from the interplay
between intrinsic activity and extrinsic stimuli. Most recently,
single studies demonstrated that there is direct interaction
between extrinsically induced emotion and the brains intrin-
sic activity.
Focusing on emotions, a recent study12 investigated the im-
pact of fearful, joyful, and neutral movie clips (50-s presen-
tation) on subsequent resting-state activity (90-s period with
eyes closed). After the resting-state period, participants were
asked about their thoughts, revealing that personal relevant
issues in the subjects thoughts were increased after neutral
movies, increased, but less so, after joyful movies, and sig-
nificantly decreased after fearful movies. These results show
a clear behavioral effect or better psychological effect of emo-
tions on thought content in subsequent resting-state periods;
fearful movies seem to leave the strongest traces on thought
content of subsequent resting states.
Resting-state neuronal activity in subcortical regions (palli-
dum, anterior thalamus, and hypothalamus) was higher after
viewing fearful movies than after viewing neutral movies (rest-
Emotions and the brain Northoff
E MOTI O N S AND DEPRESSION
ing-state activity greater after fearful stimulation than after neu-
tral stimulation). Most interestingly, the reverse comparison
(resting-state activity greater after neutral stimulation than after
fearful stimulation) revealed more pronounced signal changes
in various regions of the DMN (vmPFC, PACC, dmPFC, supe-
rior temporal gyrus) (see analogous overlap between emo-
tion processing and the DMN13,14).
This means that the inclusion of fearful emotions in the pre-
ceding movie had a clear effect on the level of subsequent rest-
ing-state activity. The stronger resting-state effects of the pre-
ceding emotional movies are further confirmed by the more
delayed recovery from the signal changes during the resting-
state period (90 s) after emotional movies.
Taken together, it seems that emotions are closely related to
the resting-state activity. Studies show that emotions affect
the level of activity in the resting state, thus indicating what
can be described as stimulus-rest interaction.15 Conversely,
one may also expect the resting-state activity to have an im-
pact on emotions during presentation of particular stimuli.
While such rest-stimulus interaction has been described in
perception and cognitive functions, it remains to be demon-
strated for emotion. The degree and intensity of emotions in
psychological regard and the recruitment of particular regions
and networks may then depend not only on the extrinsic stim-
ulus itself and its associated emotional content, but also on
the characteristics of the brains intrinsic activity.
N Relevance of resting-state activity to depression
Why is all that relevant to depression? To start with, human
and animal studies in depression demonstrate abnormal rest-
ing-state activity in various regions. For instance, the resting-
state activity in the PACC seems to be abnormally high in ma-
jor depressive disorder, while that in the dlPFC is abnormally
low in these patients (see overview16). Given the above-de-
scribed findings, it seems certain that such resting-state ab-
normalities must have an impact on subsequent emotion pro-
cessing in the various regions described above.
One may consequently hypothesize that some of the psy-
chological and neural abnormalities observed in emotion pro-
cessing in depression may be related to yet-to-be-specified
abnormalities in intrinsic activity. In addition to providing in-
sight into the pathophysiology of depression, this may lead
to opportunities for more specific and effective therapeutic
intervention. For instance, if we understand the biochemical
mechanisms underlying the resting-state abnormalities in de-
pression, we may be able to design drugs that specifically
target those mechanisms and may thereby normalize subse-
quent emotion processing. That, however, is a scenario of the
future, hopefully the near future. I
Acknowledgments: My work is financially supported by CIHR, EJLB-
CIHR, and ISAN/HDRF.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 285
E MOT I O N S AND DEPRESSION

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Keywords: brain; depression; emotions; imaging; intrinsic activity; networks; regions

MOTIONS ET NEURO - IMAGERIE

Les motions, essentielles dans notre vie, sont trs altres dans de nombreux troubles psychiatriques comme la d-
pression. Des tudes rcentes dimagerie ont cherch localiser dans des rgions spcifiques du cerveau diffrents
types dmotions comme la colre, la peur, la tristesse, le dgot et la joie. Ces tudes ont montr que de nombreuses
rgions (amygdale, insula, cortex prfrontal ventro- et dorsolatral, cortex prfrontal ventro- et dorsomdian, subs-
tance grise priaqueducale, cortex cingulaire antrieur) sont concernes par diffrents types dmotions, ce qui sem-
ble indiquer le traitement des motions est plus affaire de rseaux neuronaux que de rgions spcifiques du cerveau.
Ce schma se complique encore du fait que lactivit spontane du cerveau ou activit intrinsque (cest--dire lac-
tivit ltat de repos) est galement troitement implique dans les processus motionnels. Des tudes rcentes
montrent que le niveau dactivit de repos peut tre modul par des motions antrieures, comme si ces motions
taient, dune certaine faon et par des voies encore mal connues, encodes dans les modles neuronaux de lac-
tivit crbrale intrinsque. Lactivit neuronale que nous observons lors dmotions ressenties pourrait donc rsul-
ter de lintgration de stimuli extrinsques et dune activit intrinsque. Ceci prend tout son sens dans la dpression
o lactivit intrinsque crbrale est anormalement dsquilibre avec une hyperactivit de repos dans les rgions
mdiales et une hypoactivit de repos dans les rgions latrales.

286 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Emotions and the brain Northoff

Distinguishing between sad-
ness and depression is important,
but not always easy. Both are of-
ten associated with loss, but the
difference is that the depressed
individual feels, and often actually
is, incapable of dealing with the
loss: the depression must be re-
solved before the individual can
attempt to deal with the loss. By
contrast, in simple sadness, the in-
dividual is capable of taking an-
other look at the source of trouble
and doing something about it.
Koen DEMYTTENAERE
MD, PhD
Section of Psychiatry, Chair
University Psychiatric Center
KuLeuven, Campus Gasthuisberg
Leuven, BELGIUM
Address for correspondence:
Professor Koen Demyttenaere, MD,
PhD, Section of Psychiatry, University
Psychiatric Center KuLeuven -
Campus Gasthuisberg, Herestraat 49,
B-3000 Leuven, Belgium
(e-mail: koen.demyttenaere@
med.kuleuven.be)
www.medicographia.com
From sadness to depressed mood and from anhedonia to positive mood Demyttenaere
E MOTI O N S AND DEPRESSION
From sadness to depressed
mood and from anhedonia to
positive mood and well-being
b y K . D e m y t t e n ae re , B e l g i u m
D
epressed mood and anhedonia are the two core symptoms of major
depression as defined in the Diagnostic and Statistical Manual of Men-
tal Disorders, but both symptoms are more complex than generally
thought. The differentiation between depressed mood and sadness or be-
tween depressed mood and bereavement remains a clinically relevant ques-
tion in daily practice. While the former is rather a mood or affect state and is
usually considered independent from loss, the latter is an emotion and is usu-
ally considered as being linked to a loss situation. However, clinical reality
shows that, especially in first episode depression (less in recurrent depres-
sion), patients frequently report stressful life events often linked to loss. An-
hedonia, or lack of interest or pleasure, is a compound criterion, since loss of
interest (appetitive or motivational anhedonia) and loss of pleasure (consum-
matory anhedonia) are different phenomena. Another clinically relevant ques-
tion is whether the opposite of anhedonia is absence of anhedonia or whether
it is the presence of positive mood and well-being. The tools most frequent-
ly used to assess change during antidepressant treatment give significantly
more attention to depressed mood than to anhedonia. This is worrying, since
it is in sharp contrast with what patients expect from treatment. Indeed, it has
been documented that patients consider the restoration of positive mental
health (optimism, vigor, self-confidence) to be the most important expecta-
tion. In conclusion, more careful differentiation between (normal) sadness and
depressed mood could probably enhance diagnostic accuracy in depression,
and a more careful taking into account of positive mood would probably be
beneficial to the depressed patient.
Medicographia. 2013;35:287-291 (see French abstract on page 291)
n the more recent versions of the Diagnostic and Statistical Manual of Mental Dis-
I orders (DSM), the two core symptoms of depression are depressed mood and
lack of interest or pleasure.1-4 This is in contrast with the more recent versions of
the International Classifications of Diseases (ICD), where three core symptoms of
depression are mentioned: depressed mood, lack of interest or pleasure, and fa-
tigue.5,6 The present paper focuses on depressed mood and how it is related to sad-
ness, and on anhedonia and how it is related to positive mood or well-being.
In daily life, we all experience positive and negative emotions, positive and nega-
tive affect, positive and negative mood, and it is probably a lifelong challenge to find
a balance between them.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 287
E MOT I O N S AND DEPRESSION
German E. Berrios, making an attempt to carefully order the
words mood, affect, sentiment, emotion, and passion, and to
help us out of the terminology confusion, cites Ribot7:
Sentiment, emotion and passion have been customarily dis-
tinguished from mood, affect and feeling in terms of criteria
such as duration, polarity, intensity, insight, saliency, associa-
tion with an inner or outer object, bodily sensations and mo-
tivational force. Sentiment, emotion and passion are defined as
feeling states that are short-lived, intense, salient, and related
to a recognizable object.Mood and affect, on the other hand,
are defined as longer lasting and objectless states capable
of providing a sort of background feeling tone to the individual.
From sadness to depressed mood
Izard stated that sadness is generally considered to be a neg-
ative emotion, an emotional response to separation, death,
disappointment, failure to achieve an important goal, or to the
sorrow of another.8(pp185-186) But he also stated that we too of-
ten forget that sadness can be an appropriate response: for
example, to the death of someone you love. Shared sadness
can reunite a family or friends, can strengthen the sources of
social support, can invite you to slow down the pace of your
life, can communicate to the self that all is not well, can mo-
tivate one to renew and strengthen bonds with others, and
can play a role in empathy. Distinguishing between sadness
and depression is important, but not always easy. Both are
often associated with loss (death, loss of a companion, the
loss of friends or a love relationship, or even less easily de-
finable losses), but the difference is that the depressed indi-
vidual feels, and often actually is, incapable of dealing with the
loss: the depression must be resolved before the individual
can attempt to deal with the loss. By contrast, in simple sad-
ness, the individual is capable of taking another look at the
source of trouble and doing something about it.8(p209) It is,
however, well documented that stressors (most often loss
situations) are more frequently found in the months preced-
ing a first episode depression than in the months preceding
recurrent episode depression, where new episodes seem to
become more and more independent of life stressors or loss-
es.9 So from a qualitative point of view, first episode depres-
sion seems to be closer to sadness as an emotion, while re-
current depression seems to be closer to depressed mood or
depressed affect. The wording of the DSM diagnostic criteria
for depression seems to combine both aspects: depressed
mood is defined as feeling sad or empty as indicated by self-
report or as appearing tearful as observed by others.4
SELECTED ABBREVIATIONS AND ACRONYMS
DSM Diagnostic and Statistical Manual of Mental Disorders
HAM-D Hamilton Depression Rating Scale
ICD International Classification of Diseases
MADRS Montgomery-Asberg Depression Rating Scale
RDC Research Diagnostic Criteria
288 MEDICOGRAPHIA, Vol 35, No. 3, 2013 From sadness to depressed mood and from anhedonia to positive mood Demyttenaere
If we accept that sadness is a negative emotion related to
separation or loss and that depressed mood or depressed af-
fect is a longer lasting and maybe more objectless state, the
subsequent versions of psychiatric classification systems seem
to have struggled with this difference. Indeed, neither the Feigh-
ner criteria nor the Research Diagnostic Criteria (RDC) con-
tained an exclusion for bereavement or any other normal re-
actions, although they did require researchers to ascertain
during their interview with patients whether bereavement was
present.10,11 But DSM-III did contain bereavement as an ex-
clusion criterion, where it was the single exception to defin-
ing sad or depressed mood as a depressive symptom.1 How-
ever, DSM-III overlooked the fact that reactions to other types
of loss may have similar features to bereavement; for exam-
ple, reactions to separation, illness, or economic reversal. Re-
actions to these types of loss were hence not included, per-
haps because they could lack the relatively clear-cut nature
of bereavement.1 An intermediate solution has been proposed
to differentiate between bereavement and depression on top
of bereavement: is the sadness a proportionate response to
the real loss? This does not seem to solve the problem, how-
ever, since the discussion then just shifts to what is propor-
tionate or not. Moreover, it has also been argued that the be-
reavement issue then becomes an etiological one that has
no place in a theory-neutral manual, which DSM claims to aim
to be.12 Aside from disproportionate, other attempts at ex-
clusions-from-the-exclusion have been when no close tem-
poral relationship (eg, 3 months?) between bereavement and
depression was found and when the bereavement reaction
was too long lasting (2 months? 6 months?), but again, these
specifications are debatable and not very helpful. The addition-
al diagnostic criteria for adjustment disorder with depressed
mood are also not very helpful in qualitatively differentiating
the two mood states.
Ghaemi takes this discussion back to Freud, who compared
bereavement and depression (Mourning and Melancholia,
1917) and found that depression is phenomenologically sim-
ilar to mourning and that what happens in mourning could
provide the key to depression: sad at our loved ones death,
guilty about the anger toward him, we turn our anger inward,
repressing its outward expression, and become even sadder.
Freud hypothesized that pathological depression also involved
these kinds of feelings toward others, repressed by an anger
turned inward and directed at oneself.13(pp212-215) It becomes
clear that sadness here can be understood as being part of
a broader domain that also includes some degree of emo-
tional emptiness, shame, humiliation, or loss of self-esteem.14(p24)
In a mourning process, the world seems to be empty, while in
depression, the world and the self seem to be empty.
Ghaemi then brings this discussion to two opposite models
of depression, leaving the bereavement-depression debate
and focusing more on cognitive distortions as being at the
origin of depressed mood.13 It is therefore no longer the de-

pressed or sad mood that specifies depression, but the cog-
nitive distortions around it. The learned helplessness model
indeed postulates that individuals develop depression in adult-
hood based on experiences earlier in life in which they suf-
fered, but from which they had no means of escaping. They re-
tain these feelings even when escape routes are later offered:
they learned to be helpless, and they remain so.15 Hence, de-
pressed patients would suffer from depression because of
these cognitive distortions, present in response to sadness in
depressed patients, but absent in normal sadness. By con-
trast, the depressive realism model, based on experiments
with college students that involved guessing when they did
and did not have control over an outcome through their ac-
tions in a test situation, postulates that it is not the depressed
individuals, but rather the healthy nondepressed individuals
that have cognitive distortions, not seeing the world too much
as it is, with all its pain and mortality and with all our weakness
and cosmic insignificance as individuals.16 Depressed pa-
tients, hence, would suffer from depression because of their
lack of cognitive distortions. Depression might seem simple,
but it is definitely not.
From anhedonia to positive mood and well-being
The second core symptom in the DSM criteria for depres-
sion is lack of interest or pleasure. A more careful look at the
way this symptom has been treated in different classifications
reveals the ambivalence or the hesitations regarding the im-
portance to be given to this symptom.
The Feighner criteria had only one necessary condition for the
diagnosis of depression (dysphoric mood marked by symp-
toms such as being depressed, sad, despondent, or hope-
less), and loss of interest in usual activities was only one of
the minimum five additional symptoms needed to make the
diagnosis of depression (at the same level as loss of appetite,
sleep difficulty, loss of energy, agitation, guilt feelings, slow
thinking, and recurrent suicidal thoughts).12
The major changes in the RDC from the Feighner criteria were
stipulations that pervasive loss of interest or pleasure could
be substituted for dysphoric mood as a necessary condition
(reflecting a growing view that loss of capacity for pleasure
is central to depression).14(p95) In other words, anhedonia be-
came a symptom that was as important as depressed mood,
and theoretically a patient could suffer from major depression
with anhedonia and no depressed mood, or with depressed
mood and no anhedonia, or with both core symptoms. From
DSM-III onward, anhedonia (loss of interest and pleasure)
became a core symptom of depression, at the same level as
depressed mood.1-4
Anhedonia (lack of, loss of) is considered to be opposite
to the notions of positive mental health, (positive emotions,
positive affect, positive mood), and these notions continue
to elicit conflicting opinions. Health can be seen as merely the
From sadness to depressed mood and from anhedonia to positive mood Demyttenaere
E MOTI O N S AND DEPRESSION
absence of illness: illness is defined positively and health neg-
atively.13 The World Health Organization (WHO) defined health
as a state of complete physical, mental, and social well-be-
ing, and not merely the absence of disease or infirmity (WHO,
1948). As Ghaemi stated, other authors are opposed to this
view and reject the unattainable wholeness of body, mind,
and soul, while arguing that it is the presence of disease that
can be recognized, not the presence of health.17 In any case,
the question remains as to whether the opposite of anhedo-
nia is the absence of anhedonia or the presence of hedonia;
in other words, is lack of anhedonia enough to consider some-
body to be in positive mental health or should there be pos-
itive hedonia?
Another problem with symptoms of anhedonia is that they are
considered as a compound diagnostic criterion: loss of in-
terest (appetitive or motivational anhedonia, wanting) and
loss of pleasure (consummatory anhedonia, liking) in re-
sponse to stimuli that were previously perceived as rewarding.
This aggregation hence lacks precision, and from a psycho-
logical as well as neurobiological point of view, these two sub-
symptoms are not the same.18
One could even go one step further and try to read other de-
pressive symptoms as being decreased hedonic function: de-
pressed mood as decreased positive affect, fatigue as dimin-
ished motivation and/or decreased energy to pursue enjoyable
and goal-directed activities, and social withdrawal as reduced
enthusiasm for interactions with others or difficulty obtaining
enjoyment from these interactions. One could also differen-
tiate between experiencing positive emotions (pride, enthu-
siasm, determination, strength, inspiration, joy, enjoyment, sur-
prise, pleasure, excitement, vigor, etc) and the anticipation of
responding with positive emotions to pleasurable situations
(I would enjoy seeing other peoples smiling faces, I would en-
joy a warm bath or refreshing shower, I would find pleasure in
the scent of flowers or the smell of a fresh sea breeze or fresh-
ly baked bread, someone complimenting me would have a
great effect on me, someone I am very attracted to asking me
out for coffee would have a great effect on me, etc).19-21 The
dysregulation of positive affect in depression could even be fur-
ther differentiated between an elevated threshold for activat-
ing positive affect, a less intense response once positive affect
is activated, difficulty sustaining a positive affect response, fail-
ure to activate positive affect in appropriate contexts, or insuf-
ficient devotion of cognitive resources to initiating, sustaining,
or enhancing a typical internal positive affect response.
Assessment of treatment effects on sadness and
depressed mood, on anhedonia, positive mood,
and well-being
The assessment of change during antidepressant treatment
is usually carried out with an observer rating scale: the Hamil-
ton Depression Rating Scale (HAM-D) or the Montgomery-
Asberg Depression Rating Scale (MADRS).22,23 The two core
MEDICOGRAPHIA, Vol 35, No. 3, 2013 289
E MOT I O N S AND DEPRESSION
symptoms of the DSM diagnostic criteria are included in the
rating scales to a different degree, but in any case lose their
privileged position. Sad or depressed mood is well repre-
sented in both scales, but anhedonia has a more marginal
position in both scales.
The 17-item HAM-D also gives more attention to negative
affect items than to anhedonia: depressed mood (sadness,
hopeless, helpless, worthlessness; hence, not only referring to
affect, but also to cognitions), psychological anxiety (subjec-
tive tension and irritability, worrying), and somatic anxiety.
Again, only one item is more or less referring to anhedonia:
work and activities (thoughts and feelings of incapacity; fa-
tigue or weakness; loss of interest in activities, hobbies, or
work; decrease in actual time spent in activities or decrease
in productivity; stopping workinghence, not only referring to
anhedonia, but also to functioning).22
The 10-item MADRS has three negative affect items: appar-
ent sadness (representing despondency, gloom, and despair
[more than just ordinary transient low spirits]), reported sad-
ness (representing depressed mood, low spirits, desponden-
cy, or feelings of being beyond help without hope), and inner
tension (representing feelings of ill-defined discomfort, edgi-
ness, inner turmoil mounting to either panic, dread, or an-
guish). Only one item refers to anhedonia, although in the high-
er scores, there is a reference to the complete inability to feel
positive as well as negative emotion: inability to feel (repre-
senting the subjective experience of reduced interest in the
surroundings or in activities that normally give pleasure, up to
the experience of being emotionally paralyzed, unable to feel
anger, grief, or pleasure).23
References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 3rd ed, rev. Washington, DC: Author; 1987.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Dis-
orders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
5. World Health Organization. Mental disorders: Glossary and Guide to the Clas-
sification in Accordance with the Ninth Revision of the International Classifi-
cation of Diseases. Geneva, Switzerland: World Health Organization; 1978.
6. World Health Organization. The ICD-10 Classification of Mental and Behaviou-
ral Disorders. Geneva, Switzerland: World Health Organization; 1992.
7. Berrios GE. The History of Mental Symptoms. Descriptive Psychopathology
Since the Nineteenth Century. Cambridge, UK: Cambridge University Press;1996.
8. Izard CE. The Psychology of Emotions. New York and London: Plenum Press;
1991.
9. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous
episodes in the etiology of major depression in women: an evaluation of the kin-
dling hypothesis. Am J Psychiatry. 2000;157(8):1243-1251.
10. Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R. Diagnos-
tic criteria for use in psychiatric research. Arch Gen Psychiatry. 1972;26:57-63.
11. Spitzer RL, Endicott J, Robins E. Clinical criteria for psychiatric diagnosis and
DSM-III. Am J Psychiatry. 1975;132:1187-1192.
12. Woodruff RA, Goodwin DW, Guze SB. Psychiatric Diagnosis. New York, NY: Uni-
versity Press; 1974.
13. Ghaemi SN. The Concepts of Psychiatry. A Pluralistic Approach to the Mind and
Mental Illness. Baltimore and London: The Johns Hopkins University Press; 2003.
290 MEDICOGRAPHIA, Vol 35, No. 3, 2013 From sadness to depressed mood and from anhedonia to positive mood Demyttenaere
The rather marginal place of anhedonia is hence somewhat
in contrast with the DSM criteria. What is more worrying, how-
ever, is that this is in sharp contrast with what patients them-
selves expect as an outcome from treatment when suffering
from depression. Zimmerman showed that from a patient per-
spective, the rank order of the most important expectations
from antidepressant treatment are first, presence of positive
mental health (optimism, vigor, self-confidence); second, feel-
ing like your usual, normal self; third, return to usual level of
functioning at work, home, or school; fourth, feeling in emo-
tional control; fifth, participating in and enjoying relationships
with family and friends; and only sixth, absence of symptoms
of depression (negative affect). This indeed suggests that pa-
tients put a much larger emphasis on positive affect in their ex-
pectations.24 The question indeed is whether cure from depres-
sion results from a decrease in (negatively defined) anhedonia
or from an increase in (positively defined) interest or pleasure?
Many clinicians take it for granted that a decrease in negative
affect will automatically result in an increase in positive affect,
but research shows that the relation between negative and
positive affect is more complicated: correlation coefficients be-
tween both are reported to be only about 0.3021.
In conclusion, the difference between (normal) sadness and
depression, as well as the difference between anhedonia and
positive mood or well-being, has a history of reflection, debate,
and hesitation, not only in terms of the classification systems,
but also in the assessment of outcome in depression. A more
careful differentiation between (normal) sadness and depres-
sion could probably enhance diagnostic accuracy, and a more
careful taking into account of positive affect would probably
be beneficial to the depressed patient. I
14. Horwitz VA, Wakefield JC. The Loss of Sadness: How Psychiatry Transformed
Normal Sorrow Into Depressive Disorder. New York, NY: Oxford University Press;
2007.
15. Huesmann, LR. Learned Helplessness as a Model of Depression. Washington,
DC: American Psychological Association; 1978.
16. Alloy LB and Abramson LY. Depressive realism: four theoretical pespectives. In:
Alloy LB ed. Cognitive Processes in Depression. New York, NY: Guilford Press;
1988:223-265.
17. Lewis A. The State of Psychiatry: Essays and Addresses. New York, NY: Sci-
ence House; 1967.
18. McCabe C, Mishor Z, Cowen PJ, Harmer CJ. Diminished neural processing
of aversive and rewarding stimuli during selective serotonin reuptake inhibitor
treatment. Biol Psychiatry. 2010;67:439-445.
19. Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves O, Trigwell P. A scale
for the assessment of hedonic tone: the Snaith-Hamilton Pleasure Scale. Br J
Psychiatry. 1995;167:99-103.
20. Bachorowski JA, Braaten EB. Emotional intensity: measurement and theoreti-
cal implications. Pers Individ Dif. 1994;17(2):191-199.
21. Watson D, Clark LA, Tellegen A. Development and validation of brief measures
of positive and negative affect: the PANAS Scales. J Pers Soc Psychol. 1988;54
(6):1063-1070.
22. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;
23:56-62.
23. Montgomery SA and Asberg M. A new depression scale designed to be sensi-
tive to change. Br J Psychiatry. 1979;134:382-389.
24. Zimmerman M, McGlinchey JB, Posternak MA, Friedman M, Attiullah N, Boeres-
cu D. How should remission from depression be defined? The depressed pa-
tients perspective. Am J Psychiatry. 2006;163(1):148-150.
 E MOTI O N S AND DEPRESSION

Keywords: anhedonia; depressed mood; DSM; Feighner criteria; HAM-D; ICD; MADRS; positive mood; Research Diag-
nostic Criteria; sadness

DE LA TRISTESSE L HUMEUR DPRESSIVE ET DE LANHDONIE

L HUMEUR POSITIVE ET AU BIEN - TRE
Lhumeur dpressive et lanhdonie, deux symptmes cls de la dpression majeure telle quelle est dfinie dans le
Diagnostic and Statistical Manual of Mental Disorders (DSM), sont plus complexes quon ne le pense gnralement.
Dans la pratique quotidienne, il est cliniquement pertinent de faire la diffrence entre lhumeur dpressive et la tris-
tesse, et entre lhumeur dpressive et le deuil. La premire est davantage un tat dme ou un tat affectif habituel-
lement indpendant dune perte, la seconde une motion plutt lie une perte. La ralit clinique montre cepen-
dant que les patients, surtout lors du premier pisode dpressif (moins lors dune rcidive), rapportent volontiers des
vnements de vie stressants souvent lis une perte. Lanhdonie, manque dintrt ou de plaisir, est un critre
compos puisque la perte dintrt (anhdonie de motivation ou dapptence) et la perte de plaisir (anhdonie de
consommation) sont des phnomnes diffrents. Une autre question clinique pertinente est de savoir si loppos de
lanhdonie est labsence danhdonie ou bien une humeur positive et un bien-tre. Les outils les plus frquemment
utiliss pour valuer un changement au cours dun traitement antidpresseur se concentrent davantage sur lhumeur
dpressive que sur lanhdonie. Ceci est inquitant car trs loign des attentes des patients en termes de traite-
ment. Des tudes ont en effet montr que le critre le plus important pour les patients tait la restauration dune sant
mentale positive (optimisme, entrain, confiance en soi). Pour conclure, le diagnostic de la dpression pourrait tre
plus fiable si la diffrence entre tristesse (normale) et humeur dpressive tait plus rigoureusement tablie, et le pa-
tient dpressif bnficierait dune meilleure prise en compte dune humeur positive.

From sadness to depressed mood and from anhedonia to positive mood Demyttenaere MEDICOGRAPHIA, Vol 35, No. 3, 2013 291

For many authors, anhedonia
is considered a particularly diffi-
cult symptom to treat, as accruing
evidence suggests that current
first-line pharmacotherapies (eg,
selective serotonin reuptake inhib-
itors) do not adequately address
motivational and reward-process-
ing deficits in depression. Indeed,
their ability to improve diminished
positive affect by relieving symp-
toms of low energy, decreased
motivation, and anhedonia has
been questioned.
Massimo DI GIANNANTONIO, MD
Dipartimento di Neuroscienze
ed Imaging
Universit G. DAnnunzio
Chieti, ITALY
Address for correspondence:
Dipartimento di Neuroscienze ed
Imaging, Universit G. DAnnunzio,
Via dei Vestini, 31, 66013 Chieti, Italy
(e-mail: digiannantonio@unich.it)
www.medicographia.com
292 MEDICOGRAPHIA, Vol 35, No. 3, 2013
E MOT I O NS AND DEPRESSION
Pleasure and depression:
anhedonia as a core feature
by M. Di Giannantonio, Italy
A
nhedonia is a condition in which the capacity to experience pleasure
is totally or partially lost. Although anhedonia is a feature of major de-
pressive disorder according to the diagnostic criteria for major depres-
sion in the fourth edition of the Diagnostic and Statistical Manual of Mental
Disorders, to date it has received relatively little attention in terms of clinical
research. In the past, however, anhedonia has played an important role in the-
ories of psychopathology. In this paper, we review anhedonia by starting with
the different historical conceptualizations of pleasure, which have both prac-
tical and theoretical implications for the analysis of anhedonia. Anhedonia can
refer both to a state symptom in various psychiatric disorders and a person-
ality trait. The main methods utilized to investigate and assess anhedonia (or
hedonic capacity) are presented. The neural system underlying reward is be-
coming increasingly well defined in humans, and there are multiple constructs
embedded within the concept of pleasure. We review the neurobiology of an-
hedonia that reflects the deficits in hedonic capacity. Currently, there is no
definitive specific pharmacological approach to the treatment of anhedonia
in depression. Preliminary findings have described the efficacy of agomela-
tine in the treatment of anhedonia, and the effect of agomelatine on anhedo-
nia may be a novel property among antidepressant agents, warranting further
investigation. The efficacy of agomelatine on this dimension may hold partic-
ular importance for the treatment of patients with major depression.
Medicographia. 2013;35:292-298 (see French abstract on page 298)
he word anhedonia was coined by the French psychologist Thodule-Ar-
T mand Ribot in 1896,1 and its meaning stems etymologically from the Greek
- (an-; without) + (hedone; pleasure). Ribot defined anhedonia as
the inability to experience pleasure. Pleasure may be considered a specific sensa-
tion or a general quality of any state of consciousness. In the latter situation, emo-
tions can be measured against a yardstick of pleasure or pain such that one or
the other of these opposites gives the basic feeling tone to each emotion.2 Pleas-
ure and pain are also believed to be essential forces for human motivation (ie, hu-
man beings seek one and avoid the other), and hence anhedonia might be expect-
ed to be accompanied by a reduction in the general energy of a persons behavior.
Ribots point of view was that pleasure was not a constitutive element of the var-
ious feelings, but rather a complex state derived from the satisfaction of certain ten-
dencies.1 Obviously, different conceptualizations of pleasure have practical and the-
oretical implications for the analysis of anhedonia.
Pleasure and depression: anhedonia as a core feature Di Giannantonio
 E MOTI O N S AND DEPRESSION

Anhedonia played an important role in theories relating to

psychopathology at the beginning of the 20th century.3 For N Anhedonia by type:
Kraepelin, loss of pleasure and interest and the annihilation - Generalized anhedonia
of emotional activity were aspects of his wider concept of in- - Social anhedonia
difference.4 He spoke about anhedonia as a core symptom - Physical anhedonia

N Anhedonia by psychiatric disorder:

of a state of individual suffering that was a part of dementia
praecox. Kraepelin described his patients as not feeling any
- Psychotic anhedonia
real joy in life; according to him, the characteristic indifference
- Depressive anhedonia
of patients toward social interactions that would previously
- Anhedonia in eating disorders
elicit emotion, the extinction of affection for family and friends,
- Anhedonia in alcohol and substance abuse
and the loss of satisfaction in their work and vocation and in
- Anhedonia in Parkinson disease
recreation and pleasure were rather often the first symptoms
to manifest, marking the onset of the disease. Bleuler, not- Table I. Classification of various types of anhedonia.
ing the indifference that some patients exhibited toward their
friends, acquaintances, and colleagues, and toward life itself, The term anhedonia can refer both to a state symptom in
defined anhedonia as a basic feature of their disease, "an ex- various psychiatric disorders and a personality trait.16 For ex-
ternal signal of their pathological condition.5 What emerges ample, anhedonia is one of the negative symptoms of schizo-
when reading the works of Kraepelin and Bleuler is that they phrenia. There are, however, important differences between
fundamentally interpreted the loss of the pleasure experience the anhedonic symptoms in mood disorders and those in
as only one facet of the deterioration of the patients emo- schizophrenia as regards time course and degree of insight.
tional life. After the turn of the century, however, psychiatric Anhedonia has also been linked to anxiety and adjustment
interest in anhedonia faded, and Jaspers in his Allgemeine disorders,17 suicidal ideation,18 successful suicide,19 and Par-
Psychopathologie does not mention it, considering loss of kinson disease.20 Moreover, in various disorders and dysfunc-
pleasure to be part of apathy.6 tional behaviors such as overeating and eating disorders in
general,21 alcohol and substance abuse,22 and impulse con-
As far back as the original Feighner criteria published in 1972, trol disorders,23 anhedonia is often considered to be a pro-
anhedonia has, however, been presumed to be a core fea- dromal state (Table I).
ture of major depressive disorder (MDD),7 and Kleins concept
in the 1970s of endogenomorphic depression revived inter-
SELECTED ABBREVIATIONS AND ACRONYMS
est in the notion of anhedonia.8 Kleins definition of anhedo-
nia was that of a sharp, unreactive, pervasive impairment of 5-HT2C serotonin 2C
the capacity to experience pleasure, or to respond affective- BDNF brain-derived neurotrophic factor
ly to the anticipation of pleasure. From the third edition of the BRMS Bech-Rafaelsen Melancholia Scale
Diagnostic and Statistical Manual of Mental Disorders (DSM) CGI Clinical Global Impression Scale
onward, anhedonia has been considered a core symptom of DA dopamine
major depression separate from depressed mood.9 Moreover, DSM Diagnostic and Statistical Manual of Mental Disorders
FCPS Fawcett-Clark Pleasure Scale
it is a necessary symptom for a diagnosis of depression with
HAM-A Hamilton Anxiety Scale
melancholic features. In 1992, anhedonia entered the lexicon
HAM-D Hamilton Depression Rating Scale
of the International Classification of Diseases. The DSM
MADRS Montgomery-Asberg Depression Rating Scale
(Fourth Edition, Text Revision; DSM-IV-TR) defines anhedo-
MDD major depressive disorder
nia as diminished interest or pleasure in response to stimuli
MRPES Mood-Related Pleasant Events Schedule
that were previously perceived as rewarding during a premor-
NAcc nucleus accumbens
bid state.10
OFC orbitofrontal cortex
PAORS Pleasurable Activity Observer Rating Scale
Recent reports estimate that approximately 37% of patients
PAS Physical Anhedonia Scale
with MDD experience clinically significant anhedonia.11 Com- PASRS Pleasurable Activity Self-Rating Scale
pared with MDD patients without anhedonia, MDD patients PES Pleasant Events Schedule
with anhedonia have been found to demonstrate greater so- RSS Reinforcement Survey Schedule
cial impairment, have higher scores on measures of depres- SANS Scale for the Assessment of Negative Symptoms
sion and hopelessness, be less neurotic, be younger, and be SAS Social Anhedonia Scale
more often female than male.12 There is also evidence to sug- SHAPS Snaith-Hamilton Pleasure Scale
gest a correlation between anhedonia and psychomotor re- SSRI selective serotonin reuptake inhibitor
tardation among adults with MDD.13 Different studies have TEPS Temporal Experience of Pleasure Scale
found that anhedonia can precede the onset of a depressive VAS visual analog scale
episode14 and is a common residual symptom after treatment.15

Pleasure and depression: anhedonia as a core feature Di Giannantonio MEDICOGRAPHIA, Vol 35, No. 3, 2013 293
E MOT I O N S AND DEPRESSION
Diagnosing anhedonia
The limited attention that anhedonia has received to date in
terms of clinical research could, in part, be the result of the
low availability of short, well-validated, and easy-to-use tools
for its assessment and investigation.24
There are two methods that are utilized the majority of the
time to investigate and assess anhedonia (or hedonic capac-
ity): laboratory-based measures and rating scales. The first
approach involves signal-detection methodology, physiologi-
cal measures, and subjective hedonic response to pleasant
stimuli. Besides these behavioral measures, anhedonia can
also be evaluated using hemodynamic and electrophysiolog-
ical measures. The second approach is primarily diagnostic
and involves the use of questionnaires. Anhedonia forms the
subject of a subsection of questions on certain popular rat-
ing instruments like the Bech-Rafaelsen Melancholia Scale
(BRMS), used in depression evaluation, and the Scale for the
Assessment of Negative Symptoms (SANS), used in schizo-
phrenia evaluation. The first attempts to assess anhedonia
alone go back to the end of the 1960s, with the Reinforcement
Survey Schedule (RSS) and the Pleasant Events Schedule
(PES). Since then, many researchers have attempted to op-
erationalize the concept, and several scales have been de-
veloped to assess anhedonia or hedonic capacity. Specific
scales in use for the measurement of anhedonia are: the Phys-
ical and Social Anhedonia Scales (PAS and SAS, respective-
ly), self-administered tests that consider anhedonia above all
as a trait; the Fawcett-Clark Pleasure Scale (FCPS), a 36-item
scale in which subjects have to imagine potentially rewarding
situations; the two scales developed by Brown and colleagues,
one self-administered (Pleasurable Activity Self-Rating Scale
[PASRS]) and the other administered by an observer (Plea-
surable Activity Observer Rating Scale [PAORS]); the Mood-
Related Pleasant Events Schedule (MRPES), derived from
the PES; and the Snaith-Hamilton Pleasure Scale (SHAPS).
Furthermore, it is worth mentioning the 10-cm visual analog
scale (VAS) for pleasure and the Temporal Experience of Pleas-
ure Scale (TEPS), which was developed to assess anticipato-
ry and consummatory pleasure.
Of these scales, the one that has been used most in the past
few years is SHAPS,25 a 14-item self-report questionnaire de-
signed to measure hedonic tone. SHAPS has shown ade-
quate overall psychometric properties in clinical and student
samples, and was found to be highly reliable in terms of in-
ternal consistency and test-retest stability. Its discriminant
validity has been supported by its lack of association with
items related to depressed mood and anxiety on the Mont-
gomery-Asberg Depression Rating Scale (MADRS).25 Further-
more, SHAPS has been found to correlate in a theoretically
meaningful way with other measures of affect and person-
ality. Patients with depression, psychosis, or substance de-
pendence scored significantly higher on SHAPS than healthy
controls, while patients with depression displayed the highest
294 MEDICOGRAPHIA, Vol 35, No. 3, 2013
SHAPS score. The items on SHAPS cover four domains of he-
donic experience: interest/pastimes, social interaction, sen-
sory experience, and food/drink. SHAPS instructs participants
to agree or disagree with statements of hedonic response in
pleasurable situations. Four responses are possible: strong-
ly disagree, disagree, agree, or strongly agree. If the subject
answers strongly agree or agree, the item is assigned a
score of zero, while for disagree or strongly disagree, the
score is 1. A total score can be derived by summing the scores
for the answers to each item, thereby producing a total score
ranging from 0 (absence of anhedonia) to 14 (complete an-
hedonia). Thus, higher SHAPS total scores indicate greater
anhedonia, and a score of 3 or more indicates a significant
reduction in hedonic capacity and seems to discriminate be-
tween healthy and clinically depressed patients. Participants
completing SHAPS are instructed to respond on the basis of
their ability to experience pleasure in the last few days.
Neurobiology of pleasure and anhedonia
The neural system underlying reward is quite well defined in
animals and humans: the euphoric response to dextroamphet-
amine, cocaine-induced euphoria, monetary reward, and even
pleasurable responses to music, pictures, and attractive faces
have all been associated with activity within the nucleus ac-
cumbens (NAcc), ventral caudate, and ventral putamen.26 More
specifically, release of dopamine (DA) within the ventral stria-
tum may be involved in the anticipation and generation of
motor responses associated with future rewards, the so-called
wanting.27 On the other hand, the main mediators of pleas-
urable hedonic experience (liking) appear to be the endoge-
nous opioids, particularly in the shell of the NAcc and the ven-
tral pallidum.28 The orbitofrontal cortex (OFC) and anterior
cingulate cortex also play important roles in the neural reward
system. The former is implicated in the subjective represen-
tation of incentive salience, hedonic impact, and hedonic ex-
perience; the latter is primarily involved in evaluating the costs
and benefits of a given set of options.29 Finally, other cerebral
structures such as the amygdala are also involved in the re-
ward system, as are neurotransmitters such as serotonin and
-aminobutyric acid (GABA). Serotonin, for example, has a rec-
ognized effect on the modulation of DA and opioid release:
serotonin reuptake inhibitors raise the threshold for brain
stimulation reward and reduce the firing rate of DA neurons
in the ventral tegmental area.30
L-3,4-dihydroxyphenylalanine (L-DOPA) alterations in the stria-
tum are present in depressed individuals with flat affect or
psychomotor slowing, but not in depressed individuals with-
out these symptoms.31 One study restricted to patients with
MDD and anhedonic symptoms reported decreased DA trans-
port binding in the striatum.32 Data supporting a role of DA in
MDD come from studies of DA turnover, in which it has been
observed that individuals with MDD have decreased cerebro-
spinal fluid levels of homovanillic acid, the primary metabolite
of DA.28 These studies suggest the presence of a reduced
Pleasure and depression: anhedonia as a core feature Di Giannantonio

basal dopaminergic tone in MDD. Additionally, pharmacolog-
ical interventions that block or deplete DA can induce or deep-
en depressive symptoms in currently depressed or remitted
individuals, further implicating DA dysfunction in MDD. More-
over, in animal models of depression, several lines of evidence
support the role of DA dysfunction.33 Studies investigating the
effects of a deficient endogenous opioid system in depression
and anhedonia have by contrast produced largely equivocal
findings,34 and to date, no studies have specifically evaluated
opioid systems in reward liking or other aspects of reward pro-
cessing in MDD patients. In MDD, both the OFC and the an-
terior cingulate cortex have shown a variety of alterations in
gross morphology, neuronal structure, function, connectivity,
and neurochemistry.28
AGOMELATINE
MT1 /MT2 5-HT2C
receptor agonist receptor antagonist
DA NA
MT1 MT2 D2R 2R
RESYNCHRONIZATION OF CIRCADIAN
RHYTHMS AT INTRACELLULAR LEVEL
Transcription factors: BDNF
Synaptogenesis and neuroplasticity
ENHANCED HEDONIC TONE
Figure 1. Putative agomelatine mechanism of action in relieving
anhedonia.
Abbreviations: 5-HT2C , serotonin 2C; 2 R, 2 -adrenergic receptor; BDNF,
brain-derived neurotrophic factor; DA, dopamine; D2 R, dopamine receptor 2;
MT1 and MT2 , melatonergic receptor subtypes; NA, norepinephrine.
The deficit in DA transmission could be associated with de-
creased availability of brain-derived neurotrophic factor (BDNF)
and increased glucocorticoid signaling.35 BDNF has been
shown in particular to regulate DA neurons in the ventral teg-
mental area, and alterations in BDNF concentrations can in-
fluence mesolimbic DA responses to reward and resiliency to
stress.36 Treatment with antidepressant medication increases
BDNF concentrations, stimulates neurogenesis, and reverses
the inhibitory effects of stress, particularly in the hippocam-
pus.37 In recent preclinical studies, the new-generation anti-
depressant agomelatine showed the ability to enhance BDNF
Pleasure and depression: anhedonia as a core feature Di Giannantonio
E MOTI O N S AND DEPRESSION
levels38 and modulate neuronal plasticity, both in the hippo-
campus and the prefrontal cortex.39 These effects seem to be
associated with antidepressant-like effects and an increase
in motor activity and exploratory behavior, hypothetically re-
versing a deficit in motivational drive and reward (Figure 1).39
Treating anhedonia in major depression
Currently, there is no definitive specific pharmacological ap-
proach to the treatment of anhedonia in depression. An im-
portant issue concerns whether patients with anhedonia have
a different pattern of symptoms to patients without anhedo-
nia. Such differential symptom expression could have impor-
tant implications regarding the etiology of MDD and its pre-
vention and treatment.
Despite it having been shown in the 1970s that the pres-
ence of anhedonia is predictive of antidepressant response,8
studies in the current literature often neglect to assess anhe-
donia in the evaluation of antidepressant response, and effi-
cacy data on this specific dimension are sparse. Boyer showed
a late effect of sertraline on anhedonia (over 21 to 56 days),
which occurred after its effects on depression and anxiety,40
while in a study by Tomarken, the catecholaminergic effects
of bupropion SR 300 tended to produce more robust effects
than placebo on anhedonia/positive affect, particularly during
a 6-week initial treatment phase.41
However, for many authors, anhedonia is considered a par-
ticularly difficult symptom to treat, as accruing evidence sug-
gests that current first-line pharmacotherapies (eg, selective
serotonin reuptake inhibitors [SSRIs]) do not adequately ad-
dress motivational and reward-processing deficits in depres-
sion.42 Indeed, their ability to improve diminished positive affect
by relieving symptoms of low energy, decreased motivation,
and anhedonia 6 has been questioned.43 A related issue is that
some patients associate their SSRI treatment with an expe-
rience of emotional blunting, whereby emotional responses to
both aversive and pleasurable experiences are diminished.42
Thus, increases in serotonin function produced by SSRIs could
produce a form of emotional constraint in which the salience
of both rewarding and aversive stimuli is lost.44 Considering
the widespread use of SSRIs, such an effect could have con-
siderable personal, clinical, and social implications, and the
presence of anhedonic symptoms is considered a predictor
of poor treatment response.45 Moreover, investigating the ef-
fect of SSRIs on emotional responses in depressed patients is
difficult, because loss of pleasure may persist even during
clinical remission.46 In addition, modest degrees of emotion-
al blunting might be difficult for individuals to subjectively de-
tect or report.
Agomelatine (S20098, N-[2-(7-methoxynaphth-1-yl)ethyl]acet-
amide) has a novel neurochemical mechanism that is unlike
that of other antidepressants. It is an MT1 and MT2 melaton-
ergic receptor agonist and a selective antagonist of the 5-HT2C
MEDICOGRAPHIA, Vol 35, No. 3, 2013 295
E MOT I O N S AND DEPRESSION

open-label 8-week study, included 30 male and

Outcome female outpatients aged 18 to 60 years old, with a
Symptoms measure Baseline Week 8 P value
DSM-IV diagnosis of MDD. The primary end points
Depressive symptoms HAM-D 26.53.7 12.26.3 0.001 were reduction in depressive and anxiety symp-
Anxiety symptoms HAM-A 22.44.8 11.25.4 0.005 toms, expressed by the scores on the Hamilton
Anhedonia SHAPS 4.46.2 2.16.1 0.001 Depression and Anxiety Rating Scales (HAM-D;
HAM-A). The secondary end points were related to
Sleep LSEQ 35.97.3 48.52.3 0.05 the reduction in the degree of anhedonia and in-
Quality of life QOL 2.10.8 4.70.6 0.05 somnia. In this open-label study, agomelatine was
shown to be a possible therapeutic option for pa-
Table II. Agomelatine efficacy in the various dimensions of depression. tients with MDD. In line with previous studies in
Abbreviations: HAM-A, Hamilton Anxiety Scale; HAM-D, Hamilton Depression Rating Scale;
LSEQ, Leeds Sleep Evaluation Questionnaire; QOL, quality of life; SHAPS, Snaith-Hamilton which agomelatine was associated with early clin-
Pleasure Scale. ical improvement, this study also provided evidence
After reference 51: Di Giannantonio et al. J Biol Regul Homeost Agents. 2011;25(1):109-114.
2011, BIOLIFE, s.a.s.
of an early response (first week of treatment) and
improvement in depression scores following an in-
receptors. The main hypothesis explaining the antidepressant crease in the agomelatine dose, with a good tolerability pro-
action of agomelatine is that it acts synergistically on both the file (Table II).51 Moreover, agomelatine was shown to be ef-
melatonergic and the 5-HT2C receptors. This synergy may re- ficacious in the treatment of anhedonia. A reduction of 1.6
synchronize circadian rhythms. Agomelatine causes the re- points from baseline was observed on SHAPS after the first
lease of DA specifically in the prefrontal cortex (no release in week of treatment (P<0.05), with the reduction increasing at
the NAcc or striatum) and norepinephrine in the prefrontal cor- different time points until the end of the trial, whereupon the
tex and hippocampus, without affecting extracellular levels level of significance was even greater (P<0.01).51
of serotonin.47,48 Evidence from preclinical and clinical studies
suggests that agomelatine has antidepressant properties, al- In the second study, the effects of agomelatine on anhedonia
leviates symptoms of anxiety associated with depression, and were compared with those of venlafaxine XR. In this open-la-
rapidly relieves symptoms compared with placebo.49 In addi- bel, 8-week parallel-group pilot study, patients with MDD were
tion, the tolerability and safety profile of agomelatine includes randomly started on either agomelatine at a dose of 25-50
a low propensity to cause sexual dysfunction, absence of dis- mg/day (n=30) or venlafaxine XR at a dose of 75-150 mg/
continuation symptoms upon withdrawal, and improvement day (n=30). Treatment outcomes in terms of improvement in
in daytime functioning and quality of sleep associated with anhedonia (SHAPS), depression, and anxiety scores (HAM-D;
depression.49 HAM-A) were assessed after 1 (T1), 2 (T2), and 8 (T3) weeks.
A significant reduction over time was observed in SHAPS
Given its novel neurochemical mechanism, the antidepres- scores in both the agomelatine (F=20.74; P<0.001) and the
sant activity of agomelatine may have different and specific venlafaxine XR (F=3.27; P<0.5) groups. However, there was
effects on the broad range of symptoms usually observed in a significant difference between groups in favor of agome-
a depressive syndrome. The specific effect of circadian rhythm latine at T1 (P<0.05), T2 (P<0.01), and T3 (P<0.01), with the
resynchronization may contribute to the regulation of hedonic number needed to treat being 8 subjects in favor of agome-
capacity.50 In view of the latter, a line of studies was inaugu- latine in terms of the presence or absence of an anhedonic
rated to test the possible use of agomelatine in the treatment state (SHAPS 3) at study end (Figure 2).52 A significant re-
of anhedonia. Two studies have described the efficacy of duction in HAM-D and HAM-A scores was observed for both
agomelatine in the treatment of anhedonia.51,52 The first, an groups (P<0.05), with no difference between groups, but only

Figure 2. SHAPS HAM-D HAM-A

Agomelatine versus 0 0 0
venlafaxine in treat-
Mean change

Mean change

Mean change

ing anhedonia. 1 5 5
Abbreviations: HAM-A,
Hamilton Anxiety Scale; 2 10 10
HAM-D, Hamilton De-
pression Rating Scale;
SHAPS, Snaith-Hamilton 3 15 15
Pleasure Scale. *
After reference 52: 4 20 20
Martinotti et al. J Clin
Psychopharmacol.
2012;32(4):487-491. Agomelatine Venlafaxine Mean change from baseline to last assessment (T3)
2012, Lippincott *P<0.01 (significant difference between groups)
Williams & Wilkins.

296 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Pleasure and depression: anhedonia as a core feature Di Giannantonio

patients who were treated with agomelatine showed a statis-
tically significant improvement in scores on the Clinical Glob-
al Impression (CGI) scale (t=2.94; P<0.05). Improvements in
anhedonia scores were detected as early as 1 week after
treatment initiation with agomelatine, which was a beneficial
characteristic, especially given the usually relatively slow on-
set of antidepressant efficacy with current agents. In both of
these studies, use of agomelatine did not determine the on-
set of hypomanic or manic symptoms.52
The results of these two studies need to be interpreted with
caution due to some limitations. First, the small sample size
does not allow for firm conclusions to be drawn. Second, the
absence of a placebo group and the open design are weak-
nesses that temper the interpretation of the results. The re-
sults regarding agomelatine and anhedonia are difficult to
compare with those from other clinical studies, as anhedonia
is a dimension that has been poorly characterized in all the
major clinical trials involving treatment of MDD.
Conclusion
Different studies have found that anhedonia can precede the
onset of a depressive episode,14 influence its severity, and
predict poor outcome 12 months later.45 Moreover, anhedonia
is considered to be a common residual symptom after treat-
ment15 and is associated with dysfunction in the brain reward
system.26
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50. Monteleone P, Martiadis V, Maj M. Circadian rhythms and treatment implications
in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(7):1569-
1574.
51. Di Giannantonio M, Di Iorio G, Guglielmo R, et al. Major depressive disorder, an-
hedonia and agomelatine: an open-label study. J Biol Regul Homeost Agents.
2011;25(1):109-114.
52. Martinotti G, Sepede G, Gambi F, et al. Agomelatine versus venlafaxine XR in
the treatment of anhedonia in major depressive disorder: a pilot study. J Clin
Psychopharmacol. 2012;32(4):487-491.

Keywords: agomelatine; anhedonia; depression; pleasure; SHAPS

PLAISIR ET DPRESSION : LANHDONIE, UN SYMPTME CL

Lanhdonie est un tat dans lequel laptitude prouver du plaisir est totalement ou partiellement perdue. Bien
qutant caractristique de lpisode dpressif majeur selon le critre diagnostique de la dpression majeure dans
la quatrime dition du Diagnostic and Statistical Manual of Mental Disorders, la recherche clinique sy est, ce jour,
relativement peu intresse. Jadis cependant, lanhdonie a jou un rle important dans les thories de la psycho-
pathologie. Dans cet article, nous tudions lanhdonie en commenant par les diffrentes thories historiques du
plaisir, dont les implications sont la fois pratiques et thoriques. Lanhdonie peut se rfrer un symptme parti-
culier dans plusieurs troubles psychiatriques ou un trait de personnalit. Nous prsentons les principales mthodes
utilises pour rechercher et valuer lanhdonie (ou capacit hdonique). Le systme neural de la rcompense est
de mieux en mieux compris chez les humains, et de nombreuses ides sont ancres dans le concept de plaisir. Nous
analysons la neurobiologie de lanhdonie qui reflte le dficit de la capacit hdonique. Il nexiste pas actuellement
dapproche pharmacologique spcifique du traitement de lanhdonie dans la dpression. Lefficacit de lagom-
latine dans le traitement de lanhdonie a t prouve par des rsultats prliminaires, et cet effet pourrait tre une
nouvelle proprit des antidpresseurs, justifiant des recherches plus pousses. Lefficacit de lagomlatine sur lan-
hdonie peut revtir une importance particulire pour le traitement des patients atteints de dpression majeure.

298 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Pleasure and depression: anhedonia as a core feature Di Giannantonio

One useful approach to the
psychobiology of anxious depres-
sion may be to pay greater atten-
tion to the effects of anxiety on key
psychological processes in de-
pression. There has been increased
attention recently, for example, to
disturbances in emotion regula-
tion in several psychiatric disor-
ders, including mood and anxiety
disorders. Anxious depression may
be associated with particular kinds
of cognitive distortion and with in-
creased avoidance strategies.
I
Dan J. STEIN, FRCPC, PhD
Dept of Psychiatry & Mental Health
University of Cape Town
SOUTH AFRICA
Address for correspondence:
Dan J. Stein, UCT Dept of Psychiatry,
Groote Schuur Hospital J-2, Anzio Rd,
Observatory 7925, Cape Town,
South Africa
(e-mail: Dan.Stein@uct.ac.za)
www.medicographia.com
Anxiety in depression: clinical and conceptual considerations Stein
E MOTI O N S AND DEPRESSION
Anxiety symptoms in
depression: clinical and
conceptual considerations
by D. J. Stein, South Africa
t is increasingly accepted that anxiety in depression is associated with in-
creased morbidity, that anxiety disorders typically precede the develop-
ment of major depression, and that patients with major depression and
anxiety respond to efficacious treatments and so deserve early and robust
intervention. However, the occurrence of anxiety in depression raises many
complex questions: Should the co-occurrence of depression and anxiety be
conceptualized as a comorbidity or as a separate diagnostic construct? Does
anxiety in depression have particular psychobiological correlates and deserve
distinctive treatments? What are the implications of co-occurring anxiety for
understanding the nature of depression? This review emphasizes that both
categorical and dimensional approaches to co-occurring depression and anx-
iety are needed, that anxiety in depression is a heterogeneous construct, and
that variants of anxious depression, such as stressor-related depression and
agitated depression, likely require quite different approaches.
Medicographia. 2013;35:299-303 (see French abstract on page 303)
he topic of anxiety in depression is, on the one hand, a reasonably straight-
T forward one. The literature emphasizes a number of clinically important les-
sons: anxiety is a potentially important symptom of major depression that is
associated with increased morbidity; anxiety disorders typically precede the devel-
opment of major depression; and patients with major depression and anxiety respond
to efficacious treatments and, therefore, deserve early and robust intervention.
On the other hand, the occurrence of anxiety in depression raises many complex
questions: Should the co-occurrence of depression and anxiety be conceptualized
as a comorbidity or as a separate diagnostic construct? Does anxiety in depres-
sion have particular psychobiological correlates and, therefore, deserve distinc-
tive treatments? Is anxiety in depression merely a clinical observation, or can this
co-occurrence shed light on some deeper questions about our understanding of
the nature and experience of depression?
Here, I will briefly review some of the clinically important lessons that the literature has
provided on anxiety in major depression, but also address some of the more com-
plex conceptual issues in this area in an attempt to outline some clinically relevant
approaches to these debates. I will briefly address in turn the phenomenology, psy-
chobiology, and management of anxiety in major depression.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 299
E MOT I O N S AND DEPRESSION

Phenomenology of depression-anxiety
comorbidity Depression Overlap Anxiety
It has long been recognized that anxiety is a central clinical Depressed mood, Irritability, apprehension/ Hypervigilance,
feature of major depression.1 Anxiety is a prevalent symptom anhedonia panic startle
in depression, and patients with anxious depression have response
greater morbidity, as assessed by a number of indices, includ- Ruminations Negative rumination/ Worried about
ing symptom severity, illness chronicity, functional impairment, about past/ worry future
and suicide risk.2,3 Indeed, participants in the revision of the guilt/dying
Diagnostic and Statistical Manual of Mental Disorders (Fifth Loss of interest Social withdrawal, Agoraphobia
Edition) (DSM-5) have proposed that severity of anxiety symp- distress, dysfunction
toms should be specified in patients with major depression.3 Retardation Agitation Muscle tension
Conversely, patients with anxiety disorders often have signif-
Hypersomnia Insomnia
icant levels of depressive symptoms.
Weight gain/loss Gastrointestinal
complaints
It is important to also consider the overlap between anxiety
disorders and major depression. Several symptoms of gen- Chronic pain,
eralized anxiety disorder (GAD), eg, anxiety and insomnia, are decreased concen-
tration, fatigue
core features both of major depression and GAD (Table I), and
psychological models indicate that major depression and GAD
Table I. Overlap in symptoms of depression and anxiety.
share negative affect.4 Panic attacks are found in both de- After reference 2: Stein and Hollander. Anxiety Disorders Comorbid with De-
pression and several anxiety disorders. Furthermore, many pression: Social Anxiety Disorder, Post-Traumatic Stress Disorder, Generalized
Anxiety Disorder and Obsessive-Compulsive Disorder. London: Martin Dunitz;
individuals with depression have obsessive-compulsive and 2002. 2002, Martin Dunitz Ltd, a member of the Taylor & Francis group.
related disorder symptomatology, and many individuals either
with depression or trauma and stress-related disorders have On the other hand, it is also important to recognize that anx-
been exposed to stressors. iety disorders are the most prevalent psychiatric disorders,
and that they are underdiagnosed and undertreated. Thus, a
Given such overlaps, an immediate nosological question is contrary view is that epidemiological data on mixed anxiety-
whether co-occurrence of depression and anxiety represents depressive disorder have significant methodological limita-
an artifact of the diagnostic system? 5,6 Indeed, it has been sug- tions, and that in patients with both depressive and anxiety
gested that mixed anxiety-depressive disorder, characterized symptoms, it is crucial to determine if a particular anxiety dis-
by subthreshold depressive and anxiety symptoms, is highly order is currently present or will develop over time.11 There are
prevalent and disabling, and therefore deserves recognition important differences in the management of different anxiety
as an independent diagnostic entity.7,8 This disorder is listed disorders, so these need carefully tailored assessment and
in the appendix of the DSM, Fourth Edition (DSM-IV), and is intervention.
widely employed when International Classification of Diseases,
Tenth Revision (ICD-10) diagnoses are used. A potential compromise here is to recognize the importance
of both categorical and dimensional approaches to psychi-
Such a view may be supported by many who work in primary atric disorders in general, and to depression and anxiety in par-
care settings. Mixed presentations of depressive and anxiety ticular.12,13 Separate diagnostic categories for different mood
symptoms are common in these settings, and practitioners and anxiety disorders have been useful in ensuring efficient
who have relatively little time to undertake detailed assess- clinical communication, and also in preliminary neurobiologi-
ments may argue that an encompassing entity (ie, mixed anx- cal research. At the same time, the use of dimensional assess-
iety-depressive disorder) facilitates efficient diagnosis and treat- ments of anxiety in major depression may be useful in empha-
ment planning.9 Certainly, a number of antidepressants are sizing the spectrum of anxiety symptoms seen in depression,
currently considered first-line agents for the treatment both of and in encouraging researchers and clinicians to evaluate this
major depression and anxiety disorders.10 set of symptoms more rigorously.

Psychobiology of depression-anxiety comorbidity

SELECTED ABBREVIATIONS AND ACRONYMS
It has long been recognized that anxiety in major depression
DSM Diagnostic and Statistical Manual of Mental Disorders is associated with significantly worse treatment outcome.14,15
GAD generalized anxiety disorder The recent STAR*D trial (Sequenced Treatment Alternatives to
ICD-10 International Classification of Diseases, Tenth Revision Relieve Depression) similarly found that anxious depression
SSRI selective serotonin reuptake inhibitor is associated with lower response and remission rates, as well
STAR*D Sequenced Treatment Alternatives to Relieve Depression as slower response, than nonanxious depression, with a poor-
er response not only to first-line antidepressant treatment, but

300 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Anxiety in depression: clinical and conceptual considerations Stein

also after second-line switching and augmentation pharma-
cotherapy or psychotherapy.16,17 Furthermore, patients with
anxious depression had increased side-effect frequency, in-
tensity, and burden.
It is also important to emphasize that anxiety disorders typi-
cally precede the onset of major depression. It is notable that
an animal literature has emphasized that after maternal sep-
aration, there is first a separation anxiety response, and sub-
sequently a despair response.18 Along these lines, an early
neurobiological explanation suggested initial involvement of
the GABAergic system in anxiety, with subsequent dysregula-
tion of monoamine neurotransmitters in major depression.19
Ultimately, however, the relevant mechanisms which medi-
ate the temporal sequence from anxiety to depression remain
poorly delineated.
Indeed, it is far from clear that anxious depression is char-
acterized by specific neurocircuitry alterations, or by a partic-
ular neurochemical or neurogenetic signature. The STAR*D
authors conceded that as anxious depression was associ-
ated with greater severity of depression, lower socioeconom-
ic status, and higher physical illness burden, anxious depres-
sion may not represent a different depression subtype.16 While
participants at a recent DSM-5 conference agreed that de-
pression and GAD are different disorders, there was also a
view that the relevant neurobiological data in this area are
hardly conclusive.20
Clearly, much further psychobiological research is needed.
Still, even with future advances, biomarkers will not necessar-
ily be able to carve nature at her joints.21 Nesse and colleagues
have emphasized, for example, that there may be many routes
by which genetic variations could influence vulnerability to
mood and anxiety disorders, including preference for alcohol
or for very exciting mates, a tendency to persist in pursuing a
life goal even when there is no chance of success, or anxiety
that impedes making a needed major life change.22 Thus, we
should not be looking only for a few genes specific for, say,
co-occurrence of major depression and anxiety, but rather
for many genes that influence risk via multiple overlapping
pathways.
One useful approach to the psychobiology of anxious depres-
sion may be to pay greater attention to the effects of anxiety
on key psychological processes in depression. There has been
increased attention recently, for example, to disturbances in
emotion regulation in several psychiatric disorders, including
mood and anxiety disorders.23-25 Anxious depression may be
associated with particular kinds of cognitive distortion and
with increased avoidance strategies. Such processes may
have certain psychobiological correlates; for example, corti-
colimbic circuitry mediates reappraisal and suppression.23
Furthermore, such processes might then be targeted during
treatment.
Anxiety in depression: clinical and conceptual considerations Stein
E MOTI O N S AND DEPRESSION
Along complementary lines, Nesse has argued that there is
a need to consider subtypes of disorders based not only on
neurocircuitry and genotype findings, but on a deeper un-
derstanding of the functions of the underlying motivational
systems.26 The profound overlap between anxiety and de-
pression may arise because they are responses to related
kinds of danger; a threat that creates anxiety may lead to an
actual loss that precipitates depression.27 This kind of evo-
lutionary explanation is important in supplementing proximate
explanations (focused on underlying psychobiological mech-
anisms) with distal explanations (focused on evolved adap-
tive responses).
Management of depression-anxiety comorbidity
It seems clear that patients with major depression and anxi-
ety symptoms deserve early and robust intervention. Multiple
studies with multiple antidepressants have indicated that these
agents are efficacious and well tolerated in the treatment of
patients with major depression with co-occurring anxiety symp-
toms.28 Given that anxiety symptoms in depression are an im-
portant prognostic indicator, patients with such symptoms
need to be evaluated carefully and treated appropriately.
While it is very difficult to demonstrate conclusively that early
treatment of anxiety disorders is effective for decreasing the
development of subsequent comorbid depression, there are
some data which point in this direction.29 It would seem en-
tirely reasonable to encourage the early detection and man-
agement of anxiety disorders in order to help prevent the sub-
sequent onset of comorbid major depression, substance use
disorders, and other negative outcomes.
An immediate question, however, is whether co-occurrence
of depression and anxiety deserves a unique treatment? The
presence of unique biological markers would certainly en-
courage that interventions address the relevant targets. The
lack of such markers is consistent with the opinion that no
specific pharmacotherapeutic intervention has yet proven dis-
tinctively superior in the treatment of anxious depression.28,30
That said, it is noteworthy that there may be a modest ad-
vantage for selective serotonin reuptake inhibitors (SSRIs)
over bupropion,31 and of agomelatine over SSRIs, in the treat-
ment of anxious depression.32
Work on the management of anxious depression raises the
key question of why anxiety is so often overlooked in the man-
agement of depression. A key clinical lesson may emerge from
a deeper consideration of the experience of depression; we
have a tendency to think of depression as a down, and to
use language consistent with this metaphor (eg, low mood,
low energy). This in turn may make it hard to recognize such
conditions as bipolar disorder (with its phases of mania) and
more agitated depressions (where anxiety plays a key role).
This failure to recognize the full spectrum of the experience
of depression can have significant negative consequences; in
MEDICOGRAPHIA, Vol 35, No. 3, 2013 301
E MOT I O N S AND DEPRESSION
particular, clinicians may underestimate the severity of anxious
depression and its clear link with negative outcomes such as
suicide.
Perhaps a second clinical lesson emerges from literature
which emphasizes the heterogeneity of anxious depression,
and the importance of understanding the context of the rel-
evant symptoms. Ghaemi, for example, has emphasized the
neglect of the old concept of neurotic depression, a form
of depression in which there is increased anxiety, often in re-
sponse to life stressors.33 Similarly, Nesse has emphasized
that in such cases a clear understanding of the adaptive val-
ue of the relevant emotional responses may be useful.27 In-
deed, from a DSM-5 perspective, some forms of anxious de-
pression are perhaps best conceptualized using constructs
from the chapter on trauma and stress-related disorders, such
as adjustment disorder with mixed anxiety and depression
mood,34 rather than as major depression.
On the other hand, the psychobiology of neurotic depres-
sion may well differ from other forms of depression with anx-
iety, such as depression with panic attacks or agitated de-
pression. Some psychopathology is best understood using a
References
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illness. J Clin Psychiatry. 1983;44(8 Pt 2):8-11.
2. Stein JD, Hollander E. Anxiety Disorders Comorbid with Depression: Social
Anxiety Disorder, Post-Traumatic Stress Disorder, Generalized Anxiety Disorder
and Obsessive-Compulsive Disorder. London, UK: Martin Dunitz; 2002.
3. Goldberg D, Fawcett J. The importance of anxiety in both major depression and
bipolar disorder. Depress Anxiety. 2012;29(6):471-478.
4. Mineka S, Watson D, Clark AL. Comorbidity of anxiety and unipolar mood dis-
orders. Annu Rev Psychol. 1998;377-412.
5. van Praag HM. Comorbidity (psycho) analysed. Br J Psychiatry Suppl. 1996;
30:129-134.
6. Maj M. Psychiatric comorbidity: an artefact of current diagnostic systems?
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7. Zinbarg RE, Barlow DH, Liebowitz M, et al. The DSM-IV field trial for mixed
anxiety-depression. Am J Psychiatry. 1994;151(8):1153-1162.
8. Das-Munshi J, Goldberg D, Bebbington PE, et al. Public health significance of
mixed anxiety and depression: beyond current classification. Br J Psychiatry.
2008;192(3):171-177.
9. Stein D, Patel V, Heinze G. Commentary on Confirmatory factor analysis of
common mental disorders across cultures. In: Goldberg D, Kendler K, Sirovat-
ka P, Regier D, eds. Diagnostic Issues in Depression and Generalized Anxiety
Disorder: Refining the Research Agenda for DSM-V. Arlington, VA: American
Psychiatric Publishing; 2010.
10. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Bi-
ological Psychiatry (WFSBP) guidelines for the pharmacological treatment of
anxiety, obsessive-compulsive and post-traumatic stress disordersfirst revi-
sion. World J Biol Psychiatry. 2008;9(4):248-312.
11. Weisberg RB, Maki KM, Culpepper L, Keller MB. Is anyone really M.A.D.?: the
occurrence and course of mixed anxiety-depressive disorder in a sample of
primary care patients. J Nerv Ment Dis. 2005;193(4):223-230.
12. Kessler RC. The categorical versus dimensional assessment controversy in the
sociology of mental illness. J Health Soc Behav. 2002;43(2):171-188.
13. Stein D. Dimensional or categorical: different classifications and measures of anx-
iety and depression. Medicographia. 2012;34:270-275.
14. VanValkenburg C, Akiskal HS, Puzantian V, Rosenthal T. Anxious depressions.
Clinical, family history, and naturalistic outcomecomparisons with panic and
major depressive disorders. J Affect Disord. 1984;6(1):67-82.
15. Grunhaus L. Clinical and psychobiological characteristics of simultaneous pan-
ic disorder and major depression. Am J Psychiatry. 1988;145(10):1214-1221.
302 MEDICOGRAPHIA, Vol 35, No. 3, 2013
model of defect rather than defense, and these kinds of
anxious depression may represent maladaptive responses
with significant disruptions in the underlying functional sys-
tems. Although the neurobiology of agitated depression is
poorly understood, there is some evidence that this lies on
the bipolar spectrum.35 Thus, some forms of anxious depres-
sion should be viewed as indicators of rather serious forms of
psychopathology, and clinical interventions should be target-
ed appropriately.
Conclusion
Anxiety in depression is associated with increased morbid-
ity; anxiety disorders typically precede the development of ma-
jor depression; and patients with major depression and anx-
iety respond to efficacious treatments and so deserve early
and robust intervention. However, the occurrence of anxiety
in depression raises many complex questions. This review em-
phasizes that both categorical and dimensional approaches
to co-occurring depression and anxiety are needed, that anx-
iety in depression is a heterogeneous construct, and that vari-
ants of anxious depression, such as stressor-related depres-
sion and agitated depression, likely require quite different
approaches. I
16. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpa-
tients with anxious versus nonanxious depression: a STAR*D report. Am J Psy-
chiatry. 2008;165(3):342-351.
17. Farabaugh A, Alpert J, Wisniewski SR, et al. Cognitive therapy for anxious de-
pression in STAR*D: what have we learned? J Affect Disord. 2012;142(1-3):
213-218.
18. Bowlby J. Attachment and Loss. Vol 3. New York, NY: Basic Books; 1980.
19. Roy-Byrne PP, Katon W. Generalized anxiety disorder in primary care: the pre-
cursor/modifier pathway to increased health care utilization. J Clin Psychiatry.
1997:58(suppl 3):34-38.
20. Goldberg D. Towards DSM-V: the relationship between generalized anxiety
disorder and major depressive episode. Psychol Med. 2008;38(11):1671-
1675.
21. Nesse RM, Stein DJ. Towards a genuinely medical model for psychiatric nosol-
ogy. BMC Medicine. 2012;10:5.
22. Nesse RM, Ganten D, Gregory TR, Omenn GS. Evolutionary molecular medicine.
J Mol Med. 2012;90(5):509-522.
23. Stein DJ. Emotional regulation: implications for the psychobiology of psycho-
therapy. CNS Spectr. 2008;13(3):195-198.
24. Amstadter A. Emotion regulation and anxiety disorders. J Anxiety Disord. 2008;
22(2):211-221.
25. Cisler JM, Olatunji BO. Emotion regulation and anxiety disorders. Curr Psychia-
try Rep. 2012;14(3):182-187.
26. Keller MC, Nesse RM. The evolutionary significance of depressive symptoms:
different adverse situations lead to different depressive symptom patterns. J Pers
Soc Psychol. 2006;91(2):316-330.
27. Nesse RM. Proximate and evolutionary studies of anxiety, stress and depres-
sion: synergy at the interface. Neurosci Biobehav Rev. 1999;23(7):895-903.
28. Schaffer A, McIntosh D, Goldstein BI, et al. The CANMAT task force recommen-
dations for the management of patients with mood disorders and comorbid anx-
iety disorders. Ann Clin Psychiatry. 2012;24(1):6-22.
29. Goodwin MR, Gorman MJ. Psychopharmacologic treatment of generalized anx-
iety disorder and the risk of major depression. Am J Psychiatry. 2002;159(11):
1935-1937.
30. Panzer MJ. Are SSRIs really more effective for anxious depression? Ann Clin
Psychiatry. 2005;17(1):23-29.
31. Papakostas GI, Stahl SM, Krishen A, et al. Efficacy of bupropion and the se-
lective serotonin reuptake inhibitors in the treatment of major depressive dis-
order with high levels of anxiety (anxious depression): a pooled analysis of 10
Anxiety in depression: clinical and conceptual considerations Stein
 E MOTI O N S AND DEPRESSION

studies. J Clin Psychiatry. 2008;69(8):1287-1292.
32. Stein D, Picarel-Blanchot F, Kennedy S. Efficacy of the novel antidepressant
agomelatine on anxiety symptoms in major depression. Hum Psychopharma-
col. In press.
33. Ghaemi SN. Why antidepressants are not antidepressants: STEP-BD, STAR*D,
and the return of neurotic depression. Bipolar Disord. 2008;10(8):957-968.
34. Friedman MJ, Resick PA, Bryant RA, Strain J, Horowitz M, Spiegel D. Classi-
fication of trauma and stressor-related disorders in DSM-5. Depress Anxiety.
2011;28(9):737-749.
35. Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated unipolar depression re-
conceptualized as a depressive mixed state: implications for the antidepres-
sant-suicide controversy. J Affect Disord. 2005;85(3):245-258.

Keywords: anxiety; comorbidity; co-occurrence; depression; diagnostic categories; DSM-5; management; phenomenology;
psychobiology

LES SYMPTMES DE LANXIT DANS LA DPRESSION :

CONSIDRATIONS CLINIQUES ET CONCEPTUELLES
Il est de plus en plus reconnu que lanxit dans la dpression est associe une morbidit augmente, que les
troubles anxieux prcdent de faon typique lapparition dune dpression majeure et que les patients souffrant dune
dpression majeure et danxit, rpondant aux traitements efficaces, mritent dtre pris en charge de faon pr-
coce et nergique. Des questions complexes sont nanmoins souleves par la survenue de lanxit dans la dpres-
sion : la coexistence dune dpression et dune anxit doit-elle tre considre comme une comorbidit ou bien
comme deux diagnostics spars ? Lanxit dans la dpression a-t-elle des corrlats psychobiologiques particuliers
justifiant de traitements spcifiques ? Quapporte lapparition dune anxit dans la comprhension de la nature de
la dpression ? Cet article souligne la ncessit dune approche la fois dimensionnelle et catgorielle de la coexis-
tence dpression-anxit, lhtrognit de lentit anxit dans la dpression et le besoin probable dapproches
diffrentes pour les variantes de dpression anxieuse, comme la dpression lie au stress et la dpression agite.

Anxiety in depression: clinical and conceptual considerations Stein MEDICOGRAPHIA, Vol 35, No. 3, 2013 303

Antidepressants maywork
in a manner quite similar to that of
psychological treatment that aims
to redress negative biases in in-
formation processing. Given the
possibility that antidepressants
especially selective serotonin re-
uptake inhibitorsmay neutralize
the processing both of negative
and positive emotions, one might
speculate that such an iatrogenic
effect could also blunt subjective
response in patients who take
them.
Hans-Jrgen MLLER, MD, PhD
Florian SEEMLLER, MD
Department of Psychiatry and
Psychotherapy, Ludwig-Maximilians-
University Munich
Munich, GERMANY
Address for correspondence:
Florian Seemller, Department
of Psychiatry and Psychotherapy,
Ludwig-Maximilians-University
Munich, Nussbaumstr. 7,
80336 Munich, Germany
(e-mail: fseemuel@med.lmu.de)
www.medicographia.com
304 MEDICOGRAPHIA, Vol 35, No. 3, 2013
E MOT I O NS AND DEPRESSION
Antidepressants and
emotions: therapeutics
and iatrogenic effects
b y H . J . M l l e r a n d
F. S e e m l l e r, G e r m a n y
A
ntidepressants can ameliorate depressive symptoms. Apart from the
specific pharmacological action of the respective compound, we still
have little knowledge about the way antidepressant drugs modulate
neural processing of emotional and affective information. One proposed
mechanism is an antidepressant-induced increase in processing of positive
information in healthy volunteers and acutely depressed patients early in treat-
ment. Such action may help explain the role of monoamines in emotional dys-
function in depression and how antidepressants work. This article will first pro-
vide an overview of pathomechanisms of emotional processing in depression
and then review data on emotional processing of serotonergic and noradren-
ergic compounds. It has also been speculated that antidepressants may, in
the same manner that they have positive effects on depression, lead to un-
wanted secondary emotional effects. Some early case reports suggested that
selective serotonin reuptake inhibitors, especially, may lead to emotional blunt-
ing, a term commonly referred to as a restricted range of emotions. In the
years that followed, this side effect was systematically studied. Relevant ar-
ticles have been critically reviewed and are summarized in the manner of a
systematic review. This article will also discuss the neurobiological under-
pinnings and possible clinical implications of emotional blunting.
Medicographia. 2013;35:304-309 (see French abstract on page 309)
he effects of antidepressant drugs on emotion and on negative biases in de-
T pression were usually thought to reflect nonspecific consequences of mood
improvement. In recent years, the pharmacological modulation of emotion
has become a growing field of research. One of the basic theories on the role of
emotional modulation and depression is the so-called mood congruency hypoth-
esis. It suggests that mood may enhance the processing of mood-congruent mate-
rial and impair the processing of mood-incongruent material. This in turn may imply
a pronounced tendency to attribute negative emotions to neutral faces in depressed
patients.1,2 Recent findings suggest that antidepressants directly affect the way in
which emotional information is processed and, therefore, help to reduce the neg-
ative bias in perception and memory in depression.2 However, it is noteworthy that
even in remission the impairment in processing of neutral faces was evident. Re-
mitted patients attributed not only sadness, but also happiness, to neutral faces.
This suggests that this impairment may also be a trait characteristic independent of
mood improvement.3 In other words, patients in remission after a major depressive
episode may also interpret emotionally neutral social cues as emotionally meaning-
Antidepressants and emotions: therapeutics and iatrogenic effects Mller and Seemller

ful. This may explain why remitted patients are still vulnera-
ble to development of further depressive episodes.2 Antide-
pressants seem to affect the way in which emotional informa-
tion is processed, finally leading to a reduced negative bias
in perception and memory that are believed to contribute to
the symptoms of depression. Antidepressants may, therefore,
work in a manner quite similar to that of psychological treat-
ment that aims to redress negative biases in information pro-
cessing. Given the possibility that antidepressantsespecially
selective serotonin reuptake inhibitors (SSRIs)may neutral-
ize the processing both of negative and positive emotions,
one might speculate that such an iatrogenic effect could also
blunt subjective response in patients who take them.
In the early nineties, some case reports described a new di-
mension of side effects which were described as blunted emo-
tional behavior.4,5 The term blunted emotion is commonly re-
ferred to as a restricted range of emotions.
Blunted emotions are also commonly thought to be one of
the main obstacles in combining pharmacologic SSRI treat-
ment with psychotherapy. For example, some psychothera-
pists recommend cessation of antidepressant SSRI treatments
before exposure therapy in anxiety patients. The rationale be-
hind this is that exposure treatment, in theory, can only be
effective if emotions, including anxiety, are not suppressed or
blunted by drugs. Consequently, antidepressants are some-
times tapered down or stopped, which is unfortunate, taking
into account the significant risk of a recurrence or relapse of
the depressive episode.
However, the question remains unanswered whether such
side effects really exist or whether they, for example, only rep-
resent residual symptoms of the major depressive disorder,
such as affective rigidity, or whether they represent personal-
ity traits. Recently, with the growing database on side effects
of antidepressants, some treatment-emergent emotional side
effects for tricyclic antidepressants (TCAs), such as sudden
appearance of anger and outburst, have been described.
This article will review the therapeutic effects of serotonergic
and adrenergic antidepressants on emotional processing on
SELECTED ABBREVIATIONS AND ACRONYMS
5-HT2C serotonin 2C
AES Apathy Evaluation Scale
BDI Beck Depression Inventory
HAM-D Hamilton Depression Rating Scale
LEIS Laukes Emotional Intensity Scale
MADRS Montgomery-Asberg Depression Rating Scale
OQuESA Oxford Questionnaire on the Emotional Side effects
of Antidepressants
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
Antidepressants and emotions: therapeutics and iatrogenic effects Mller and Seemller
E MOTI O N S AND DEPRESSION
the one hand, and summarize what is known about the con-
cept of emotional blunting on the other, and will, finally, briefly
comment on the clinical management of emotional blunting.
Therapeutic effects of antidepressants on
emotional processing
The improvement of symptoms on a depression rating scale
provides good evidence for the efficacy of an antidepressant.
While the actions of antidepressants are well characterized
(eg, serotonin reuptake inhibition) there is only little under-
standing of how these mechanisms lead to an improvement
of symptoms. However, the effects of antidepressants on the
modulation of emotional processing might provide a deeper
understanding of its psychological mode of action.6 It also
helps us as clinicians to explain to our patients what psycho-
logical changes can be expected on an antidepressant med-
ication.
There are many studies of acute and long-term administra-
tion of antidepressants in animal models, healthy volunteers,
and depressed populations. In the following, we will focus on
studies in healthy volunteers and in clinical samples.
For example, a single-dose administration of citalopram helped
healthy females to correctly process happy facial expressions
and to recognize fear. However, citalopram had no effect on
any other negative emotions like sadness, anger, and disgust.7
Another electrophysiological study by Kemp investigated the
effects of acute serotonergic administration of citalopram on
cortical electrophysiological responses to the processing of
pleasant and unpleasant visual stimuli. Kemps findings sug-
gest that acute serotonergic augmentation with citalopram
modulates cortical processing of emotionally valenced stim-
uli, such that the response to pleasant valence is potentiated,
whereas the response to unpleasant valence is suppressed.8
With respect to long-term administration of SSRIs, Harmer9,10
found a reduction in the processing of negative emotional stim-
uli following a seven-day trial of citalopram at a daily dose of
20 mg. At the end of the seven-day period, healthy subjects
showed reduced recognition of negative facial expressions
and also an improved memory for positive information. A rever-
sal in fear processing from acute to chronic treatment with
SSRIs has also been described in many preclinical anxiety
models and clinical anxiety can easily be exacerbated initially
with SSRI treatment. It is thus tempting to speculate that the
initial increase followed by a final decrease in fear perception
may relate to opposing effects on neural substrates involved
in fear processing and that these changes may relate to the
therapeutic effects of SSRIs in depression and anxiety.11
With respect to the noradrenergic effect of a single dose of the
compound reboxetine, Harmer and coworkers have conduct-
ed several important studies. She examined the effect of re-
MEDICOGRAPHIA, Vol 35, No. 3, 2013 305
E MOT I O N S AND DEPRESSION
boxetine on emotional processing compared with placebo in
24 healthy controls. On three different measures, reboxetine
biased perception toward positive rather than negative in-
formation in the absence of effects on neurocognitive perform-
ance. For example, the facial expression task revealed greater
recognition of happy facial emotions after reboxetine com-
pared with placebo, without improvement in cognitive per-
formance.12
The effect of depression on emotional processing and its cor-
rection by reboxetine is also nicely illustrated in Figure 1.6,9
Harmer and colleagues demonstrate that healthy controls
seem to have a positive recall bias regarding the recall of pos-
itive adjectives, which cannot be found in depressed subjects.
However, after single-dose administration of 4 mg of rebox-
etine, as compared with placebo, the patients regain the usu-
al healthy positive recall bias (Figure 1).9
A Effects of depression B Effects of acute reboxetine
5 Comparison subjects 5 Depressed patients, placebo
Depressed subjects
4 4
of items recalled
of items recalled
Mean number
Mean number
3 3
2 2
1 1
0 0
Negative Positive
Another interesting study by Harmer13 compared reboxetine
or citalopram with placebo over seven days in a double-blind
manner in 42 healthy volunteers. Both compounds signifi-
cantly reduced the recognition of fearful and angry facial ex-
pression as compared with placebo. Of note, subjects receiv-
ing citalopram were more likely to misclassify anger, disgust,
and fear than happy emotions, suggesting again a positive bias
in facial expression tasks.
These findings suggest that antidepressants can have early
effects on emotional processing with some effects being seen
with acute administration and independently of changes in
mood. Serotonin potentiation might lead to positive biases
in emotional processing and memory. This is exactly the op-
posite effect seen in depressed states. However, it is well es-
tablished that drug treatments for depression usually require
repeated administration before their effects become clinical-
ly apparent. Some theories, therefore, assume that the delay
in antidepressant action arises because of apparent delay in
the initiation or expression of the relevant pharmacological
and/or cellular actions. The delay might also be caused by the
requirement for psychological consolidation and processing
of the effects of these neurochemical actions.
306 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Antidepressants and emotions: therapeutics and iatrogenic effects Mller and Seemller
Generally speaking, the hypothesis is that correcting emotion-
al bias may lead to an improved homeostatic mood response
to experience and that recovery in depression is delayed be-
cause of the need for relearning of external contingencies and
internal states under more positive emotional bias.14 On the
other hand, the neutralization of negative emotions might in
the long run lead to secondary effects like emotional blunting,
which will be critically reviewed in the following paragraph.
Iatrogenic, secondary effects of antidepressants
on emotions
In 1990, Hoehn-Saric et al reported apathy, indifference, loss
of initiative, and disinhibition in panic disorder and depressed
patients on SSRIs.5 A bit later, in 1991, Hoehn-Saric reported
apathy, indifference, inattention, and perseveration in an ob-
sessive-compulsive patient taking fluoxetine.4,15 Subsequently,
Oleshansky and Labbate (1996) described rapid improvement
Figure 1. Mean numbers of
positive and negative self-refer-
ent adjectives in a recall task.
Depressed patients, reboxetine (A) The effects of depression per se.
Comparison for positive stimuli between
depressed patients and comparison
subjects receiving placebo significant
at P<0.05. (B) The acute effect of oral
reboxetine (4 mg) or placebo in de-
pressed group only. Comparison for
positive stimuli between depressed pa-
tients receiving placebo and those re-
ceiving reboxetine significant at P<0.01.
After reference 9: Harmer et al. Am J
Psychiatry. 2009;166(10):1178-1184.
Negative Positive 2009, American Psychiatric Asso-
ciation.
of excessive or inappropriate crying without apathy or indiffer-
ence in depressed patients on SSRI treatment.15 Finally, Vinar
et al reported that eight depressed women spontaneously
cried while watching movie scenes on television over a peri-
od of years. This crying disappeared during long-term treat-
ment with SSRIs.
The first systematic case-control study on blunted emotions
was a brief report by Opbroek published in 2002.16 The au-
thors studied 15 depressed patients in remission, who took
three different SSRIs (fluoxetine, paroxetine, and sertraline).
They were all recruited from a study of patients reporting SSRI-
induced sexual dysfunction. Patients and healthy controls were
rated with a newly developed blunted-emotions rating scale
(Laukes Emotional Intensity Scale, [LEIS]).16 About 80% of
the 15 SSRI-treated remitted patients reported emotional blunt-
ing. The LEIS consists of 17 items. In only two itemswork
and energy levelsdid the authors find no significant differ-
ence as compared with the healthy controls. The frequency of
patients experiencing diminished emotional response was
93% for sexual interest, 80% for sexual pleasure, 60% for in-
ability to cry, 53% for erotic dreams, 50% for creativity, and
47% for becoming irritated or upset. There was no difference

in the total LEIS score between the different antidepressant
classes. The author finally concluded that sexual dysfunction
as seen with SSRI treatment may be just one of a larger set
of diminished emotional responses as a consequence of in-
creased serotonin neurotransmission.
Despite the numerous methodological limitations of this study,
this paper has stimulated a wider debate and enthusiastic re-
actions from some researchers. Luckily enough, a detailed
comment on this study, published in the same issue, sum-
marized the most important limitations17: The applied scale
was used for the first time and lacked validity as well as re-
liability. There was no baseline measurement of the LEIS. The
patients were instructed to rate the 18 questions relative to
their usual state. This may bias the memory of the respondents
toward attribution of the experienced phenomena to side ef-
fects of SSRIs. The lacking correlation with depressive symp-
toms in remitted patients also is not surprising given the min-
imal variance of depressed symptoms in remitted patients. In
addition, the comparison of depressed patients undergoing
SSRI treatment with healthy controls not undergoing SSRI
treatment, rather than making the comparison with a placebo
control group, does not make much sense. Thus, it is impos-
sible to distinguish depressive symptoms from side effects.
Moreover, the patient sample consisted of a subsample of pa-
tients reporting sexual side effects; the LEIS scale is biased
toward sexual dysfunction as it (i) contains four sexual items
and (ii) highly correlates with a sexual side effect scale. In
contrast to the authors conclusion that sexual side effects
may only be the tip of the iceberg regarding unwanted emo-
tional side effects, it may well be the other way around: se-
vere sexual dysfunction and impairment may cause or at
least contribute to emotional blunting. Sexual dysfunction is a
known SSRI side effect due to two main mechanisms: (i) el-
evation of prolactin levels (as has been shown for almost all an-
tidepressants,18 leading to a decrease in libido and (ii) SSRI-
specific orgasm delay.19 Thus, it could also be that the decrease
in libido secondarily leads to other emotional phenomena,
since a healthy sexual life might substantially contribute to a
higher quality of life and might thus be a prerequisite for a vi-
tal emotional life. Furthermore, it has not been distinguished
whether these phenomena impaired patients quality of life
or whether they might also have been wanted and desired
effects of the treatment, as in some of the reports described
above.
Finally, these questions remain unanswered: Exactly what
symptoms constitute the concept of emotional blunting? Is
the normalization of pathologic symptoms such as patholog-
ic crying emotional blunting? Do our standardized depres-
sion rating scales like the Hamilton Depression Rating Scale
(HAM-D) or the Montgomery-Asberg Depression Rating Scale
(MADRS) not capture similar symptoms which would be clas-
sified as residual symptoms?
Antidepressants and emotions: therapeutics and iatrogenic effects Mller and Seemller
E MOTI O N S AND DEPRESSION
Measuring emotional blunting
A different approach has been suggested by Barnhart et al.20
He introduced the term apathy in the context of SSRI-induced
emotional blunting and adopted a definition from Marin et al21:
a syndrome in which there is a primary absence of motivation
that is not attributable to cognitive impairment, emotional dis-
tress, or diminished level of consciousness. However, this ap-
proach also lacks specificity regarding side effects of antide-
pressants, as Marin himself suggested the following possible
psychiatric differential diagnoses of apathy: delirium, demen-
tia, abulia, akinesia, despair, and depression.21 We would like
to suggest including other common psychiatric diagnoses,
such as negative symptoms in schizophrenia and chronic
residual states as well. However, important longitudinal infor-
mation, such as the late appearance of apathy during SSRI
treatment in the absence of depressive symptoms and dimin-
ishing apathy during titration downward may provide more
helpful information in distinguishing apathy or emotional blunt-
ing as a side effect from depressive residual symptoms.
Rating scales for blunted emotions
Regarding standardized rating scales, there are four instru-
ments for the measurement of SSRI-emergent emotional blunt-
ing thus far available: the first is the Marin Apathy Evaluation
Scale (AES). However, the scale was developed for an older
population and has been used in schizophrenia trials and neu-
rological disorders.22 The second is the above-mentioned
LEIS, comprising 18 questions, which thus far lacks validity
and specificity, as outlined above.16 The third is the Bell-Ship-
man Apathy/Emotional Blunting Questionnaire.6,23 In the liter-
ature, it is described as under development, but up to now
there is still no published evidence of its completion. The fourth
and perhaps most comprehensive and elaborate question-
naire is the recently published Oxford Questionnaire on the
Emotional Side effects of Antidepressants (OQuESA).6,24 It com-
prises three different sections with 26 self-reported items al-
together. It has been tested in a cohort of 207 depressed peo-
ple: 26% reported that they did not experience side effects;
16% reported insignificant emotional side effects, 30% mild
side effects, 23% moderate, and 6% severe. Patients with
emotional side effects were significantly younger, had a sig-
nificantly higher Beck Depression Inventory (BDI) score and
shorter treatment duration. The association with depressive
symptoms raises the possibility that the OQuESA may not be
specific for side effects, but might rather capture depressive
symptomatology. Moreover, emotional side effects were more
common in patients with a shorter treatment duration, which
also suggests greater illness activity and acuity and contrasts
with findings from case reports where emotional blunting
seems to appear more often in the long run with antidepres-
sant treatment. In fact, the authors themselves state in their
discussion that: the OQuESA measures one or more aspects
of depression, rather than necessarily measuring only emotion-
al effects.24 The authors state that appropriate double-blind
studies are under way using the questionnaire, hopefully clar-
MEDICOGRAPHIA, Vol 35, No. 3, 2013 307
E MOT I O N S AND DEPRESSION
ifying the question of overlap between depressive and resid-
ual symptomatology.24 However, it would have also been in-
teresting to look for correlations between the BDI and the
OQuESA, which unfortunately has not been analyzed in this
study.
Possible mechanisms of emotional blunting
In an excellent review of case reports, Barnhart et al discuss-
es two mechanisms:
(i) Frontal lobe activity may be modulated though serotoner-
gic projections, finally leading to emotional blunting.20
(ii) SSRIs may influence serotonergic systems, which in turn
might modulate midbrain dopaminergic systems also pro-
jecting to the prefrontal cortex and triggering emotional blunt-
ing.4,20
Clinical management of emotional blunting
According to Barnhart et al, there are three different ways to
manage or respond to emotional blunting.20 Probably, the
simplest approach is to reduce the dosage of the antidepres-
sant. In most case reports, particularly in patients taking SSRIs
with a shorter half-life, a dose reduction led to complete reso-
lution of emotional blunting. However, in these cases, this side
effect typically occurred later, after several months of treat-
ment with an antidepressant. Earlier, it might be even more dif-
ficult to distinguish emotional blunting from depressive symp-
tomatology. Thus, one might not want to put the patient at
risk of worsening depression through antidepressant dose
reduction. A case report described the resolution of emotion-
al blunting when buproprion was added. The addition of bu-
proprion is also a well-established augmentation strategy.25
This strategy might especially be helpful in patients with a par-
tial response to an antidepressant and where it is not clear
to what extent the phenomena might be attributable to the
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initial depressive episode. The third and last management
option would be to switch the antidepressant. Based on the
above observation that dose titration was a more effective
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did not experience apathy after switching to monoamine ox-
idase inhibitors or TCAs.20
An interesting new alternative might be a switch to agome-
latine. This is an antidepressant whose properties (MT1 /MT2
agonist and serotonin 2C [5-HT2C ] antagonist, causing no re-
lease of serotonin in the brain) might protect from emotion-
al blunting with a pharmacologic effect that is primarily upon
circadian synchronization and enhancement of dopaminer-
gic and adrenergic input to the frontal cortex through the
synergy of its receptors.26,27 Agomelatine facilitates positive
versus negative affective processing, including emotional
memory and fear-potentiated startle.6,28
Conclusion
There is a wide range of evidence available suggesting that
the psychological antidepressant effect of pharmacologic
treatments can arise from a reduction in negative bias in emo-
tional processing. Apart from positive effects, emotional blunt-
ing has been discussed as an unwanted emotional side effect.
There are specific rating instruments available and several re-
ports suggest the existence of emotional blunting under SSRI
treatment. However, so far there are no convincing criteria
that can separate emotional blunting from residual depres-
sive symptoms. Clinical reports suggest that emotional blunt-
ing tends to appear rather late with SSRI treatment and also
seems to be dose dependent. Thus, a dose reduction or
switch to an SSRI with a shorter half-life might be the first
choice in the management of emotional blunting. I
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2009;166(10):1178-1184.
10. Harmer CJ, Bhagwagar Z, Cowen PJ, Goodwin GM. Acute administration of
citalopram facilitates memory consolidation in healthy volunteers. Psychophar-
macology (Berl). 2002;163(1):106-110.
11. Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. In-
creased amygdala response to masked emotional faces in depressed subjects
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50(9):651-658.
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990-992.
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tive serotonin and norepinephrine reuptake inhibition. Am J Psychiatry. 2004;
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try. 1996;57(12):593.
16. Opbroek A, Delgado PL, Laukes C, et al. Emotional blunting associated with
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SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? Int
J Neuropsychopharmacol. 2002;5(2):147-151.
17. Balon R. Emotional blunting, sexual dysfunction and SSRIs. Int J Neuropsy-
chopharmacol. 2002;5(4):415-416; author reply 7.
18. Coker F, Taylor D. Antidepressant-induced hyperprolactinaemia: incidence,
mechanisms and management. CNS Drugs. 2010;24(7):563-574.
19. Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients
taking antipsychotics. Int Clin Psychopharmacol. 2011;26(3):130-140.
20. Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clin-
ical review. J Psychiatr Pract. 2004;10(3):196-199.
21. Marin RS. Differential diagnosis and classification of apathy. Am J Psychiatry.
1990;147(1):22-30.
22. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy
Evaluation Scale. Psychiatry Res. 1991;38(2):143-162.
23. Bell S, Shipman M, Bystritsky A, Haifley T. Fluoxetine treatment and testosterone
levels. Ann Clin Psychiatry. 2006;18(1):19-22.
24. Price J, Cole V, Doll H, Goodwin GM. The Oxford Questionnaire on the Emotion-
al Side-effects of Antidepressants (OQuESA): development, validity, reliability
and sensitivity to change. J Affect Disord. 2012;140(1):66-74.
25. Bech P, Fava M, Trivedi MH, Wisniewski SR, Rush AJ. Outcomes on the phar-
macopsychometric triangle in bupropion-SR vs. buspirone augmentation of
citalopram in the STAR*D trial. Acta Psychiatr Scand. 2012;125(4):342-348.
26. de Bodinat C, Guardiola-Lemaitre B, Mocar E, Renard P, Muoz C, Millan MJ.
Agomelatine, the first melatonergic antidepressant: discovery, characterization
and development. Nat Rev Drug Discov. 2010;9(8):628-642.
27. Racagni G, Riva MA, Molteni R, et al. Mode of action of agomelatine: synergy
between melatonergic and 5-HT2C receptors. World J Biol Psychiatry. 2010;1
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Keywords: agomelatine; antidepressants; emotional blunting; iatrogenic effect; SSRI; tricyclic antidepressants

ANTIDPRESSEURS ET MOTIONS : TRAITEMENTS ET EFFETS IATROGNES

Les antidpresseurs peuvent amliorer les symptmes dpressifs. Si nous connaissons le mode daction pharma-
cologique spcifique de chaque compos, nous en savons encore peu sur la faon dont les antidpresseurs agis-
sent sur le traitement neural de linformation affective et motionnelle. Un des mcanismes proposs est celui dune
augmentation du traitement de linformation positive, induite par les antidpresseurs, chez des volontaires sains
ainsi que chez des patients souffrant de dpression aigu, au dbut du traitement. Ceci pourrait expliquer le rle des
monoamines dans la dysfonction motionnelle de la dpression et dans le mode daction des antidpresseurs. Cet
article passe dabord en revue les mcanismes pathologiques du traitement des motions dans la dpression, puis
les donnes du traitement motionnel des composs srotoninergiques et noradrnergiques. Les antidpresseurs
sont souponns dentraner, de la mme faon quils ont un effet positif sur la dpression, des effets motionnels
secondaires indsirables. Certaines tudes prcoces ont suggr que les inhibiteurs slectifs de la recapture de la
srotonine pouvaient conduire un moussement des motions, cest--dire une gamme dmotions restreinte.
Cet effet secondaire a t systmatiquement tudi dans les annes qui ont suivi. Des articles pertinents ont t
analyss de faon critique et sont rsums la manire dune mise au point systmatique. Cet article analyse ga-
lement les bases neurobiologiques et les implications cliniques potentielles dun moussement affectif.

Antidepressants and emotions: therapeutics and iatrogenic effects Mller and Seemller MEDICOGRAPHIA, Vol 35, No. 3, 2013 309
 THE QUESTION CONTROVERSIAL QUESTION

hen treating depressed

W patients, physicians usu-

ally first consider neg-
ative emotions. But isnt that only
one side of the story? It is increas-
ingly appreciated that there is more
Do you take positive emotions
to the management of depression
than the war against the darker
side of things. Contributors to this
into account while treating
section draw on their experience
to discuss the rationale for simul-
taneously taking positive and neg-
depressive patients?
ative emotions into account and
the potential implications this has
for the patients.

1. A. S. Avedisova, Russia

2. M. Bauer, Germany

3. K. Bazaid, Saudi Arabia

4. R. Evsegneev, Belarus

5. V. Gentil, Brazil

6. D. Marazziti, Italy

7. J. Marques-Teixeira, Portugal

8. Y. M. Mok, Singapore

9. M. Nasreldin, Egypt

10 . E. T. Oral, Turkey

11. M. A. Rangel, Mexico

12 . M. Rufer, Switzerland

13 . A. B. Singh, Australia

14 . M. H. Tyal, Morocco

15 . A. M. Zain, Malaysia

Do you take positive emotions into account while treating depressive patients? MEDICOGRAPHIA, Vol 35, No. 3, 2013 311
CONTROVERSIAL QUESTION
1. A. S. Avedisova, Russia
Alla Sergeevna AVEDISOVA, MD
Department of Psychic and
Behavioral Disorder Therapy
Serbsky National Research Centre
for Social and Forensic Psychiatry
23 Kropotkinsky per.
119992 Moscow
RUSSIA
(e-mail: alla.avedisova@gmail.com)
E
motional disorders are paid less attention in psychia-
try than affective disorders. It is not a coincidence, as
discrete emotional reactions to specific events are rare
causes for medical consultation, and usually reflect an under-
lying mood alteration such as depression. For depressive pa-
tients, the issue is not so much the loss of their usual and
almost imperceptibly normal mood, but rather an emotion-
al reaction that develops in acute form (eg, anguish, sadness,
anger), instantly uniting all body functions. The essence of the
psychic mechanisms that develop and intensify these emo-
tions lies not in their potentiation by depressive affect, but in
their compensatory role: the emotions compensate, at least
in part, for lowered mood, and are thus necessary to main-
tain life activity. Consideration of emotional reactions plays an
important role when choosing a treatment strategy and in-
dividualizing therapy, and also in ensuring treatment compli-
ance and predicting antidepressant effectiveness.
The decisive role of emotions in governing human actions is
reflected in the motivation theory of emotional origin, which
postulates that emotions and motivations are essentially sim-
ilar. The question of which emotions to consider in ensuring
compliance and motivation of a patient is not rhetorical. In pos-
itive psychotherapy, positive emotions are developed, where-
as psychoanalysis focuses on eliminating negative emotions.
The issue is tied to numerous psychological theories on the
origin and role of emotions in human life. A black-and-white
division into positive and negative emotional states is an over-
simplification of complex events: negative emotions may give
rise to a positive emotion (eg, envy of a person changes into
joy after that persons defeat) and emotions may be positive
and negative in different moments (eg, melancholy caused
by romantic love). It is not emotions themselves, rather their
312 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Do you take positive emotions into account while treating depressive patients?
effects on human activity and the impression they make on
others that is positive or negative. Therefore, negative emo-
tions are as necessary and adaptive as positive ones. Doc-
tors should consider the entire emotional spectrum in depres-
sive patients to attain compliance. The more a patient shows
both positive and negative emotions (especially during first
treatment steps), the more successful is the process of moti-
vation. To a great extent, this depends on the doctors compe-
tence in helping patients become aware of their own emo-
tions and to value them (reflective training); not trying to replace
the negative emotional background with an artificial positive
one. When the quality and amount of information given is inad-
equate (including about planned treatment), emotions also fill
in for lacking information, compensating for unavailable knowl-
edge (cognitive component of emotions). Thus, the process
of informing a patient is an additional part of emotion man-
agement in depression.
Emotions are closely connected to neurophysiological sys-
tems, and there is a relative interaction with cognition and de-
pendence on needs. Notions of negative and positive emo-
tions are also relative. This ambivalence is especially obvious
for the emotion of expectation (anticipation): it combines the
wish for something to happen (positive component) with con-
cern that this might not happen (negative component). Ex-
pectation performs a prognostic function and manifests as
stress augmented by uncertainty. This emotion (expectation,
feeling of future treatment success or failure) is considered a
trigger to the placebo effect. We developed the Questionnaire
of Therapy Expectations (14 items) to obtain information about
depressive patients expectations of pharmacological treat-
ment. Several topics were surveyed: whether patients consid-
er their condition to be (un)treatable, previous experiences with
depression treatment (positive or negative), expected time
frame for onset of therapeutic effect, and whether treatment
side effects are expected and, if so, how severe. After a week
of placebo therapy, most responders were found to have pos-
itive expectations (39.7%) and only 3.6% had been unsure.
Placebo nonresponders included all patients with negative
expectations (34.9%) and 21.6% of unsure patients. As the
placebo effect is an important part of antidepressant activity,
the emotion of expectation may predict whether or not phar-
macological treatment will be effective. I

2. M. Bauer, Germany
Michael BAUER, MD, PhD
Professor of Psychiatry
Department of Psychiatry and Psychotherapy
University Hospital Carl Gustav Carus
Technische Universitt Dresden
Fetscherstr. 74
D-01307 Dresden
GERMANY
(e-mail: michael.bauer@uniklinikum-dresden.de)
E
motion is the generic term for subjective, conscious ex-
perience characterized primarily by psychophysiolog-
ical expressions, biological reactions, and mental states.
The most distinct classification of emotions to date is proba-
bly Parrots 2001 theory.1 Parrot identified over 100 emotions
and conceptualized them in a tree-structured list comprising
primary (fear, anger, sadness, surprise, joy, and love), second-
ary, and tertiary emotions. Emotions can also be grouped on
a positive or negative basis; eg, joy versus sadness, trust ver-
sus distrust, or surprise versus anticipation.
Many different components of emotion form integral parts of
the clinical syndrome of depression, but a mood disturbance
is considered the core symptom in depressive disorders. How-
ever, depressed mood and negative emotions like sadness do
not necessarily constitute a psychiatric disorder. They are a
normal reaction to certain life events, symptoms of some med-
ical conditions, and a side effect of some medical treatments.2
Although the subjective feelings described and expressed by
most melancholic people do bear some resemblance to the
mood changes of everyday life, they clearly go beyond the
common experience.2 A patient suffering from depression
experiences painful negative emotions, and has an inability
to respond to or generate pleasurable stimuli. The painful di-
mension of depressive experience during illness is usually re-
lated to anxiety, guilt, anguish, and restlessnessan agitated
state of emotional arousal that we consider to comprise neg-
ative emotions. A general blunting of emotions is considered
an important feature of clinical depression.3 Positive emotions
such as enjoyment, happiness, passion, enthusiasm, and ex-
citement are typically reduced in people suffering from de-
pression. Most importantly, negative emotions like sadness,
anger, aggression, and anxiety are usually increased in depres-
sive states. Interestingly, the term emotion does not appear
in the symptom description of major depression in both the
fourth edition of the Diagnostic and Statistical Manual of Men-
tal Disorders (DSM-IV) and the International Statistical Clas-
sification of Diseases, Tenth Revision (ICD-10) classification
systems of mental illness.
Do you take positive emotions into account while treating depressive patients?
CONTROVERSIAL QUESTION
Some patients suffering depression report subjective negative
emotional symptoms that seem to arise as an adverse effect
of antidepressants and lithium salts. This phenomenon was
described in the early 1990s as emotional blunting; for exam-
ple, in patients treated with selective serotonin reuptake in-
hibitors (SSRIs). Dose-related symptoms that disappeared
shortly after withdrawal of fluvoxamine or fluoxetine were ap-
athy, indifference, loss of initiative, and disinhibition.4 Overall,
relatively little research has been published to clarify whether
symptoms of emotional blunting are indeed related to treat-
ment with SSRIs or represent residual symptoms of depres-
sion.3 Recently, a rating instrument, the Oxford Questionnaire
on the Emotional Side-Effects of Antidepressants has been
developed and validated.5 This scale offers the opportunity to
measure emotional blunting during treatment with antide-
pressants in the clinical setting.
Depressed people may experience a variety of different pos-
itive and negative emotions, the latter including sadness, anx-
iety, emptiness, hopelessness, worry, helplessness, worth-
lessness, guilt, irritability, hurt, or restlessness. They may lose
interest in activities that once were pleasurable, experience
loss of appetite or overeating, have problems concentrating
and in remembering details or making decisions, and may
contemplate or attempt suicide. These symptoms can come
and go within hours, days, or weeks, and may give the patient
the feeling of riding a frightening rollercoaster of emotions.
When positive emotions slowly return in a patient suffering
from melancholic depression, it is often a first sign of response
to treatment. Therefore, it is important to monitor not only the
reduction in negative emotions, but also the return of posi-
tive emotions during treatment. It is also of clinical relevance
to identify symptoms of emotional blunting that may occur
during a course of treatment with psychotropic medications.
This latter area of research has been widely neglected in the
past. I
References
1. Parrott W. Emotions in Social Psychology. Philadelphia, PA: Psychology Press;
2001.
2. Whybrow PC, Akiskal HS, McKinney WT Jr. Mood Disorders: Toward a New
Psychobiology. Plenum Press; 1984.
3. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin re-
uptake inhibitors: qualitative study. Br J Psychiatry. 2009;195(3):211-217.
4. Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy and indifference in patients on
fluvoxamine and fluoxetine. J Clin Psychopharmacol. 1990;10(5):343-345.
5. Price J, Cole V, Doll H, Goodwin GM. The Oxford Questionnaire on the Emo-
tional Side-effects of Antidepressants (OQuESA): development, validity, relia-
bility and sensitivity to change. J Affect Disord. 2012;140(1):66-74.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 313
CONTROVERSIAL QUESTION
3. K. Bazaid, Saudi Arabia
Khalid BAZAID, MBBS, FRCPC
Psychiatry Department
College of Medicine
King Sand University
PO Box 2611971
Riyadh 113112
SAUDI ARABIA
(e-mail: bazaidka@gmail.com)
M
ood is an emotional state, although the terms mood
and emotion may be used interchangeably. Moods
differ from emotions in that they are less specific,
less intense, and less likely to be triggered by a particular
stimulus or event. Moods generally have either a positive or
negative valence.
Clinicians usually manage to alleviate depressive symptoms,
and most of the time they will be satisfied that they have re-
gained the patients baseline (euthymic) mood. Patients will
be pleased to regain their energy and restart functioning, but
they will not necessarily feel or think positively about them-
selves, particularly if only treated with antidepressants. Stud-
ies indicate that the majority are apprehensive and worried
that they may go back to their horrible gloomy mood, and usu-
ally fail to resist the recurrent negative themes during their re-
covery course.
Even though research on emotions has flourished in recent
years, investigations that expressly target positive emotions
remain few and far between. Any review of the psychological
literature on emotions will show that psychologists have typ-
ically favored negative emotions in theory building and hypoth-
esis testing. In doing so, psychologists have inadvertently mar-
ginalized the emotions such as joy, interest, contentment, and
love that share a pleasant subjective feeling.1
In contrast with biological treatment of depression, most if not
all psychotherapy treatment models aim to alter the content
of underlying cognitive structures that influence affective state
and behavioral patterns. For example, in the case of apathy,
resulting from a persons expectation of failure in all areas,
the patient is actively taught to experience reactive emotions
through correction of their cognitive state.
In my clinical practice, I work with patients presenting with de-
pression to try and understand its correlation with their adap-
tive abilities during stressful and difficult times, and I may use
their intellectual belief, eg, belief in Gods will, which is cultur-
314 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Do you take positive emotions into account while treating depressive patients?
ally accepted, to relieve their guilt and decrease sense of self-
blame. In doing so, most of them will gradually experience joy,
which will eventually help to improve their cognitive state. Ad-
ditionally, I work with them on improving their social skills as
an alternative means of reducing subsequent negative impacts
resulting from and/or causing their depression, whether re-
lated to study, work, or even relationships.
Studies have reported impaired executive function in patients
with major depressive disorder, with positive correlations with
depression severity and illness duration. There are also stud-
ies suggesting that these patients have the same level of im-
pairment, or less impairment, as depressed bipolar patients.2
Happy people are more likely to succeed in achieving cultur-
ally valued goals (eg, work, love, and health) than their less
happy peers. However, the large number of available correla-
tional studies in this area includes research examining behav-
ior and cognition in parallel with successful life outcomes
that is, the characteristics, resources, and skills that help people
to succeed (attributes such as self-efficacy, creativity, socia-
bility, altruism, immunity, and coping).3
Despite the increased focus on self-esteem over the past three
decades, depression in children has continued to grow, now
affecting a quarter of all children today. Although the midterm
outcome is often favorable, the prognosis of depression in
the young is often poor, with 75% experiencing relapse at 5
years,4 thus considerably increasing the risk of depression in
adulthood.5 To combat this trend, Dr Seligman began the Penn
Depression Prevention Project, the first long-term study aimed
at 8- to 12-year-olds. His findings were revolutionary, proving
that children can be protected against depression by being
taught how to challenge their pessimistic thoughts (Selig-
mans learned optimism). I
References
1. Fredrickson BL. What good are positive emotions? Rev Gen Psychol. 1998;2(3):
300-319.
2. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion percep-
tion II: implications for major psychiatric disorders. Biol Psychiatry. 2003;54:
515-528.
3. Lyubomirsky S, King L, Diener E. The benefits of frequent positive affect: does
happiness lead to success. Psychol Bull. 2005;131(6):803-855.
4. Kovacs M, Feinberg TL, Crouse-Novak MA, Paulauskas SL, Finkelstein R. De-
pressive disorders in childhood. I. A longitudinal prospective study of charac-
teristics and recovery. Arch Gen Psychiatry. 1984;41:229-237.
5. Harrington R, Fudge H, Rutter M, Pickles A, Hill J. Adult outcomes of childhood
and adolescent depression: II. Links with antisocial disorders. J Am Acad Child
Adolesc Psychiatry. 1991;30:434-439.

4. R. Evsegneev, Belarus
Roman EVSEGNEEV, MD, DSci
Professor and Head
Department of Psychiatry and Narcology
Byelorussian Medical Academy of
Postgraduate Education
Republican Scientific and Practical Centre
of Mental Health
Dolginovskyi tract, 152
220056, Minsk, BELARUS
(e-mail: bpa@cervus.unibel.by)
A
t first glance, the question seems to be nontradition-
al and unusual, especially for psychiatrists with a strict
psychopathological, Kraepelinian, and antipsycho-
dynamic orientation, which is common in the post-Soviet
countries. This approach is considered to help avoid missing
the transition to hypomania, and differentiates unipolar de-
pression from bipolar II and mixed states.
However, the meaning of the question, and hence the role of
positive emotions in the treatment process, appears much
more profound when one considers the dramatic impact that
psychodynamic and interpersonal factors have on respon-
siveness to pharmacological treatment for depressionie,
transference and countertransference, defense, conscious
and unconscious benefits derived from the state of depres-
sion, etc.1 An important part of the treatment process also in-
volves knowledge of a patients previous life experienceie,
their behavior and interactions when in a good mood state
with positive emotions.
Practical experience suggests that psychological and psy-
chodynamic factors such as the image of psychiatrists, the
style of doctor-patient communication, therapeutic alliance
and positive transference, patient expectations and readiness
to change, and secondary gain could be even more potent
in determining treatment outcome than the biological effects
of antidepressants.2 It seems to be very important during the
treatment process to demonstrate and remind patients of their
lifeincluding emotions, attitudes, activities, and interactions
before and outside of the period of depression. In other words,
not to tell them what is bad when in low spirits, but why it is
good to be cheerful and positive and what secondary gains
Do you take positive emotions into account while treating depressive patients?
CONTROVERSIAL QUESTION
could be reached in different areas of their life from a good
mood state with positive emotions. In doing so, it is necessary
to emphasize that depression is not an eternal punishment,
but a time-limited state of illness that ,without fail, will eventu-
ally give way to a state of health and good mood. This gives
an opportunity to make a patient ready to change, and in
many cases, his motivation to be healthy and cheerful is the
most powerful determinant of treatment effectivenesssome-
times more powerful than the type of antidepressant and its
dosing, etc. When communicating with patients, it is vital to
convey that drug treatment is not a mechanical process of
taking pills, but the route away from sadness and suffering to
a healthy emotional state and a good, valuable life.
One of the most potent ingredients in antidepressant treat-
ment is the positive transference to the doctor, as well as his
or her capacity to stimulate the patients positive emotions
and expectations. At this point, it is of value to emphasize the
importance of proper communication skills and a nondepres-
sive manner; to be able to emit confidence, calmness, en-
durance, and professional competence. The doctors ability
to be positive, emotionally stable, cheerful, and tolerant pro-
motes positive transference and hence a therapeutic alliance,2
adherence, and higher placebo response,3,4 with a positive
therapeutic outcome as a result. By contrast, pessimism on
the part of the doctor and a lack of the aforementioned qual-
ities is associated with negative transference and hence non-
adherence, distorted communication, and a paradoxical sit-
uation in which medications serve to be countertherapeutic
or the aims of the patient become defensive. I
References
1. Mintz D. Psychodynamic psychopharmacology. Psychiatric Times. 2011;28:1-6.
2. Krupnick JL, Sotsky SM, Simmens S, et al. The role of therapeutic alliance in
psychotherapy and pharmacotherapy outcome: findings in the National Institute
of Mental Health Treatment of Depression Collaborative Research Program.
J Consult Clin Psychol. 1996;64:532-539.
3. Posternak MA, Zimmerman M. Therapeutic effect of follow-up assessments on
antidepressant and placebo response rates in antidepressant efficacy trial: meta-
analysis. Br J Psychiatry. 2007;190:287-292.
4. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of ma-
jor depression: variable, substantial, and growing. JAMA. 2002;287:1840-1847.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 315
 CONTROVERSIAL QUESTION
5. V. Gentil, Brazil
Joao Claudio Coteoffice Editora
Valentim GENTIL, MD, PhD
Professor of Psychiatry
University of Sao Paulo Medical School
Rua Oscar Freire, 587/11
01426-001 - Sao Paulo
BRAZIL
(e-mail: vgentil@usp.br)
W
hen prescribing antidepressants, one should close-
ly monitor changes in background emotional state
in addition to core therapeutic response. Negative
emotions naturally command the patients attention, but sub-
tle (extratherapeutic) positive changes in emotional response
to daily events also occur and may deserve recognition, as
they inform about the biology of emotional regulation. Be-
sides these often-neglected aspects of antidepressant action,
I invite your attention to a particularly distressing emotion for-
merly known in English psychiatry as precordial anguish,
and as angoisse in French and angustia in various Latin
languages, a symptom that has all but disappeared from
contemporary psychopathology.
Subtle positive changes in the emotional state of some pa-
tients in response to treatment were described early in the lit-
erature, chiefly with monoamine oxidase inhibitors, but they
only received special attention in the 1990s after the introduc-
tion of single small doses of selective serotonin reuptake in-
hibitors. Before that, they could hardly be noted due to seda-
tive or anticholinergic effects, or blunting of emotions, induced
by various medications.
To determine whether such positive effects are extratherapeu-
tic, my colleagues and I conducted a series of experiments in
volunteers without personal or family history of psychiatric dis-
orders.1,2 For the active drug we chose clomipramine, since
it induced such changes with small doses in our patients with
panic/agoraphobia. In double-blind experiments with propan-
theline as active placebo, we measured variables of person-
ality, mood, cognition, performance, sleep, and neuroimaging.
We identified four domains of subjective change: interperson-
al tolerance (decreased irritability and tension in social inter-
actions), efficiency (improved decision-making, ability to prior-
itize demands, and self-confidence), well-being (feeling better,
brighter mood), and feeling substantially changed from usual
self. About 35% of participants met the response criteria for
such changes. Selecting the responders, we carried out a fi-
nal crossover trial of three weeks on active drug or placebo.
316 MEDICOGRAPHIA, Vol 35, No. 3, 2013
All participants maintained (or reacquired) the response cri-
teria on clomipramine, and lost it on placebo. We concluded
that low doses of clomipramine may induce positive changes
in emotional response in the absence of psychopathology in
some, but not all, individuals. We are now submitting the neu-
roimaging findings of this trial for publication, which show sig-
nificant differences between responders and nonresponders
(Cerqueira et al, in preparation).
I also pay attention to negative emotional changes in my pa-
tients, and I try alternative medications to avoid them.
Turning to the concept of anguish,3 the feeling of precordial
oppression was described in psychiatric texts in most Latin
languages, as well as in English (precordial anguish) and
German (Oppressionsgefhl) texts. Specific words for this
ancient emotion are available in unrelated languages, such as
Chinese, Hungarian, and Arabic, suggesting a consistent ex-
perience across time and cultures. Its distinction from anx-
iety was lost by modern psychopathology in the 1960s due
to problems of translation for angst, and because there was
no compelling reason to discriminate it from anxiety before
modern psychiatric treatment.
Anguish combines the ideas of present pain and agony of
mind, and is not universally experienced. It occurs in about
one-third of my patients with depressive disorders, typically
in melancholic or bipolar depressive states with early morn-
ing awakening, but also in the evening in those with invert-
ed diurnal variation, as well as patients with schizoaffective
disorders. They clearly distinguish precordial anguish from
anxiety, but it may be confused with precordial pain during a
panic attack. Anguish is also described, in low intensity, by
normal adults and children. Its residual presence at an improv-
ing stage means that dysfunction is still present. The patho-
physiology of a symptom localized in the chest may primarily
involve somesthesic systems related to visceral organs. A drug
capable of promoting remission of depressive syndromes must
suppress this symptom. The mechanisms, however, require
scientific investigation. I
References
1. Gorenstein C, Gentil V, Melo M, Lotufo-Neto F, Lauriano V. Mood improvement
in normal volunteers. J Psychopharmacol. 1998;12:246-251.
2. Gentil V, Zilberman ML, Lobo D, Henna E, Moreno RA, Gorenstein C. Clomi-
pramine-induced mood and perceived performance changes in selected healthy
individuals. J Clin Psychopharmacol. 2007;27:314-315.
3. Gentil V, Gentil ML. Why anguish? J Psychopharmacol. 2011;25:146-147.
Do you take positive emotions into account while treating depressive patients?

6. D. Marazziti, Italy
Donatella MARAZZITI, MD
Professor of Psychiatry
Dipartimento di Medicina Clinica
e Specimentale
University of Pisa
via Roma, 67 - 56100 Pisa
ITALY
(e-mail: dmarazzi@psico.med.unipi.it)
E
motions can be defined as multicomponent responses
that develop in a relatively short space of time in re-
sponse to internal or external stimuli that include sub-
jective experiences, cognitive processes, and psychophysio-
logical changes. Experiencing positive and negative emotions
is unavoidable, and at times useful, and both have been se-
lected along the human evolutionary path for their adaptive
and survival value. However, negative emotions, when long
lasting, deep, or inappropriate, can trigger anxiety disorder or
depression and can impair the immune system. Perhaps this
is the reason that although research on emotions has increased
continuously in recent decades, the majority of studies has
focused on negative emotions rather than positive emotions,
such as joy, interest, contentment, and love, which all share
a pleasant subjective feeling.1 Experiences of positive emo-
tion are central to human nature and contribute richly to the
quality of peoples lives, and they have only recently begun
to attract research attention, mainly for their impact on psy-
chiatric disorders, especially depression.
In fact, according to some theorists, depression is a disorder
in which the core symptoms are represented by a deficit of
positive affect and inability to experience positive emotions.
This notion is supported by different functional magnetic res-
onance imaging studies showing that the brains of depressed
patients exhibit an overall decrease in activity in the regions of
the brain responsible for generating pleasure/reward/positive
emotions. Furthermore, other scientists report that although
the initial levels of activity in positive/pleasure-generating brain
regions are no different between depressed patients and
healthy control subjects, patients do not seem to be able to
sustain positive emotions. In terms of treatment strategies for
depressed patients, in order to take advantage of these emerg-
ing findings, more sophisticated and integrated strategies will
Do you take positive emotions into account while treating depressive patients?
CONTROVERSIAL QUESTION
be needed that are not limited to prescription of drugs, but
also include behavioral and cognitive therapies, as well as trig-
gering of coping styles marked by finding positive meaning.
With regards to behavioral interventions, patients should be
assisted in clarifying their medium- to long-term goals, and in
engaging more in pleasant activities. However, psychological
treatment should also focus on helping patients to develop
a more distributed happiness. Depressed individuals (and non-
depressed individuals, for that matter) should create a life in
which they receive pleasure and reward from multiple areas of
their existence. This bottom-up (behavior to brain influence)
approach is more likely to lead to long-term, enduring, posi-
tive emotions.
This approach can be achieved by placing more emphasis
on finding positive meaning, which seems to be fundamen-
tal to eliciting positive emotions. It is noteworthy that positive
emotions may not need to be intense or prolonged in order
to produce a beneficial effect. Positive emotions can broad-
en the individuals thought-action repertoire, which builds and
promotes their personal resources. This psychological process
can increase an individuals receptiveness to further pleasant
or significant events, while also increasing the odds of finding
positive meaning in those events and experiencing further pos-
itive emotions. This can in turn trigger an upward spiral that
might, over time, improve depressive symptoms.2 Thus, the
experience of positive emotions might facilitate coping and
alleviate depressed mood.
In conclusion, different lines of recent studies support the no-
tion that depression is best treated by an integrated psycho-
logical approach aimed at promoting positive emotions in
combination with prescription of drugs, and not use of drugs
alone. Future antidepressants should be targeted specifical-
ly at restoring or improving a patients ability to experience
positive emotions. I
References
1. Fredrickson BL. What good are positive emotions? Rev Gen Psychol. 1998;2(3):
300-319.
2. Garland EL, Fredrickson B, Kring AM, Johnson DP, Meyer PS, Penn DL. Upward
spirals of positive emotions counter downward spirals of negativity: insights from
the broaden-and-build theory and affective neuroscience on the treatment of
emotion dysfunctions and deficits in psychopathology. Clin Psychol Rev. 2010;
30(7):849-864.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 317
CONTROVERSIAL QUESTION
7. J. Marques-Teixeira, Portugal
Joo MARQUES-TEIXEIRA, MD, PhD
Aggregate Professor of University of Porto
Rua Alfredo Keil, 480
4150-048 Porto
PORTUGAL
(e-mail: marquesteixeira@netcabo.pt)
I
do take into account positive emotions in the treatment
of depressive patients, by considering their stimulation
through neurofeedback. In fact, in many depressive pa-
tients, stimulation of positive emotions can be an effective
adjunct to pharmacological treatment. Why? A robust body
of research has documented that depression is associated
with differential activation of the right and left prefrontal cor-
tex. When there is a biological predisposition to depression,
frontal asymmetry can be observed with more left frontal al-
pha activity, meaning that the left frontal area is less activat-
ed. Electroencephalogram (EEG) studies have demonstrat-
ed that the left frontal area is associated with more positive
affect and memories, and the right hemisphere is more in-
volved in negative emotion. Thus, when the left hemisphere is
basically stuck in an idling alpha rhythm, there is more with-
drawal behavior, in addition to the deficit in positive affect. This
means that depressed patients may be anticipated to be less
aware of positive emotions, while at the same time being
more in touch with the negative emotions that are associated
with the right hemisphere.
In addition, evidence also suggests that positive emotions are
important facilitators of adaptive coping and adjustment to
acute and chronic stress, mainly by sustaining coping efforts,
providing a breather, and restoring depleted resources.
It has been proposed that this frontal asymmetry (alpha asym-
metry) may represent a state marker of depression, although
such an asymmetry is not necessary or sufficient for the pro-
318 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Do you take positive emotions into account while treating depressive patients?
duction of a specific type of affective style or psychopatholo-
gy. Differences in prefrontal asymmetry may be most appro-
priately viewed as diatheses that bias a persons affective
style, and thus in turn modulate a persons vulnerability to de-
velop depression. It has also been found that alpha asym-
metry can be used to predict the response to antidepres-
sants before the beginning of pharmacological treatment, in
such a sense that it could serve as an aid in the choice of
treatment.
As we gain insight into the relationship between depression
and EEG patterns, and in view of the fact that EEG biofeed-
back (neurofeedback) has been found to be effective in mod-
ifying brain function, producing significant improvements in
several clinical symptoms, use of neurofeedback in depres-
sion is being proposed as a way of training depressed people
to change their frontal alpha asymmetry so that it resembles
the asymmetry pattern found in nondepressed individuals.
As with any form of biofeedback, neurofeedback is built upon
the self-learned practice of conscious generation of more
healthy organic patterns. The technique represents a form of
operant conditioning through which an individual may learn
to modify the electrical activity of his own brain. Some pa-
tients claimed after training that they could distinguish be-
tween emotions generated by depression and those asso-
ciated with life situations.
Taking into consideration all of the aforementioned informa-
tion, when planning a therapeutic strategy for depressive pa-
tients, I also consider adjuvant neurofeedback training in ad-
dition to pharmacological treatment to facilitate patient learning
of how to modify their frontal activity by increasing activation
of the left hemisphere and decreasing activation of the right
hemisphere.
To sum up, asymmetry training is important for controlling and
regulating emotion, and it may facilitate left frontal lobe func-
tion in depressive patients. I

8. Y. M. Mok, Singapore
Yee Ming MOK, MBBch,
MMed (psychiatry),
Grad Dip (psychotherapy)
Institute of Mental Health
Woodbridge Hospital
10 Buangkok View
539747 SINGAPORE
(e-mail: yee_ming_mok@imh.com.sg)
A
s trainees and young psychiatrists, we are taught
about psychopathology. We learn to diagnose psy-
chiatric disorders based on abnormal signs and symp-
toms related to this psychopathology. Treatment, then, aims
to eliminate these signs and symptoms. In depression, as
defined by criteria in the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (Text Revision; DSM-
IV-TR), the main therapeutic objective is remission: to improve
mood, apathy, guilt, and hopelessness, as well as sleep and
appetitein short, the clinical signs of the disorder. The ma-
jority of these symptoms will improve with current treatments.
However, a significant number of patients experience only par-
tial remission.1 Although they do not have sufficient symptoms
in number or severity to constitute a disorder, they do still have
some symptoms and they feel that they do not have the same
emotional well-being as before. For many, even though they
no longer feel depressed, the anhedonia is still present. The
presence of such residual symptoms is associated with a high-
er relapse rate, socioeconomic impairment, and increased
utilization of health care services. Positive emotions such as
love, joy, hope, and passion do not return; the joie de vivre
remains elusive.
Increasingly, there is evidence that positive and negative emo-
tions play a part in the treatment of and recovery from depres-
sion. There is a close relationship between depression and
physical illnesses such as myocardial infarction, stroke, and
cancer. Patients suffering from a physical illness with con-
comitant depression have a poorer outcome compared with
patients not suffering from depression.2-4 Patients with an ex-
isting negative emotion profile (introversion, low sensation
seeking, autonomy, dysfunctional attitudes, high displeasure
capacity, passivity, and pessimism) are at higher risk of devel-
oping depression. Positive emotions have been shown to be
protective in the prevention of stress and depression. They
Do you take positive emotions into account while treating depressive patients?
CONTROVERSIAL QUESTION
build resilience. Numerous studies show that happy individ-
uals are successful across multiple life domains, including mar-
riage, friendship, income, work performance, and health. Fur-
thermore, the evidence suggests that positive affectthe
hallmark of well-beingmay be the cause of many of the de-
sirable characteristics, resources, and successes correlated
with happiness. A twin study looking at positive emotions
found that such emotions buffer against the genetic risks of
developing depression.5 Indeed, having positive emotions has
been associated with a longer lifespan. In a study of Catholic
nuns, positive emotional content in early-life autobiographies
was strongly associated with longevity six decades later.
In light of such evidence, recognizing and optimizing the pres-
ence of such emotions early in the treatment of depression
would lead to better outcomes. A recent study suggests that
looking beyond the elimination of the abnormal signs and
symptoms of depression, the early improvement of positive
emotions predicts remission from depression after pharma-
cotherapy.6 Apart from our established treatments for de-
pression that are aimed at achieving an absence of symptoms,
we should keep in mind the use of neurobiological treatments,
psychosocial therapies, and the spiritual needs of patients to
help patients better cope with stress and optimize positive
emotions. Having the return of positive emotions as a treat-
ment goal would lead to a better quality of life and lessen
the risk of relapse for individuals suffering from depression.
To ignore this would be a disservice to our patients as well
as to ourselves. I
References
1. Kennedy N, Paykel ES. Residual symptoms at remission from depression: im-
pact on long-term outcome. J Affect Disord. 2004;80(2-3):135-144.
2. Spiegel D, Giese-Davis J. Depression and cancer: mechanisms and disease
progression. Biol Psychiatry. 2003;54(3):269-282.
3. Frasure-Smith N, Lesprance F, Talajic M. Depression following myocardial in-
farction: impact on 6-month survival. JAMA. 1993;270(15):1819-1825.
4. Pohjasvaara T, Vataja R, Leppvuori A, Kaste M, Erkinjuntti T. Depression is an
independent predictor of poor long-term functional outcome post-stroke. Eur J
Neurol. 2001;8(4):315-319.
5. Wichers MC, Myin-Germeys I, Jacobs N, et al. Evidence that moment-to-mo-
ment variation in positive emotions buffer genetic risk for depression: a momen-
tary assessment twin study. Acta Psychiatr Scand. 2007;115:451-457.
6. Geschwind N, Nicolson NA, Peeters F, van Os J, Barge-Schaapveld D, Wichers
M. Early improvement in positive rather than negative emotions predicts remission
from depression after pharmacotherapy. Eur Neuropsychopharmacol. 2011;21
(3):241-247.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 319
CONTROVERSIAL QUESTION
9. M. Nasreldin, Egypt
Mohamed NASRELDIN, MD
Professor of Psychiatry
Psychiatry and Addiction Prevention Hospital
Faculty of Medicine, Cairo University
Kasr El-Aini Hospitals, Cairo, 11451
EGYPT
(e-mail: mohnas@hotmail.com)
D
espite the importance of negative emotions as major
criteria in the diagnosis of major depression, positive
emotions are unfortunately frequently not taken into
account when treating depressive patients.
Anhedonia, a negative emotion, is considered a core symp-
tom of major depression that involves deficits in the ability to
experience positive emotions such as pleasure, pride, hap-
piness, and amusement.1 Depressed patients thus suffer from
decreased hedonic ability, which is defined as the amount
of positive affect that it is possible for an individual to expe-
rience.2 Moreover, anhedonia may not entirely be due to a
tonic decrease in the ability to experience pleasure, but rather
an inability to preserve positive impact and honor responsive-
ness over time.3
The value of positive emotions lies in their capacity to enable
individuals to build durable personal resources (ie, intellec-
tual, physical, psychological, and social). In addition, positive
emotions affect peoples thinking style, social interactions, and
physiological responses.4 Positive emotions also broaden the
breadth of peoples thinking, attention, and actions moment
to moment, while negative emotions narrow it. Thus positive
emotions are considered as efficient antidotes to the linger-
ing after-effects of negative emotions.5 However, the ultimate
goal in managing depressed patients is to understand how
positive emotions might accumulate and compound each
other to transform the lives of patients for the better. Hence,
there can be several reasons for taking positive emotions into
account when treating depressive patients.
First, the proper deconstruction of the depressive episode
into all its component positive and negative emotions through
the use of self-reports or assessment scales is crucial in de-
320 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Do you take positive emotions into account while treating depressive patients?
tecting a patients positive resources, recognizing their char-
acter strengths, and helping the patient respond actively and
constructively to positive events reported by others.
A second reason is to discuss optimism and positivity using
an explanatory style: optimism is to see bad events as tran-
sient, changeable. The retrieval of positive and negative mem-
ories in relation to current events and their role in the subse-
quent development of positive and negative emotions is also
noteworthy.6
A third reason for taking positive emotions into account is the
conceptualization of depression as involving low self-esteem,
whereby self-relevant stimuli trigger negative self-appraisals
that may dampen the individuals ability to experience pos-
itive self-relevant emotions such as pride, possibly due to a
dysfunctional emotion system. Indeed, the need to delineate
the relationship between negative self-appraisals and self-rel-
evant positive emotions is crucial when treating depressed
patients. Furthermore, it is important to bear in mind that pos-
itive self-relevant emotions are multifaceted and include pos-
itive emotions associated with personal achievement as well
as those based on group membership.6
In conclusion, in psychiatric clinical practice, therapists should
consider taking into account negative and positive emotions
simultaneously during the management of depressed patients.
With regard to positive emotions, therapeutic approaches
should not only encourage patients to participate in potential-
ly enjoyable situations, but to practice allowing their pleas-
ant emotions to surface instead of suppressing them. I
References
1. American Psychiatric Association. Diagnostic and Statistical Manual for Men-
tal Disorders, Fourth edition: DSM-IV-TR. Washington DC: American Psychiatric
Association, 2000.
2. Myerson A. Anhedonia. Am J Psychiatry. 1922;2:87-103.
3. Tomarken AJ, Keener AD. Frontal brain asymmetry and depression: a self-reg-
ulatory perspective. Cogn Emot. 1998;12:34.
4. Fredrickson BL. The value of positive emotions. American Scientist. 2003;91:
330-335.
5. Fredrickson BL, Branigan C. Positive emotions broaden the scope of attention
and thought-action repertoires. Cogn Emot. 2005;19:313-332.
6. Rottenberg J, Gross JJ, Gotlib IH. Emotion context insensitivity in major depres-
sive disorder. J Abnorm Psychol. 2005;114:627-639.

10. E. T. Oral, Turkey
E. Timuin ORAL, MD
Professor of Psychiatry
Istanbul Commerce University
Department of Psychology
Istanbul, TURKEY
(e-mail: etoral@superonline.com)
T
he simple answer to this question is yes, of course.
However, there are other questions involving why, when,
and how that can explain the rationale behind this sim-
ple answer.
Why: it is interesting that even the scientific literature on emo-
tions includes far more publications on negative emotions
like fear, anger, and sadness than on positive emotions like
joy, interest, and contentment. In 1998, Fredrickson proposed
that positive emotions broaden a persons momentary thought-
action repertoire.1 Thus, according to this view, positive emo-
tions and related positive states are not only linked to broad-
ened scopes of attention, cognition, and action, but also to
enhanced physical, intellectual, and social resources. As emo-
tional intensity has been found to be one of the strongest pre-
dictors of outcome in depression, positive emotions may play
an important role regarding the values and objectives of pa-
tients. Depressive patients frequently want to decrease their
experience of negative emotions and increase their experi-
ence of positive ones.2
When: it has been hypothesized that a patients response to
their depressive symptoms plays a role in either amplifying
and perpetuating or alleviating their depression. In 1995, Mor-
row and Nolen-Hoeksema put forward the idea that emo-
tion-focused coping would be expected to perpetuate de-
pression symptoms, whereas task-focused coping or social
distraction might be expected to help alleviate depression.3
In a study evaluating the impact of a range of psychosocial
factors on the outcome of major depression, it was found that
interpersonal events and responses to depression (ie, cop-
ing) play an important role.4 This means that positive emo-
tions should be taken into account at every stage in the man-
agement of depression, from diagnosis to treatment.
How: antidepressants do not act as direct mood enhancers,
but rather change the relative balance of positive to negative
emotional processing, providing a platform for subsequent
Do you take positive emotions into account while treating depressive patients?
CONTROVERSIAL QUESTION
cognitive and psychological reconsolidation.5 While similar
in efficacy to other antidepressants, the selective serotonin
reuptake inhibitors (SSRIs) are generally considered to be bet-
ter tolerated, and thus have a high market share as a conse-
quence. However, an unforeseen and common side effect of
these drugs can be emotional blunting, which is really under-
estimated. Although blunting of emotion is not described as
a potential side effect in package inserts, many clinicians have
noted that patients being treated with SSRIs frequently com-
plain of this.
In a study conducted in 2002 by Opbroek and colleagues,
compared with controls, depressed patients reported signif-
icantly less irritation, ability to cry, ability to care about others
feelings, sadness, erotic dreaming, creativity, surprise, anger,
expression of their feelings, worry over things or situations,
sexual pleasure, and interest in sex.6 A qualitative study in
2009 by Price et al also revealed that almost all depressed
participants in the study described a reduction in their posi-
tive emotions, which they attributed to their drugs. Participants
reported a reduction in a wide range of positive emotions, in-
cluding happiness, enjoyment, excitement, anticipation, pas-
sion, love, affection, and enthusiasm. Yet, this may not be the
only destiny for depressed patients; agomelatine, a new drug
with a novel pharmacological action, was studied for its effects
on emotional processing in healthy volunteers and was found
to decrease subjective ratings of sadness, reduce recognition
of sad facial expressions, and improve positive affective mem-
ory. Clinicians should therefore routinely ask patients about
emotional side effects when they are assessing progress on
antidepressants, and positive and negative emotions should
simultaneously be taken into account in the early phases of
treatment. I
References
1. Fredrickson BL. What good are positive emotions? Rev Gen Psychol. 1998;2:
300-319.
2. Fitzpatrick MR, Stalikas A. Positive emotions as generators of therapeutic change.
J Psychother Integr. 2008;18(2):137-154.
3. Morrow J, Nolen-Hoeksema S. Effects of responses to depression on the reme-
diation of depressive affect. J Pers Soc Psychol. 1990;58:519-527.
4. Enns MW, Cox BJ. Psychosocial and clinical predictors of symptom persistence
vs remission in major depressive disorder. Can J Psychiatry. 2005;50:769-777.
5. Harmer CJ, Goodwin GM, Cowen PJ. Why do antidepressants take so long to
work? A cognitive neuropsychological model of antidepressant drug action. Br J
Psychiatry. 2009;195:102-108.
6. Opbroek A, Delgado PL, Laukes C, et al. Emotional blunting associated with
SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? Int J
Neuropsychopharmacol. 2002;5(2): 147-151.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 321
CONTROVERSIAL QUESTION
11. M. A. Rangel, Mexico
Miguel Angel RANGEL, MD, PhD
Maestra en Psiquiatra
Universidad Autnoma de Quertaro
Coln 6 Edif. Columbus Despacho 105
Centro histrico Quertaro
Quertaro, 76000
MEXICO
(e-mail: maarangel@hotmail.com)
M
ajor depressive disorder (MDD) is a heterogeneous
condition with complex neurobiological correlates
that are still not fully understood, and it is one of
the most prevalent mental illnesses. Current drug therapy is
suboptimal. Response rates to a single antidepressant are
generally considered to be 60%-70%, with over 80% of the
drug affect accounted for by placebo effects. Remission ap-
pears in only 30%-40% of the depressed population. Unfor-
tunately, about one-third of patients will not remit even after
two to four pharmacotherapy trials. Vulnerability to relapse
persists after remission, and this has been attributed to ab-
normal biases in the processing of emotional stimuli in limbic
circuits.
Leaving aside the limited efficiency of antidepressants, evi-
dence suggests that about 60% of improvement with an
active antidepressant takes place during the first 2 weeks of
treatment. Several meta-analyses have shown that early im-
provement after 1 or 2 weeks of treatment strongly predicts
later treatment outcome.1 Better knowledge of the mecha-
nisms involved in early treatment response may help us to op-
timize clinical decision-making and improve quality of life in
our depressive patients. MDD is characterized by impaired
cognitive and emotional processing,2 which is why modula-
tion of emotional processing is an intended outcome of both
pharmacological and psychological treatment.
Although studies show that antidepressants affect process-
ing of both positive and negative emotions, recent studies
suggest that changes in positive rather than negative emo-
tions may be important in predicting recovery from depres-
sion. Patients with MDD usually report increased suppression
of both negative and positive emotions.
Currently, recovery from a depressive episode is still meas-
ured by reduction of unpleasant symptoms and not restoration
of a normal range of emotional experience. Drugs or psycho-
therapies actively targeting the positive affect (PA) or reward
system may be more efficient in triggering recovery process-
es. Functional imaging suggests that anticipatory reward may
localize to dopaminergic areas in the nucleus accumbens, ven-
tral tegmental area, orbitofrontal cerebral cortex, and medial
322 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Do you take positive emotions into account while treating depressive patients?
prefrontal cortex. Patients who have anhedonia are impaired
in their ability to sustain upregulation of PA, and this is as-
sociated with reduced frontostriatal connectivity.
There has been an increase in the number of studies on pos-
itive emotions during the last few years.3 PA and negative af-
fect (NA) have been defined as subjective moods and feel-
ings, where PA represents pleasant engagement in positive
feelings (eg, excitement, interest) and NA reflects distress and
unpleasant reactions to the environment (eg, fear, shame).
PA and NA have only recently become a focus of pharmaco-
logical research. Harmer and colleagues were the first to sug-
gest that serotonergic antidepressants may constrain emo-
tional responses across both NA and PA. They showed that
selective serotonin reuptake inhibitors (SSRIs) diminish the
neural processing of both rewarding and aversive stimuli, and
helped to explain the often reported emotional flattening ef-
fect of SSRIs.2
The ability to generate PA boosts (reward experience) from
pleasant daily life events preserves mental health. Positive
emotions also predict psychological resilience. Novel treat-
ments that facilitate positive affective processing are required,
and in this context, agomelatine has emerged as a promis-
ing option. Agomelatine is a new antidepressant with syner-
gistic melatonergic agonism and 5-HT2c antagonism. This in-
teraction underlies its efficacy in restoring circadian rhythms
and mood; response rates of about 80% have been consis-
tently reported across several trials. Furthermore, agomelatine
increases dopamine and norepinephrine release in the lim-
bic system, which would explain its perceived benefits for PA.
Findings from the Harmer study in healthy volunteers demon-
strated early effects of agomelatine on emotional processing,
reduced subjective reports of sadness, improved positive af-
fective memory, and modulation of emotion-potentiated star-
tle response. Finally, agomelatine has additional advantages
over other available antidepressants, and has exhibited im-
provements within a week of administration, in particular in
mood, daytime functioning, and importantly, anhedonia. I
References
1. Henkel V, Seemller F, Obermeier M, et al. Does early improvement triggered by
antidepressants predict response/remission? Analysis of data from a naturalis-
tic study on a large sample of inpatients with major depression. J Affect Disord.
2009;115:439(3)-449.
2. Harmer CJ, de Bodinat C, Dawson GR, et al. Agomelatine facilitates positive ver-
sus negative affectivity processing in healthy volunteer models. J Psychophar-
macol. 2011;25(9):1159-1167.
3. Sin NL, Lyubomirsky S. Enhancing well-being and alleviating depressive symp-
toms with positive psychology interventions: a practice-friendly meta-analysis.
J Clin Psychol. 2009;65:467-487.

12. M. Rufer, Switzerland
Michael RUFER, MD
Associate Professor of Psychosocial Medicine
Psychosomatics and Psychotherapy
Department of Psychiatry and Psychotherapy
UniversityHospital Zrich
Culmannstrasse 8, 8091 Zrich
SWITZERLAND
(e-mail: michael.rufer@usz.ch)
F
rom a psychotherapeutic perspective, the question
should not be if, but rather when and how we take pos-
itive emotions into account while treating depressive
patients. Just as health is more than the absence of disease,
positive emotions are more than the absence of negative emo-
tions. Although negative emotions are the main focus of re-
search on depression, clinical practice shows that positive
emotions should and can be specifically targeted with psy-
chotherapeutic treatments. There are at least four good rea-
sons as to why this is important: (i) reducing negative emotions
does not automatically improve positive emotions; (ii) positive
emotions can reduce negative emotions; (iii) positive emo-
tions help resolve problems that play a role in the etiology and
maintenance of depression; and (iv) positive emotions may
protect against relapse and recurrence by improving quality
of life and well-being. Furthermore, there is preliminary evi-
dence that depressive symptoms are associated with diffi-
culties in adaptively regulating positive emotions.1
However, interventions for enhancing positive emotions are
not a panacea for the treatment of depression. The when
and how is crucial for their success or failure. An attempt to
simply encourage a depressed patient to feel positive will
most likely have no effect or even worsen the symptomatol-
ogy. The reasons are obvious: emotions cannot be invoked
directly, and depressed patients in particular may interpret
the failure of such an intervention as their own fault. Thus, we
need therapeutic interventions that indirectly induce positive
emotions and are integrated into a comprehensive treatment
plan that includes interventions for both positive and negative
emotions, as well as additional therapeutic aims selected on
the basis of the patients specific needs. For example, in the
acute phase of major depression, symptom-oriented inter-
ventions may be the best strategy. But for residual depressive
symptoms, interventions focused on positive emotions and
psychological well-being may yield the most beneficial effects,
especially because the absence of psychological well-being
seems to increase the risk of a relapse into depression.2
Do you take positive emotions into account while treating depressive patients?
CONTROVERSIAL QUESTION
One concrete example of a psychotherapeutic strategy that
works on positive states of mind is well-being therapy (WBT).
WBT was developed in a clinical setting by Giovanni A. Fava,3
based on Carol Ryffs cognitive model of psychological well-
being.4 With regard to positive emotions, the aims are to
encourage patients to systematically search for moments of
well-being in daily life, identify thoughts and beliefs leading to
premature interruption of well-being, engage in pleasant ac-
tivities, and challenge dysfunctional beliefs or inappropriate
expectations in certain domains of positive functioning.5
Best results may be achieved with a sequential combination of
symptom- and well-beingoriented psychotherapeutic strate-
gies. This may also be a promising option for anxiety disorders:
while considerable alleviation of symptoms was achieved in
a study of cognitive behavioral therapy for panic disorder, the
vitality dimension of quality of life remained largely unchanged
over time.6 Since deficiencies in energy and pep may create
a vulnerability to future adverse events, additional interven-
tions aimed at enhancing well-being may help to achieve more
complete and long-lasting beneficial effects.
In conclusion, although the reduction of negative emotions
is one important aim in the treatment of depression, positive
emotions play a significant role as well. Targeting positive emo-
tions may improve treatment of depression. In recent years, a
growing number of psychotherapeutic interventions aimed at
enhancing positive emotions have been developed.
However, both clinicians and researchers should pay atten-
tion to when and how interventions for positive emotions
should be integrated into a comprehensive treatment plan
for depression. I
References
1. Werner-Seidler A, Banks R, Dunn BD, Moulds ML. An investigation of the rela-
tionship between positive affect regulation and depression. Behav Res Ther. 2013;
51:46-56.
2. Wood AM, Joseph S. The absence of positive psychological (eudemonic) well-
being as a risk factor for depression: a ten year cohort study. J Affect Disord.
2010;122:213-217.
3. Fava GA. Well-being therapy: conceptual and technical issues. Psychother Psy-
chosom. 1999;68:171-179.
4. Ryff CD. Happiness is everything, or is it? Explorations on the meaning of psy-
chological well-being. J Pers Soc Psychol. 1989;57:1069-1081.
5. Ruini C, Fava GA. Role of well-being therapy in achieving a balanced and individ-
ualized path to optimal functioning. Clin Psychol Psychother. 2012;19:291-304.
6. Rufer M, Albrecht R, Schmidt O, et al. Changes in quality of life following cogni-
tive-behavioral group therapy for panic disorder. Eur Psychiatry. 2010;25:8-14.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 323
CONTROVERSIAL QUESTION
13. A. B. Singh, Australia
Ajeet B. SINGH, MBBS, MPsych, FRANZCP
School of Medicine, Deakin University, and
The Geelong Clinic, AUSTRALIA
(e-mail: a.singh@deakin.edu.au)
C
linicians are trained to explore for positive emotions
in depressive presentations, but only to the extent of
screening for bipolarity. How many clinicians focus on
positive emotions as part of their core management of unipo-
lar major depression itself? Depressingly, I suspect only a mi-
nority do. I take positive emotions into account while treating
depressive patients, not just as a nicety, but as a core element
of both patient care and safety. Moreover, patients themselves
rate the presence of positive mental health (eg, optimism,
vigor, self-confidence) as the most important factor for them
personally in determining remission from major depression.1
Traditional medical models have focused on distress, dysfunc-
tion, and mortality.2 This is understandable given that such
concerns drive patients to seek help, but it is a model under
change as societal expectations of physicians change. Ad-
ditionally, the clinicians relationship to society has changed,
with fear of litigation sometimes shaping the focus more to-
ward hazards than hopes.
Loss of enjoyment and disengagement from activities (social,
recreational, and occupational) are cardinal problems impact-
ing sufferers of depression, anhedonia being a core symptom
in definitions of major depression. Depressed patients seem
to have selective attention for negative emotions (sadness,
fear, irritability, inadequacy), potentially perpetuating their dys-
phoria, apprehension, and disengagement.3 It is important to
note that for some patients, such emotions are part of a grief
adjustment process rather than a pathological state. Where
there is a major depression-related selective attention for neg-
ative emotions, it is important not to inadvertently reinforce
these cognitions by only questioning about such symptoms.
324 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Do you take positive emotions into account while treating depressive patients?
By the same token, one must not invalidate distress by ex-
cessively minimizing its importance during sessions with pa-
tients. A balance is neededthe art behind the science of
clinical care.
Genuine ardent expression of intent to restore positive emo-
tional capacity in patients can have profoundly beneficial ther-
apeutic effects.4,5 Not only is engagement and treatment com-
pliance fostered, but instilling hope may help reduce risk
ideations.6 Once hedonic drive and energy begin to improve
in severe depressive states, full recovery relies both on reen-
gaging with and enjoying social, recreational, and occupation-
al activities. Reinforcing these positive aspects of life may help
prevent relapse during the maintenance phase of care.5
Positive emotions should be included in the assessment and
management of depressive presentations as part of diagnos-
tic formulation, risk management, and treatment of patients to
a full emotional and functional recovery. As society increas-
ingly considers well-being to be the key health outcome, fail-
ure to take positive emotions into account while treating de-
pressive patients is in some ways missing the boat with regard
to what patients and the broader community want from physi-
cians in the modern era. If you are not already doing so, I en-
courage you to take positive emotions into account while treat-
ing depressed patients. I
References
1. Zimmerman M, McGlinchey JB, Posternak MA, Friedman M, Attiullah N, Boe-
rescu D. How should remission from depression be defined? The depressed pa-
tients perspective. Am J Psychiatry. 2006;163:148-150.
2. Eisenberg L. Disease and illness. Distinctions between professional and pop-
ular ideas of sickness. Cult Med Psychiatry. 1977;1(1):9-23.
3. Maalouf FT, Clark L, Tavitian L, Sahakian BJ, Brent D, Phillips ML. Bias to nega-
tive emotions: A depression state-dependent marker in adolescent major depres-
sive disorder. Psychiatry Res. 2012;198(1):28-33.
4. Sin NL, Lyubomirsky S. Enhancing well-being and alleviating depressive symp-
toms with positive psychology interventions: a practice-friendly meta-analysis.
J Clin Psychol. 2009;65(5):467-487.
5. Dunn BD. Helping depressed clients reconnect to positive emotion experience:
current insights and future directions. Clin Psychol Psychother. 2012;19:326-340.
6. Hanna FJ. Suicide and hope: the common ground. J Ment Health Counseling.
1991;13(4):459-472.

14. M. H. Tyal, Morocco
Mohamed Hachem TYAL, MD
88-90 Bd de lOasis
Quartier Oasis, Casablanca 20103
MOROCCO
(e-mail: h.tyal@menara.ma)
W
hen dealing with the depressed patient, one can
consider two complementary layers of reality. First
of all, there is the objective, biological dimension,
which among other things, involves genetic and biochemical
factors such as serotonin or melatonin transporter proteins.
Secondly, there is the subjective, psychoaffective dimension
conveyed by the patients story, which the psychiatrist will
listen to and analyze. On the one hand, this story tells the tale
of all the breakups, grief, conflicts, and violence that the pa-
tient has lived through and the resultant anxiety, guilt, and loss
of self-esteem that these life experiences engender, and on the
other hand it also reveals the patients personal resources and
ability to bounce back. Besides use of mere words, the de-
pressed patient also conveys his or her story through tone
of voice and body language. Indeed, the patients emotions
flow through the story told.
The patients thoughts, conveyed by the narrative, will not be
meaningfully put to use during current and future therapeutic
care unless the psychiatrist takes into account the emotions,
both negative and positive, that are expressed through this dis-
Do you take positive emotions into account while treating depressive patients?
CONTROVERSIAL QUESTION
course. It is with this approach that one can best appreciate
the reality of the depressed patients psychological suffering.
Indeed, with any depressed patient, it is essential to seek to
understand how the depressive state functions within the pa-
tients unique life story. It is important to find words to express
the silent suffering of depression, to give it meaning. None of
this is possible if the emotional dimension is distanced from
the therapeutic approach. This is why, in a considerable num-
ber of cases, the use of the classic selective serotonin reup-
take inhibitor (SSRI) antidepressants acts as a barrier to the
treatment of depression, due to the significant impact these
drugs can have on emotional state. Depression is not an ac-
cident that has to be overcome at any price by drugs.
One of the goals of treatment is precisely to allow patients
to reclaim their existence and win back their self-esteem, a
process which SSRIs, with their numbing of emotions, can
repress. These drugs tend to estrange patients from reality,
making life easier to deal with because anxiety, feelings, and
sexuality are dulled, except that the patients become mere
onlookers of their own life and their emotions are not integrat-
ed into their personality. By restoring a relative feeling of well-
being, these antidepressants may prevent patients from con-
templating the reasons for their suffering and thereby cause
them to neglect the grieving process that is necessary to over-
come the depression. Furthermore, these attenuated emo-
tions may, at the same time, be displaced by somatic com-
plaints (heart disease, etc), or they may resurface in a way that
is much more dangerous to the integrity of self, in the form
of delirium. I
MEDICOGRAPHIA, Vol 35, No. 3, 2013 325
CONTROVERSIAL QUESTION
15. A. M. Zain, Malaysia
Azhar Mohd. ZAIN, MD, MPsychMed,
DipCogTh, AM
Professor of Psychiatry
Faculty of Medicine and Health Sciences
University of Putra
MALAYSIA, and
Senior Consultant Psychiatrist
Ampang Puteri Specialist Hospital
Kuala Lumpur, MALAYSIA
(e-mail: azhar_mdzain@yahoo.com)
T
he diagnostic criteria for major depressive disorder
(MDD), dysthymic disorder, and bipolar I disorder in the
fourth edition of the Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV) are the same for children and
adolescents as they are for adults, with some minor modi-
fications. To make a diagnosis of a depressive disorder, the
most defining symptom is depressed mood. DSM-IV de-
scribes this as depressed mood most of the day, nearly every
day, indicated by subjective report or observation by others.
The other defining symptom is anhedonia (loss of pleasure),
which DSM-IV describes as markedly diminished interest or
pleasure in all, or almost all, activities for most of the day, near-
ly every day.
In my clinical practice, I emphasize the importance of these
two points or symptoms in order to diagnose MDD. When the
symptoms present as continuous low mood and anhedonia
not affected by environmental factors, this indicates biolog-
ical abnormalities rather than purely psychological effects.
Depressed mood that is involuntary and independent of en-
vironmental change has been investigated in several studies.
Functional neuroimaging studies have most commonly asso-
ciated depressed mood and sadness with abnormal neuronal
activity in the medial prefrontal cortex, including the anterior
cingulate cortex and orbitofrontal cortex.1 These areas receive
innervations from serotonergic, norepinephrinergic, and dop-
aminergic pathways. As such, low levels of norepinephrine,
serotonin, and dopamine may be associated with low mood.
Reduced dopaminergic activity has been linked to decreased
incentive motivation,2 anhedonia,3 and loss of interest.4 In-
creased functional dopaminergic activity has been linked to
positive affect.5
326 MEDICOGRAPHIA, Vol 35, No. 3, 2013
In view of this, it is clinically important to view negative emo-
tions, that is to say, low mood, anhedonia, and blunting of
affect, as a diagnostic tool with which to make the correct
diagnosis of biological depression, and to take into account
the amount of positive emotion present during the first visit
to establish the severity of MDD. The less positive emotion
there is present, the more severe the MDD. Scales for meas-
uring negative and positive emotions must be used so that
an objective measurement is made and patients can see the
lowering of negative emotions and the increase of positive
emotions as they progress in their treatment. An example of
such a scale would be the Snaith-Hamilton Pleasure Scale
to measure anhedonia.6
In conclusion, MDD, dysthymic disorder, and bipolar I depres-
sive disorder are all biological disorders, and changes in pos-
itive and negative emotions in patients with any of these con-
ditions are due to biological abnormalities. As such, in the
treatment of these patients, initial assessments and meas-
urements of negative and positive emotions will help to deter-
mine treatment efficacy and progress and assist in estab-
lishing better compliance. An even better prognosis can be
anticipated for patients who are able to experience and mon-
itor the change from high to low levels of negative emotions
and from low to high levels of positive emotions. I
References
1. Levesque M, Bedard A, Cossette M, Parent A. Novel aspects of the chemical
anatomy of the striatum and its efferent projections. J Chem Neuroanat. 2003;
26:271-281.
2. Salamone JD, Correa M, Mingote S, Weber SM. Nucleus accumbens dopamine
and the regulation of effort in food-seeking behaviour: implications for studies
of natural motivation, psychiatry, and drug abuse. J Pharmacol Exp Ther. 2003;
305:1-8.
3. Delgado PL. Depression: the case for a monoamine deficiency. J Clin Psychiatry.
2000;61(suppl 6):7-11.
4. Willner P. Dopamine and depression: a review of recent evidence. I. Empirical stud-
ies. Brain Res. 1983;287:211-224.
5. Depue RA, Collins PF. Neurobiology of the structure of personality: dopamine, fa-
cilitation of incentive motivation, and extraversion. Behav Brain Sci. 1999;22:491-
569.
6. Nakonezny PA, Carmody TJ, Morris DW, Kurian BT, Trivedi MH. Psychometric
evaluation of the Snaith-Hamilton pleasure scale in adult outpatients with ma-
jor depressive disorder. Int Clin Psychopharmacol. 2010;25:328-333.
Do you take positive emotions into account while treating depressive patients?

Valdoxan has powerful anti-
depressant efficacy with an early
impact on depressed mood, an-
hedonia, and anxiety. Particularly
interesting is the demonstrated
improvement in anhedonia with
Valdoxan, as anhedonia is a core,
but difficult to treat, symptom
which is curiously absent from the
major scales that assess depres-
sion. This specific efficacy on core
symptoms of depression con-
tributes to a more complete re-
covery of emotional integrity and
functioning.
Carmen MUOZ, PhD
Servier International
Suresnes, FRANCE
Address for correspondence:
Carmen Muoz, Servier International,
50 rue Carnot, 92284 Suresnes
Cedex, France (e-mail:
carmen.munoz@fr.netgrs.com)
www.medicographia.com
Valdoxans unique profile of antidepressant efficacy Muoz
VA L D OX A N
Valdoxans unique profile
of antidepressant efficacy
at the core of depression
b y C . M u o z , Fra n c e
T
his article will review the efficacy of Valdoxan (agomelatine) at the core
of depression, in other words, on main symptoms such as depressed
mood and anhedonia. Sad mood and anhedonia, together with anxiety
are regularly seen in depressed patients and are among the most distressing
symptoms of the disorder. Valdoxan demonstrated efficacy in treatment of
depressed mood and early anxiolytic efficacy even in the most anxious de-
pressed patients, both in randomized and in observational postregistration
trials. Two studies evaluating the effect on anhedonia through use of a scale
specific for that symptom (the Snaith-Hamilton Pleasure Scale) showed ear-
lier and better improvement with Valdoxan than with venlafaxine in the restora-
tion of pleasure and interest. These effects on anhedonia were reported by
doctors and patients in real-life situations and are all the more important giv-
en the scarcity of data in the literature on the effects of available antidepres-
sants on this core symptom of depression. Taken together, Valdoxans effects
at the core of depression lead to recovery of emotional integrity and of social
and cognitive functioning in depressed patients, insuring better quality of life
during and beyond depression.
Medicographia. 2013;35:327-333 (see French abstract on page 333)
o be effective, an antidepressant needs to target its antidepressant activity
T at the two main core symptoms of depression: depressed mood and anhe-
donia. Whereas most drugs have been evaluated in treatment of sad mood,
there is not much data to consult in the literature about alleviation of anhedonia with
antidepressants. Targeting the abatement of these symptoms is a challenge for an-
tidepressant treatment to achieve complete recovery. Anhedonia has been defined
by the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV) as the diminished interest or pleasure in response to stimuli that were pre-
viously perceived as a reward during the premorbid state1; anhedonia results in poor
outcome during major depression2 and is also found as a residual symptom.3 Its
recognition and treatment are key to treatment, as it is at the core of depression.4
Apart from rodents, where anhedonia serves as an animal model of depression,
most studies do not specifically look for this dimension. Some antidepressants have
been studied for their effect on anhedonia, but no specific assessment tool or scale
has been used. Among the antidepressants evaluated, moclobemide was found
to be better than clomipramide for alleviation of anhedonia in depressed patients,5
but the evaluation was done using specific items of the Depressive Mood Scale
MEDICOGRAPHIA, Vol 35, No. 3, 2013 327
VA L D OX A N
(chelle dHumeur Dpressive [EHD]).6 Sertraline was evaluat-
ed for its effect on anhedonia in an 8-week, open-label study
conducted in 140 depressed patients receiving sertraline treat-
ment, using clusters of symptoms defined in the Inventory for
Depressive Symptomatology (IDS). A significant improvement
in hedonic function was found, but this improvement appeared
late, occurring after improvement of the anxiety and depres-
sion clusters.7 Again, no specific tool assessing anhedonia
was used in this study. For both studies, the use of nonspe-
cific assessments could have led to a lack of sensitivity and
specificity in anhedonia recognition.
On the other hand, conventional antidepressants have a neg-
ative impact on emotion recognition and processing. Emo-
tional dysregulation is frequently described during conven-
tional antidepressant treatment, after depression remission, as
residual symptoms. Furthermore, these effects can be distin-
guished from the depressive process, as confirmed in healthy
subjects, such as in a recent study comparing citalopram and
reboxetine,8 in which treatment with selective serotonin re-
uptake inhibitor (SSRI) reduced activation both in response
to the reward stimuli and to the aversive ones. These results
raise the possibility of antidepressant-induced emotional blunt-
ing. However, it is difficult to differentiate residual symptoms,
revealing lack of efficacy of the treatment, from emotional side
effect of the drug. Emotional blunting is experienced by pa-
tients as impairment in resolving their own emotional issues,
modification of their personality, or insensitivity to their envi-
ronment including peers, family, and routine tasks.9 These
secondary effects have a direct impact on cognition and so-
cial functioning, and lead to pervasive impairment during main-
tenance treatment.
Valdoxan (agomelatine) has a novel and unique pharmaco-
logical profile in the antidepressant armamentarium. It is an
agonist at MT1 /MT2 receptors and an antagonist at 5-HT2C
receptors. These receptors act synergistically to contribute
to the efficacy of Valdoxan in depression.10,11 Valdoxans dis-
tinctive antidepressant properties have been evaluated and
reported in clinical randomized trials versus placebo and avail-
able antidepressants12 and, since its marketing authorization
in 2009, several observational studies have replicated and con-
firmed its antidepressant efficacy in daily clinical practice.13-15
Because of its different pharmacological profile, also charac-
terized by a lack of effect on serotonergic release in the brain,
it was of interest to determine the effect of Valdoxan in the
processing of emotional information which may be key for its
distinctive efficacy on the core symptoms of depression. In-
deed, a study with healthy volunteers demonstrated the ear-
ly effects of Valdoxan on emotional processing, evidenced by
the selective reduction in subjective reports of sadness, im-
provement in positive aspects of emotional memory, and mod-
ulation of the emotion-potentiation of startle response.16 These
first results suggested that Valdoxan could have an impact
328 MEDICOGRAPHIA, Vol 35, No. 3, 2013
on emotional processing in depression and anxiety and an
earlier efficacy on positive affect in particular, therefore mak-
ing the efficacy of Valdoxan different from conventional anti-
depressants.
This article will review the unique efficacy of Valdoxan on the
core symptoms of depression that leads to improvement in
emotional processing and functioning of depressed patients.
Valdoxan provides efficacy at the core of depression
The efficacy of Valdoxan in depression has been evaluated by
the effects on all symptoms, with special attention to the key
symptoms of depressed mood, anhedonia, and anxiety. In-
deed, these symptoms are regularly seen in depressed pa-
tients and belong to the most distressing ones of the disorder.
N Valdoxan is effective on depressed mood
The effect of Valdoxan on depressed mood has been evalu-
ated in comparison with placebo treatment in an analysis of a
pool of three placebo-controlled studies,17-19 and confirmed
in two observational studies.13,14 The three placebo-controlled
studies were multicenter, double-blind, randomized trials of
Valdoxan for major depressive disorder (MDD) and the patient
population was similar: outpatients fulfilling DSM-IV criteria for
MDD, with a higher proportion of females than males (around
2/3) and a Hamilton Depression Rating Scale (HAM-D) score
at inclusion of 20-22.
After 6 to 8 weeks of treatment, Valdoxan was significantly
better than placebo in the exploratory analysis of item 1, de-
pressed mood, in the HAM-D scale, and this whatever the
SELECTED ABBREVIATIONS AND ACRONYMS
DSM Diagnostic and Statistical Manual of Mental Disorders
CGI Clinical Global Impression Scale
EHD chelle dHumeur Dpressive (Depressive Mood
Scale)
HAM-A Hamilton Anxiety Scale
HAM-D Hamilton Depression Rating Scale
ICD International Classification of Disease
IDS Inventory for Depressive Symptomatology
MADRS Montgomery-Asberg Depression Rating Scale
MDD major depressive disorder
ODQ Oxford Depression Questionnaire
SDS Sheehan Disability Scale
SHAPS Snaith-Hamilton Pleasure Scale
SNRI selective serotonin-norepinephrine reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
svMADRS shortened version of Montgomery-Asberg Depres-
sion Rating Scale
VALID VALdoxan In Depression
VIVALDI Valdoxan Improves depressiVe symptoms And
normaLizes circaDIan rhythms
Valdoxans unique profile of antidepressant efficacy Muoz
 VA L D OX A N

significant (P<0.00001) improvement in the total HAM-D score,

0.4 0.35 already present at week 1 (decrease to 19.57.1) and contin-
P<0.001
0.29 0.30 uing onwards. The final score after the 8 weeks of treatment
Difference from placebo

P<0.001 P<0.001 was of 4.74.7 (P<0.00001). The score for the depressed
0.3
mood item of the HAM-D scale decreased in the patients treat-
at week 6/8

0.2
ed with Valdoxan early in the treatment.14

0.1
N Valdoxan demonstrated early and continuous restoration
of pleasure and interest
0
Anhedonia has been evaluated in two specific studies, one
Total Population Population versus baseline and the second versus venlafaxine.21,22 These
population HAM-DM25 HAM-DM25
(ITT) + CGIM5 studies used a specific and validated anhedonia scale, the
Snaith-Hamilton Pleasure Scale (SHAPS).23 A significant im-
Figure 1. Effect of 6 to 8 weeks of Valdoxan treatment on de- provement in anhedonia was demonstrated with Valdoxan
pressed mood regardless of baseline severity. from the first week and over the course of treatment and was
Valdoxans efficacy, whatever the severity of the disorder, is demonstrated by
a significant difference from placebo for item 1 of the HAM-D scale, crucial for greater than with venlafaxine (Figure 2).22 Also, at the end of
the diagnosis of depression. the study, Clinical Global Impression Scale (CGI) scores were
Abbreviations: , difference in item 1 (depressed mood) of the HAM-D scale significantly improved only in patients treated with Valdoxan.
between patients receiving placebo and those receiving Valdoxan 25-50 mg
over 6 to 8 weeks; CGI, Clinical Global Impression Scale; HAM-D, Hamilton Details of the methodology and results of these two studies
Depression Rating Scale; ITT, intention-to-treat. can be found in the article by Di Giannantonio21 in this issue.
After reference 20: Demyttenaere. Eur Neuropsychopharmacol. 2011;21(suppl

N Valdoxan demonstrates early anxiolytic efficacy even

4):S703-S709. 2011, Elsevier B. V. and ECNP.

severity of depression at inclusion. The difference with place- in more anxious depressed patients
bo in favor of Valdoxan was significant not only for the total Valdoxans anxiolytic efficacy in depression has been evalu-
population, but also for severely depressed patients at inclu- ated in this pool of three placebo-controlled, short-term stud-
sion (Figure 1).20 ies and also in a pool of three short-term studies versus SSRIs
(eg, fluoxetine and sertraline) and a selective serotonin-nor-
The observational study VIVALDI (Valdoxan Improves de- epinephrine reuptake inhibitor (SNRI; eg, venlafaxine) over 6
pressiVe symptoms And normaLizes circaDIan rhythms) used to 8 weeks.24 These three studies versus comparators were
the shortened version of the Montgomery-Asberg Depres- also multicenter, double-blind, randomized trials of Valdoxan
sion Rating Scale (svMADRS) to evaluate the antidepressant for MDD and the patient population was similar, suffering from
efficacy of Valdoxan in 3317 depressed outpatients in Ger- moderate to severe depression, except the study with fluoxe-
many, of which 38.1% had neuropsychiatric comor-
bidity. The mean score of the svMADRS at inclusion
Venlafaxine XR Valdoxan 25-50 mg (n=30)
was 30.6 (8.7). The results showed a general de- 75-150 mg (n=30)
crease in the svMADRS total score to 24.2 (9.7) al- *P<0.05; **P<0.01
7
ready after 2 weeks of treatment and to 12.8 (9.7) 6.4 6.5 * ** **
after 12 weeks. After the treatment period, the in- 6
5.5
dividual item representing depressed mood, ap- 5.1 5.1
parent sadness, showed an improvement in 72.3% 5
(SHAPS) score

of the patients.13 4
Anhedonia

4
3.5 3.4
Another observational study, CHRONOS (not an 3
acronym), was performed in the Russian Federa-
tion with a total of 6276 patients included in the 2

study. The majority of patients (80%) were treated 1

as outpatients and 20% as inpatients in psychiatric
facilities. Considering all patients, most of them 0
W0 W1 W2 W8
(82%) suffered from moderate (according to Inter-
national Classification of Disease [ICD]-10 criteria)
Figure 2. Snaith-Hamilton Pleasure Scale scores for anhedonia at baseline
depressive episodes, either single (44%) or recur- and at week 1, 2, and 8 in patients treated with Valdoxan or venlafaxine.
rent (38%). The mean 17-item HAM-D total score at Valdoxan improves anhedonia early in treatment and this improvement is greater than with
baseline was 22.56.9. Valdoxan was usually given venlafaxine.
Abbreviations: SHAPS, Snaith-Hamilton Pleasure Scale; W, week.
as monotherapy and comorbidities excluded psy- Adapted from reference 22: Martinotti et al. J Clin Psychopharmacol. 2012;32:487-491.
chotic symptoms. This study showed a rapid and 2012, Lippincott Williams & Wilkins.

Valdoxans unique profile of antidepressant efficacy Muoz MEDICOGRAPHIA, Vol 35, No. 3, 2013 329
VA L D OX A N
tine where the patients were severely depressed with a HAM-D
score 25 at inclusion. The anxiolytic efficacy was assessed
in the total population and in the more severely anxious pa-
tients (defined as those entering the study with a score 5 in
the items of the HAM-D reflecting psychic [item 10] and so-
matic [item 11] anxiety). The evaluation tools were the items
10 and 11 of the HAM-D and the more specific scale, the
Hamilton Anxiety Scale (HAM-A).
Valdoxan demonstrated anxiolytic efficacy in depression ver-
sus placebo early in the treatment. The evaluation of the items
10 and 11 of the HAM-D scale showed a significant difference
in the total population (=0.29; P=0.004) and also in the high-
ly anxious population (=0.34; P=0.005) after 2 weeks of treat-
ment (first evaluation) and over the course of treatment in
favor of Valdoxan. The anxiolytic efficacy was independent of
the concomitant use of benzodiazepines.
The efficacy in anxiety in depressed patients was also signif-
icantly greater with Valdoxan when compared with SSRIs or
the SNRI venlafaxine. A meta-analysis of these studies showed
that the comparison of HAM-D anxiety subscores and the de-
crease in the HAM-A scale was in favor of Valdoxan in the to-
tal population and even more so in the highly anxious popu-
lation ( between Valdoxan and comparators at the last value
[HAM-A score, 6-8 week period] was 1.72; P=0.032). For
more extensive details of the methodology of the evaluations
and of the results, please refer to reference 25.
Valdoxans efficacy in the three dimensions
of depression
While an effect on the core symptoms of depression is an es-
sential element of antidepressant efficacy, it is also a prereq-
uisite for a full and sustained recovery from depression. Such
a recovery implicates the restoration of emotional capacities
as well as good cognitive and social functioning.
N Valdoxans efficacy in helping patients to recover their
emotional integrity
Conventional antidepressants, namely SSRIs, may tend to neu-
tralize the processing of both negative and positive emotions,
and this emotional detachment that is observed during and
after treatment may persist even after the clinical signs of de-
pression have disappeared.26 The results obtained after ad-
ministering Valdoxan to healthy volunteers, namely the spe-
cific reduction in recognition of only sad facial expressions,
could suggest that treatment with Valdoxan may prevent the
emotional detachment often seen with antidepressant treat-
ment. To demonstrate this hypothesis, patients treated with
Valdoxan 25-50 mg and escitalopram 10-20 mg were evalu-
ated by means of the Oxford Depression Questionnaire (ODQ)
after 24 weeks of treatment.27 This questionnaire investigates
the prevalence of emotional side effects of antidepressants in
patients with MDD.28 The patients evaluated were a subset of
English-speaking patients (36 treated with Valdoxan and 30
330 MEDICOGRAPHIA, Vol 35, No. 3, 2013
with escitalopram) belonging to an international, multicenter,
randomized, double-blind study with parallel groups (Val-
doxan and escitalopram). Patients (males and females) had
MDD of moderate or severe intensity with a 17-item HAM-D
score at inclusion of 22. Statistical analysis using descriptive
statistics were carried out to compare the emotional dimen-
sion of the patients treated with Valdoxan versus escitalopram.
The results demonstrated that 60% of patients treated with
escitalopram felt that their emotions lacked intensity versus
only 28% treated with Valdoxan (P=0.063) and that more
than half of the patients treated with escitalopram (53%) felt
that things that they cared about before illness did not seem
important anymore versus only 16% treated with Valdoxan.
This clearly demonstrated the more favorable effect of Val-
doxan versus escitalopram on the emotional dimension af-
ter 6 months of treatment in the depressed.27
The German study VIVALDI corroborates in daily clinical prac-
tice the restoration of emotions induced by Valdoxan: nearly
70% of patients had improvement in their emotions after the
acute treatment period (12 weeks).13
More recently, the effects of Valdoxan on emotions have been
studied by functional imaging. Depressed patients show re-
duced attention to others with a shift of attention from others
to self. This increased self-focus, which is a core feature in
major depression, is associated with hyperactivity of prefrontal
structures, such as the ventrolateral prefrontal cortex, the dor-
solateral prefrontal cortex, and the dorsal anterior cingulate
cortex. Depressed patients treated with Valdoxan 25 mg (n=13)
or placebo (n=12) were scanned, as were healthy volunteers
(n=14), while performing self-referential processing using emo-
tional pictures. Results demonstrate that Valdoxan has an ear-
ly effect (after 1 week) in modifying functions in strategic brain
areas involved in emotional processing; these changes in brain
activity after only 7 days of treatment could contribute to the
early clinical effects of Valdoxan.29
N Improvement in cognitive functioning
The effects of Valdoxan in cognition were evaluated versus
escitalopram in a double-blind, randomized, head-to-head
study. A total of 138 outpatients with MDD received Valdox-
an 25-50 mg (n=71) or escitalopram 10-20 mg (n=67) for 6
weeks followed by an optional treatment up to 24 weeks. Cog-
nitive functioning was assessed by visual analog scales. After
6 weeks of treatment, Valdoxan induced more clear thinking
(P=0.003) and improved the feeling of being wide awake
(P=0.005) compared with baseline, while escitalopram did not
(Figure 3).30
The study VIVALDI shows again the positive effect of Valdox-
an in the cognitive functioning of depressed patients, with
improvement in concentration difficulties observed in 70% of
these patients at the end of the acute treatment period.13
Valdoxans unique profile of antidepressant efficacy Muoz
 VA L D OX A N

Disability Scale (SDS), and it was demonstrated that from the

Valdoxan **P=0.003 vs baseline first week of treatment, the three subscores of the scale,
10
Escitalopram work/school activities, social life, and family life were sig-
8 ** nificantly improved (P<0.001). At the end of the treatment,
the 3 subscores had decreased from a baseline of 7.3, 7.7,
6
and 6.9 to 2.5, 2.4, and 2.1, respectively.15
from baseline (mm)

4
Median change

2 The tolerability and safety of Valdoxan is good. Liver transam-

0
2 continued in these patients, the serum transaminases usually
4 returned to normal levels. Valdoxan is contraindicated in pa-
6
8 W2
Figure 3. Changes in cognitive functioning (clear thinking) as as-
sessed by visual analog scale after 2 and 6 weeks of treatment
with Valdoxan or escitalopram.
Valdoxan improves cognitive functioning better than escitalopram.
Abbreviation: W, week.
After reference 30: Quera-Salva et al. Int Clin Psychopharmacol. 2011;26:252-
262. 2011, Wolters Kluwer Health/Lippincott Williams & Wilkins.
N Improvement in social functioning
Randomized studies have demonstrated the improvement in
social functioning with Valdoxan, evidenced by reduction in
items 7 and 8 (work and activities and psychomotor retar-
dation, respectively). The pooled analysis of three placebo-
controlled studies20 with 358 depressed patients treated with
Valdoxan and 363 with placebo for 6 to 8 weeks, showed a
difference in favor of Valdoxan of 0.32 (P<0.001) in item 7 and
of 0.2 (P<0.005) in item 8. This advantage of Valdoxan has
been confirmed in the observational study VALID (VALdoxan
In Depression), performed in a population of 111 depressed
patients (28 were men). The study was multicenter, open, and
lasted 8 weeks. The mean MADRS total score at baseline was
28.7 points and decreased statistically from the first week (24.7;
P<0.001) and over the 8 weeks (9.8; P<0.001) of treatment.
Patients were assessed with a specific scale, the Sheehan
Figure 4. Change in
individual items of the
svMADRS at week 12
of Valdoxan treatment. 80
In the noninterventional
70
study VIVALDI, 7-8 out of
10 patients experience im- 60
provement at the core of
Patients (%)
inase increases have been reported in 1.4% of patients treat-
ed with 25 mg and 2.5% on 50 mg; when Valdoxan was dis-
tients with hepatic impairment. Liver function tests should be
performed in all patients to ensure appropriate hepatic mon-
W6
itoring as recommended in Valdoxans summary of product
characteristics.31
Conclusion
These data clearly demonstrate that Valdoxan has powerful
antidepressant efficacy with an early impact on depressed
mood, anhedonia, and anxiety. This specific efficacy on core
symptoms of depression contributes to a more complete re-
covery of emotional integrity and of both cognitive and so-
cial functioning.
Particularly interesting is the demonstrated improvement in
anhedonia with Valdoxan, as anhedonia is a core, but diffi-
cult to treat, symptom which is curiously absent from the ma-
jor scales that assess depression. Valdoxans efficacy in reduc-
ing anhedonia occurs early in the treatment and is greater
than what is seen with venlafaxine. This has been repeatedly
reported by doctors and patients in real-life situations with a
particular regain of interest in pleasurable activities from the
first days of treatment with Valdoxan. Furthermore, CGI-scale
results are more favorable for Valdoxan than venlafaxine, sug-
gesting the importance of the improvement in anhedonia. The
recent functional magnetic resonance imaging (fMRI) study
sheds light on how Valdoxan regulates automatic control dur-
Improvement Unchanged Worsening
80.8
72.0 72.3
70.3
67.4

depression and in the differ- 50

ent dimensions of depres-
sion, thus confirming in clin- 40
ical practice the results of
the randomized studies. 30 25.2
22.0 21.5
Abbreviations: svMADRS, 20.4
20 15.1
shortened version of the
Montgomery-Asberg 10 7.6 7.7 7.4 6.3
4.1
Depression Rating Scale.
After reference 13: Laux et 0
al. Pharmacopsychiatry. Reduced sleep Tension Difficulties Lack of Sadness
2012;45:284-291. 2012, concentrating emotions
Georg Thieme Verlag KG n=3310 n=3310 n=3309 n=3308 n=3310
Stuttgart New York.

Valdoxans unique profile of antidepressant efficacy Muoz MEDICOGRAPHIA, Vol 35, No. 3, 2013 331
VA L D OX A N
ing self-processing of emotions, suggesting the early set-up
of the brain for long-term response and depression remission.
The quality of recovery achieved with Valdoxan is the result of
this efficacy and represents a unique aspect of Valdoxan. This
recovery, first observed in randomized controlled trials, has
been confirmed by consistent data from daily medical practice
(Figure 4, page 331).13
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3. Taylor DJ, Walters HM, Vittengl JR, et al. Which depressive symptoms remain
after response to cognitive therapy of depression and predict relapse and re-
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4. Goodwin GM. Symptom relief and facilitation of emotional processing. Eur Neu-
ropsychopharmacol. 2011;21(suppl 4):S710-S715.
5. Jouvent R, Le Houezec J, Payan C, et al. Dimensional assessment of onset of
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in depressed patients with blunted affect and psychomotor retardation. Psy-
chiatry Res. 1998;79(3):267-275.
6. Jouvent R, Vindreau C, Montreuil M, et al. La clinique polydimensionnelle de
lhumeur dpressive. Nouvelle version de l'chelle EHD. Psychiatrie et Psycho-
biologie. 1988;3:245-253.
7. Boyer P, Tassin JP, Falissart B, Troy S. Sequential improvement of anxiety, de-
pression and anhedonia with sertraline treatment in patients with major depres-
sion. J Clin Pharm Ther. 2000;25(5):363-371.
8. McCabe C, Mishor Z, Cowen PJ, Harmer CJ. Diminished neural processing of
aversive and rewarding stimuli during selective serotonin reuptake inhibitor treat-
ment. Biol Psychiatry. 2010;67(5):439-445.
9. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin re-
uptake inhibitors: qualitative study. Br J Psychiatry. 2009;195(3):211-217.
10. Racagni G, Riva MA, Molteni R, et al. Mode of action of agomelatine: synergy
between melatonergic and 5-HT2C receptors. World J Biol Psychiatry. 2011;12:
574-587.
11. de Bodinat C, Guardiola-Lemaitre B, Mocar B, et al. Agomelatine, the first mela-
tonergic antidepressant: discovery, characterization and development. Drug Dis-
covery. 2010;9:628-642.
12. Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in
the treatment of major depression. Lancet. 2011;378:621-631.
13. Laux G; VIVALDI Study Group. The antidepressant agomelatine in daily practice:
results of the non-interventional study VIVALDI. Pharmacopsychiatry. 2012;
45:284-291.
14. Ivanov SV, Samuchia MA. Agomelatine (Valdoxan) in clinical practice: results from
the Russian observational program CHRONOS. Int J Psychiatry Clin Pract. 2011;
15(S2):Abstract P 29.
15. Novotny V, Pezenak J. Agomelatine in depression treatment, multicenter study
in Slovakia. Int J Psychiatry Clin Pract. 2011;15(S2):Abstract P 44.
Keywords: anhedonia; depression; emotions; functioning; Valdoxan
332 MEDICOGRAPHIA, Vol 35, No. 3, 2013
The results presented in this article support the difference
between Valdoxan and conventional antidepressants in terms
of efficacy, where Valdoxan not only gives the patients the pos-
sibility to begin to enjoy life and to connect with their emo-
tions early in the treatment, but also leads to recovery of so-
cial and cognitive functioning, which ensures a better quality
of life during and even beyond depression. I
16. Harmer CJ, de Bodinat C, Dawson GR, et al. Agomelatine facilitates positive
versus negative affective processing in healthy volunteer models. J Psycho-
pharmacol. 2011;25(9):1159-1167.
17. Lo H, Hale A, DHaenen H. Determination of the dose of agomelatine, a mela-
tonergic agonist and selective 5-HT2C antagonist, in the treatment of major de-
pressive disorder: a placebo-controlled dose range study. Int Clin Psychophar-
macol. 2002;17:239-247.
18. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment
of major depressive disorder. Eur Neuropsychopharmacol. 2006;16:93-100.
19. Oli JP, Kasper S. Efficacy of agomelatine, a MT1 /MT2 receptor agonist with
5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsy-
chopharmacol. 2007;10:661-673.
20. Demyttenaere K. Agomelatine: a narrative review. Eur Neuropsychopharmacol.
2011;21(suppl 4):S703-S709.
21. Di Giannantonio M, Di Iorio G, Guglielmo R, et al. Major depressive disorder, an-
hedonia and agomelatine: an open-label study. J Biol Regul Homeost Agents.
2011;25(1):109-114.
22. Martinotti G, Sepede G, Di Nicola M, et al. Agomelatine versus venlafaxine XR
in the treatment of anhedonia in major depressive disorder: a pilot study. J Clin
Psychopharmacol. 2012;32:487-491.
23. Snaith RP, Hamilton M, Morley S, et al. A scale for the assessment of hedonic
tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167(1):99-103.
24. Stein DJ, Picarel-Blanchot F, Kennedy SH. Efficacy of the novel antidepressant
agomelatine on anxiety symptoms in major depression. Hum Psychopharma-
col Clin Exp. 2013;28:151-159.
25. Muoz C. Efficacy of Valdoxan, the first melatonergic antidepressant, in anxiety
within depression. Medicographia. 2012;34(3):328-333.
26. Goodwin GM. Symptom relief and facilitation of emotional processing. Eur Neu-
ropsychopharmacol. 2011;21:S710-S715.
27. Corruble E, Blaidi C, Goodwin GM. Agomelatine versus escitalopram in major
depressive disorders: a randomized double-blind, long term study focusing on
sleep satisfaction and emotional blunting. Eur Psychiatry. 2011;26(1):P02-P24.
28. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin re-
uptake inhibitors: qualitative study. Br J Psychiatry. 2009;195(3):211-217.
29. Fossati P, Jabourian M, Laredo J, Allailli N, Lehericy S, Delaveau P. Early effects
of agomelatine on self-referential processing in acute depressed patients: a fMRI
study. Poster presented at the 21st European Congress of Psychiatry (EPA 2013);
April 6-9, 2013; Nice, France.
30. Quera-Salva MA, Hajak G, Philip P, et al. Comparison of agomelatine and esci-
talopram on nighttime sleep and daytime condition and efficacy in major de-
pressive disorder patients. Int Clin Psychopharmacol. 2011;26:252-262.
31. Summary of product characteristicsValdoxan (agomelatine); www.ema.
europa.eu
Valdoxans unique profile of antidepressant efficacy Muoz
 VA L D OX A N

LE PROFIL D EFFICACIT ANTIDPRESSIVE ORIGINAL DE VALDOXAN

AU CUR DE LA DPRESSION
Cet article analyse lefficacit de Valdoxan au cur de la dpression, cest--dire sur les principaux symptmes comme
lhumeur dpressive et lanhdonie. Lhumeur triste et lanhdonie, ainsi que lanxit, sont courantes chez les pa-
tients dprims et font partie des symptmes les plus pnibles de cette pathologie. Dans des tudes post-enregis-
trement randomises et observationnelles, Valdoxan est efficace sur lhumeur dpressive et prsente une activit
anxiolytique prcoce mme chez les patients dprims les plus anxieux. Au cours de deux tudes valuant leffet de
lanhdonie sur une chelle spcifique, la Snaith-Hamilton Pleasure Scale, Valdoxan permet une amlioration plus
prcoce et de meilleure qualit du plaisir et de lintrt, que la venlafaxine. Ces effets sur lanhdonie ont t rappor-
ts par des mdecins et des patients en situation de vie relle et ils sont encore plus intressants vu la raret des
donnes de la littrature concernant les effets des autres antidpresseurs sur ce symptme au cur de la dpres-
sion. En rsum, lefficacit de Valdoxan au cur de la dpression permet le rtablissement de lintgrit motion-
nelle et du fonctionnement social et cognitif des patients dprims, assurant une meilleure qualit de vie pendant
et aprs la dpression.

Valdoxans unique profile of antidepressant efficacy Muoz MEDICOGRAPHIA, Vol 35, No. 3, 2013 333

Medication changes the pa-
tients emotions and behavior to
such an extent that some claim
antidepressants can even change
the personality of the patient.
An antidepressant treatment must
not only remove the suffering, the
guilt, and the sadness, but also re-
store the capacity to feel pleasure,
happiness, and interest. Merely
substituting the suffering for the
absence of feelings is not a good
strategy for the patients; it is only
good for the scores in scales.
Pedro Antnio SCHMIDT DO
PRADO-LIMA, MD, PhD
CNRG, Porto Alegre, BRAZIL
Address for correspondence:
Dr Pedro Antnio Schmidt do
Prado-Lima, Rua lvares Machado
44-305 (Zip Code 90630-010),
Porto Alegre, Brazil
(e-mail: paspl@uol.com.br)
www.medicographia.com
334 MEDICOGRAPHIA, Vol 35, No. 3, 2013
INTERVIEW
Treating emotions
in depression:
clinical experience
Interview with
P. A . S c h m i d t d o P rad o - L i m a , B ra z i l
T
argeting emotions in the treatment of major depressive disorder is not a
new idea. Since tricyclic antidepressants were first used, psychiatrists
have been trying to fully understand the differences in the profiles be-
tween the various drugs, not only in terms of side effects, but also in terms of
therapeutic effects. For example, is there a difference between imipramine
and clomipramine? Is one or the other more apt to protect against suicidal be-
havior? Is one or the other more apt to provoke this behavior in some patients?
Is one or the other more likely to be effective in cases of panic disorder or ob-
sessive-compulsive disorder? Is one or the other better at diminishing impul-
sivity? I believe such differences exist and think that we must use this knowl-
edge, often easy to recognize in clinical practice, but difficult to demonstrate
in clinical trials.
Medicographia. 2013;35:334-336 (see French abstract on page 336)
Are positive and negative emotions connected during major
depressive disorder?
or such a complex question, there is no single, simple answer. However, from one
F point of view, I think that two different scenarios may occur in relation to emo-
tions during major depressive disorder, and both of them could be present to
some extent in the same patient at the same time. Firstly, there is a predominance of
negative emotions over positive ones. It is this scenario, the expression of negative
emotions, which is most frequently recognized in depression. Even memory is affect-
ed by this valence, allowing depressive people to remember negative events in their
lives perfectly, while other memories are difficult for them to recall.1 Secondly, patients
may experience blunted emotions. This is not a new idea, for example, this incapac-
ity to feel is rated in item 8 of the Montgomery-Asberg Depression Rating Scale
(MADRS).2 For patients that experience this flattening of emotions during depression,
selective serotonin reuptake inhibitors (SSRIs) may often maintain or even increase
this neutrality, although improving other aspects of depressive syndrome. In this
sense, negative and positive emotions could be connected in depressive patients.
What is the clinical advantage of targeting emotions in depression?
his question could be approached in two ways: based on use of psychother-
T
apy (mainly cognitive behavioral therapy) or based on use of medications. Re-
garding use of medications, we must first take into account that different drugs
Treating emotions in depression: clinical experience Schmidt do Prado-Lima

act in different ways; we need to take advantage of this to im-
prove the treatment response. In general, though these differ-
ences between drugs are not evidenced by clinical trials, we
must not deny their existence because we do not as yet have
the means of identifying them in standard psychopharmaco-
logical clinical trials. It is usually difficult to clinically recognize
and develop a consensus about subtle profile differences
among drugs within the same class.
The most popular class of antidepressants is the selective sero-
tonin reuptake inhibitors (SSRIs). We often observe patients
that respond partially to these medications, while maintaining
symptoms of emotional blunting. Addition of a dopaminergic
medication in the treatment regimen could improve the re-
sponse. Looking at this effect, it seems that we have medica-
tions that prompt people to be more phlegmatic, British (for
example, SSRIs), and medications that allow people to be
more exuberant in expressing emotions, more Italian (for ex-
ample, bupropion). Taking this into consideration, we can help
patients that seek more intensity in their feelings, for exam-
ple, those complaining that they are incapable of crying in
appropriate situations, which is very common.
What does the emergence of positive feeling tell
us about the recovery process?
e have to recognize that antidepressant treatment
W is different from some endocrinological ones. In
hypothyroidism, the use of thyroid hormone reg-
ularizes thyroid function so that it is as if the disorder were not
present. Likewise, patients and even doctors often imagine
that antidepressant treatment can regularize the level of brain
amines to ideal levels and thus return the brain to the prede-
pressive state. Unfortunately, that is not the case. The medica-
tion changes the patients emotions and behavior to such an
extent that some claim antidepressants can even change the
personality of the patient. So, the treatment must take these
changes into account.
For example, we can diminish impulsivity (and emotion) using
SSRIs. Indeed, for some patients this could be beneficial, but
for others absolutely not. In general, an antidepressant treat-
ment must not only remove the suffering, the guilt, and the
sadness, but also restore the capacity to feel pleasure, hap-
SELECTED ABBREVIATIONS AND ACRONYMS
MADRS Montgomery-Asberg Depression Rating Scale
SSRI selective serotonin reuptake inhibitor
Keywords: antidepressants; blunted emotions; major depressive disorder; negative emotions; positive emotions
Treating emotions in depression: clinical experience Schmidt do Prado-Lima
INTERVIEW
piness, and interest. Merely substituting absence of feelings
for the suffering is not a good strategy for the patients; it is only
good for the scores in scales.
Are positive and negative emotions equally blunted
after a major depressive disorder?
ome patients can have a partial recovery after depres-
S sion, treated or not. If they were treated, this partial re-
sponse could be related to the medication used, as ex-
plained above.
One of the symptoms that may persist is blunted positive and/
or negative emotion. At first glance, this could be viewed as
an advantage for the patient, as a lack of emotion is better
than suffering, but over time treatment must deal with this par-
tial response. By contrast, ignoring this symptom (if it is a par-
tial response) or side effect (if it is due to the antidepressant
used) changes the patients perspectives, options, behavior,
and attitude.
Why is treatment based on targeting emotions
not popular in major depressive disorder?
ur clinical practice must be scientifically oriented. That
O is the reason that we have adopted evidence-based
medicine and why we expend so much effort and so
many resources to find evidence to justify one or another clin-
ical decision. The problem is that we must recognize that we
are not able to investigate and establish the evidence for all
clinical aspects. For example, guidelines in general do not take
into account comorbidities, which are very frequent in psy-
chiatry. In regards to major depressive disorders, only now are
we beginning to identify the evidence for treating clinical sub-
types and the differences in the therapeutic effect of different
antidepressants. It is important to remember that twenty years
ago even the differences between tricyclic antidepressants
and SSRIs were not recognized, although now they appear
obvious. Recently, the advent of new antidepressants with dif-
ferent mechanisms of action has stirred up interest in whether
or not those different drugs produce different therapeutic ef-
fects.3 I
References
1. Murphy FC, Sahakian BJ, OCarroll RE. Cognitive impairment in depression: psy-
chological models and clinical issues. In: Ebert D, Ebmeier KP, eds. New Models
for Depression. Basel: Karger;1998. Adv Biol Psychiatry; vol 19:1-19.
2. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to
change. Br J Psychiatry. 1979;134:382-389.
3. Millan MJ. Multi-target strategies for the improved treatment of depressive states:
conceptual foundations and neuronal substrates, drug discovery and therapeu-
tic application. Pharmacol Ther. 2006;110:135-370.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 335
INTERVIEW

EXPRIENCE CLINIQUE DU TRAITEMENT DES MOTIONS DANS LA DEPRESSION

Il nest pas nouveau de vouloir cibler les motions dans le traitement de lpisode dpressif majeur. Depuis la pre-
mire utilisation des antidpresseurs tricycliques, les psychiatres ont essay de bien comprendre les diffrences
entre chaque mdicament, non seulement en termes deffets indsirables, mais aussi en termes deffets thrapeu-
tiques. Par exemple, y a-t-il une diffrence entre limipramine et la clomipramine ? Lune protge-t-elle plus que lautre
contre un comportement suicidaire ? Lune provoque-t-elle plus que lautre ce comportement chez certains patients ?
Lune serait-elle plus efficace que lautre en cas de trouble panique ou de troubles obsessionnels compulsifs ? Lune
diminue-t-elle plus que lautre limpulsivit ? Je crois que de telles ces diffrences existent et je pense que nous de-
vons utiliser ces connaissances, souvent faciles reconnatre en pratique clinique, mais difficiles dmontrer dans
le cadre dtudes cliniques.

336 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Treating emotions in depression: clinical experience Schmidt do Prado-Lima

Our ability to identify emo-
tional states of others from rapid
emotional expressions is a key as-
pect of social cognition which is
affected in various psychiatric dis-
orders. Depression has been asso-
ciated with negative biases in the
interpretation of facial expressions
characterized as a relative inability
to detect positive facial expres-
sions, such as happiness and/or
increased sensitivity to facial ex-
pressions displaying negative
cues, such as sadness or fear.
Catherine HARMER, DPhil
University Department
of Psychiatry
Warneford Hospital
Oxford, UK
Address for correspondence:
Catherine Harmer, University
Department of Psychiatry, Warneford
Hospital, Oxford, OX3 7JX, UK
(e-mail:
catherine.harmer@psych.ox.ac.uk)
www.medicographia.com
Assessment of emotion Harmer
FOCUS
Assessment of emotion
b y C . H a r m e r, U n i t e d K i n g d o m
E
motional dysfunction is a critical feature of disorders such as depres-
sion and anxiety, but it can be difficult to fully quantify and explore using
clinical rating scales alone. In recent years, there has been significant
progress in the development of cognitive paradigms to tap into different as-
pects of emotional processing across the domains of attention, interpretation,
and memory. These approaches have been applied to characterize both the
cognitive neuropsychology and the role of emotional dysfunction in depression
and anxiety and to elucidate pharmacological and psychological treatment ac-
tion. This article reviews different approaches for assessing emotion in healthy
volunteers and in patient groups using cognitive paradigms in behavioral and
neuroimaging models. These studies have revealed consistent and partly dis-
sociable effects of depression and anxiety on emotional processing measures.
Furthermore, these emotional processing markers are targeted early follow-
ing administration of antidepressant and anxiolytic drug treatments. Such ef-
fects have been seen in the absence of changes in subjective experience, sug-
gesting that they may be more sensitive measures to index emotional bias and
response. This approach is a useful strategy to understand depression and
anxiety and provides an experimental medicine model to test out hypotheses
of treatment action and to evaluate novel compounds in development for dis-
orders involving emotional dysfunction.
Medicographia. 2013;35:337-343 (see French abstract on page 343)
isorders such as major depression and anxiety involve dysfunction of various
D aspects of emotional response and regulation. These disorders are typically
diagnosed by clinical interview involving assessment of subjective experiences
(for example, low mood or anhedonia). A variety of measurements exist to aid the cli-
nician in diagnosing, monitoring, or quantifying levels of depression and anxiety. How-
ever, different clinical scales are often used in different contexts (such as primary com-
pared with secondary care, or with psychological compared with pharmacological
treatments) and may tap into slightly different aspects of depression.1 There is increas-
ing interest in utilizing objective measures of emotional response measured with cog-
nitive paradigms which might also be less resistant to reporting biases or difficulty
in identifying or talking about ones own emotional experiences. Such an approach
may help us understand the mechanisms underlying emotional dysfunction and its
treatment.2 This review will focus on the use of these cognitive paradigms to tap into
different aspects of emotional processing and response and also the questionnaire
and rating scale methods which may usefully complement these assessments.
MEDICOGRAPHIA, Vol 35, No. 3, 2013 337
FOCUS
Cognitive paradigms
In our day-to-day life, we are exposed to a myriad of social
and emotional cues, which are often ambiguous and can be
viewed from different perspectives. How we respond to this
kind of emotional information is affected by what information
we attend to in the first place, how we perceive or interpret
this information, and what we remember later. Consistent with
this idea, there is now broad experimental evidence that these
different cognitive domains are affected in emotional disorders
such as depression.3,4 Such evidence is consistent with cog-
nitive models which propose that negative schema (or knowl-
edge structures) in depression are maintained by negative
biases in emotional processing, which together fuel the de-
pression cycle.5 In particular, incoming information is filtered so
that stimuli or events in line with the depression schema are
overrepresented, leading to increased inflow and memory of
negative over positive items. A similar approach has been sug-
gested for anxiety, with information being oversampled for
threat-relevant cues, thereby promoting excessive reactivity
to potential threat. The existence of these biases in depres-
sion and anxiety has been widely described and characterized
and has led to the development of cognitive paradigms which
can tap into these different aspects of emotional processing.3,4
Such paradigms have the potential not only to inform us about
the mechanisms underlying emotional disorders, but also to
help us understand how different treatment approaches work
to reverse this kind of emotional dysfunction.
N Attention to emotional information
A variety of experimental paradigms can be used to assess
different aspects of attention to emotional stimuli and this re-
view will focus on two of the most common methods: the emo-
tional Stroop task and the dot-probe paradigm. The emo-
tional Stroop test is a measure of interference produced by
emotional content on an unrelated response. This is a variant
of the classic color-naming Stroop task where participants
are asked to report the color of the font in which a word is
presented, but ignore the written word itself. When the color
SELECTED ABBREVIATIONS AND ACRONYMS
BDI Beck Depression Inventory
BFS Befindlichkeits Scale
CANTAB Cambridge Neuropsychological Test Automated
Battery
EPST emotion-potentiated startle task
ETB Emotional Test Battery
fMRI functional magnetic resonance imaging
HAM-D Hamilton Depression Rating Scale
MADRS Montgomery-Asberg Depression Rating Scale
PFC prefrontal cortex
SSRI selective serotonin reuptake inhibitor
STAI Spielberger State-Trait Anxiety Inventory
vmPFC ventromedial prefrontal cortex
338 MEDICOGRAPHIA, Vol 35, No. 3, 2013
and written word are incongruent (ie, red font for the written
word yellow), interference effects give rise to slower respons-
es. In a similar vein, the emotional Stroop task utilizes word
stimuli with an emotional valence to interfere with the ability
to make a speeded response (eg, naming the color of the
word death). Studies using the emotional Stroop task have
demonstrated that anxiety disorders are associated with longer
reaction times when naming the color of threatening words
compared with neutral or positive words.6 Attentional biases
toward emotional stimuli have also been reported in depres-
sion, although this interference effect does not seem to be
restricted to depression-relevant stimuli (see meta-analysis7).
The emotional Stroop task also has a number of methodolog-
ical caveats, which can make interpretation of the behavioral
findings complex. Rather than reflecting attentional capture,
it is possible that the delayed naming of the emotional words
could reflect cognitive avoidance of the stimuli.8 In addition, in-
terference may arise from a more generalized emotional arous-
al in response to the threatening or negative words, which
could lead to a delay or inhibition in response selection.9
An alternative paradigm which has been extensively used is
the dot-probe task (Figure 1).10 In this task, two stimuli (typical-
ly words or images) are displayed simultaneously on a screen,
in two separate locations. One of these stimuli usually has
an emotional value, whereas the other one is neutral. After a
brief period, the words or images disappear and a probe (for
example, one or two dots) appears on the screen, either in
the place of the emotional stimulus or in the place of the neu-
tral stimulus. The volunteers are asked to indicate the posi-
tion or type of probe as quickly as possible. The premise be-
hind this task is that if attention favors the emotional stimulus,
relative reaction time to detect the probe will be faster when
it replaces the emotional compared with the neutral stimulus.
The results from this task are less easily explained by gener-
al arousal or bias effects and it can provide a snapshot of
attentional allocation by altering the stimulus exposure dura-
tion to enable dissection of effects on attentional capture ver-
sus disengagement.
Results from the dot-probe task suggest that anxiety is as-
sociated with relatively faster responses to probes that re-
place threatening stimuli than to probes that replace neutral
stimuli. Again, this is suggestive of increased attentional vig-
ilance to the location of a threatening cue (see review11). As
with the emotional Stroop task, such attentional biases to-
ward threat have been demonstrated even when the stim-
uli are presented subliminally, suggesting that they may be
operating at a relatively automatic level of processing.12 The
dot-probe task is also sensitive to attentional negative bias in
depression,13 which may be at least partly distinct from that
seen in anxiety. While attentional bias is apparent in depression
at relatively long stimuli durations (eg, 500 ms-1000 ms13),
there are potential differences when the stimuli are presented
for shorter durations. For example, Mogg et al reported an in-
Assessment of emotion Harmer

Time
x ing biases in depression.
Death
x
..
Model
x is affected in various psychiatric disorders. Depression has
Figure 1. An example dot-probe paradigm.
Volunteers are asked to fixate centrally and two stimuli are presented. One of
these stimuli is replaced by a probe to which the volunteer has to respond (eg,
by indicating if one or two dots have been presented). If attention has been al-
located to the negative stimulus, then relative reaction time will be faster if the
probe is in the same location as this stimulus (as in this example), compared
with its being presented in the opposite location. This allows vigilance to posi-
tive and negative stimuli to be computed.
creased shift of attention toward negative words presented
subliminally in anxious, but not depressed participants, where-
as the opposite pattern was seen with supraliminally present-
ed stimuli.12 These findings have led to the suggestion that
anxiety may be associated with increased orienting to threat,
whereas depression could represent a problem in disengag-
ing from negative stimuli.11
Studies using pharmacological challenges in the dot-probe
task of the Emotional Test Battery (ETB) have revealed effects
which are consistent with this framework. Administration of
the selective serotonin reuptake inhibitor (SSRI) citalopram in-
creased attentional vigilance toward positive stimuli and/or
away from negative stimuli in healthy volunteers compared
with double-blind administration of placebo.14,15 We have hy-
pothesized that such effects relate to action of SSRIs on anx-
iety-relevant processing, and consistent with this, the anxi-
olytic diazepam also reduced attention to negative compared
with positive information in this task.16 Such effects of diaze-
pam and citalopram were evident at relatively short exposure
durations, consistent with a role for early attentional process-
es in anxiety and drug action.
N Approach and inhibition
Information processing bias can also be assessed with the af-
fective gono go task (a measure included in the Cambridge
Neuropsychological Test Automated Battery [CANTAB]). In
this task, participants are presented with a series of words
which are either positive (eg, joyful), negative (eg, hopeless), or
neutral (eg, element). In a given block, participants are asked
to respond as quickly as possible to a given affective cate-
gory and inhibit responses to the other categories, therefore
providing a measure of approach, inhibition, and switching.
Negative bias in this task has been shown in adult and adoles-
cent depression, seen, for example, as quicker responses to
Assessment of emotion Harmer
FOCUS
sad versus happy stimuli,17,18 and a similar pattern is emulated
following depletion of the amino acid precursor of serotonin,
tryptophan, in healthy volunteers.19 Such effects suggest that
approach and inhibition in this paradigm may model process-
N Facial expression perception
Our ability to identify emotional states of others from rapid
emotional expressions is a key aspect of social cognition which
been associated with negative biases in the interpretation of
facial expressions characterized as a relative inability to de-
tect positive facial expressions, such as happiness and/or in-
creased sensitivity to facial expressions displaying negative
cues, such as sadness or fear.2 This kind of bias has been
found to predict depression levels 3 and 6 months later20 and
subsequent relapse to depression,21 consistent with a key role
for perceptual biases in the maintenance of this disorder. Fa-
cial expression recognition can be measured by different tasks,
but recent versions have capitalized on advances in comput-
erized graphic manipulation techniques to create stimuli with
different intensity levels.22 This morphing technique involves
blending two prototype photographs of the same individual in
different proportions to create a continuum between neutral ex-
pression and each emotion or between easily confused emo-
tions, such as happiness and surprise or disgust and anger.
In the ETB, different examples and intensity levels of six ba-
sic emotions (anger, disgust, fear, surprise, happy, and sad-
ness) are presented.2 Each face has been blended between
the prototype emotion and neutral expression in 10% steps,
which are then presented in a randomized order. Participants
are asked to classify the emotional expression of each face
using a labeled response box, allowing the measurement of
recognition accuracy, speed of correct responses, and mis-
classifications for each emotion. This task is sensitive to de-
pression23 and to antidepressant drug administration.23,24 In
particular, antidepressants such as the SSRI citalopram were
found to decrease the perception of negative facial expres-
sions (including anger, disgust, fear, and sadness) in healthy
volunteers.24 Such effects would be expected to reverse neg-
ative biases seen in depression and reduce the impact of this
key maintaining factor in this disorder. Indeed, early change
in perception of facial expressions of emotion is related to
the emergence of therapeutic response seen over time.2
Along with other measures included in the ETB, this method
has been applied to characterize novel drugs in development
for depression, providing information about effects in human
models, clinical profile, and dose.2 Using this approach, it was
assessed whether the novel antidepressant agomelatine,
which acts as a melatonergic agonist and 5-hydroxytrypta-
mine receptor 2C (5-HT2C ) antagonist, would also affect emo-
tional processing despite its different pharmacological profile
to conventional treatments. Consistent with this proposal,
MEDICOGRAPHIA, Vol 35, No. 3, 2013 339
FOCUS

7 days administration of agomelatine at 25 mg specifically
decreased the recognition of sad facial expressions compared
with placebo in healthy volunteers.25 This effect on sadness
was more selective than the more generalized effects found
with drugs like citalopram or reboxetine in this task,24 sug-
gesting a more targeted reversal of depression-relevant pro-
cessing bias following agomelatine. The use of this cognitive
neuropsychological approach applied to drug development
may therefore allow the dissection of different processes in-
volved in drug action and the generation of hypotheses about
antidepressant potential and application.
N Emotional memory
Memory bias in depression has been well characterized, with
negative stimuli being disproportionately remembered in short-
and long-term memory tests in depressed patients compared
with matched controls.3,4 Memory tasks used in depression
themselves would like or dislike to be referred to with each
characteristic. This is a variant on an original task which asked
volunteers whether each characteristic described them or not
(me or not me; for example28). This modification was made
to ensure relatively similar response choice across groups to
allow both reaction time and memory to be explored, uncon-
founded by differences in endorsement. This task is sensitive
to negative bias in depressed patients,23 volunteers at high risk
of depression,29 and dysphoric participants (unpublished data).
Effects on emotional memory may also help to dissociate those
processes relevant to depression versus anxiety. In particular,
the negative bias seen with explicit memory tasks in depres-
sion is not consistently found in anxiety disorders or in volun-
teers with high versus low trait scores on anxiety measures.27,30
Emotional memory also seems to be the domain most con-
sistently influenced by antidepressant drug treatment. Hence,
acute reboxetine, mirtazapine, and duloxetine,
and repeated administration of agomelatine, re-
boxetine, and citalopram all increased the recall
of positive versus negative stimuli in this task in
healthy volunteers.25,31-33

Similarly, a single dose of reboxetine was found

to reverse negative bias in memory in depressed
patients.23 Consistent with the distinction be-
tween depression and anxiety on emotional
memory bias, purer anxiolytics such as diaze-
pam do not typically affect performance on this
measure, despite having action on other tasks
in the battery related to anxiety (such as the dot-
probe task and startle responses16). Such a pro-
file suggests again that by understanding the
cognitive neuropsychology of drug action, we
can start to predict treatment effects and clin-
ical profiles to optimize randomized clinical trial
assessments of novel drugs in development.
Neutral Pleasant Unpleasant

N The emotion-potentiated startle task

Figure 2. The emotion-potentiated startle task.
Bursts of loud white noise are delivered through the headphones and the eyeblink startle response
The emotion-potentiated startle task (EPST) is
is measured with electromyography. The emotion-potentiated startle effect is seen as increased a human analog of the fear-potentiated startle
amplitude of startle in response to the loud noise when viewing unpleasant compared with neutral task used to screen for anxiolytic agents in pre-
or pleasant stimuli. Please note that to retain integrity of the affective stimuli used in this kind of
paradigm, fictitious example stimuli are displayed. clinical studies. There are a number of variations
Top: Image of female performing emotion-potentiated startle task. The Author. Left: Clay pot on in the way in which this task can be adminis-
light background. bryljaev/123RF. Middle: Flying Balloons. Alexander Fediachov/123RF.
Right: Image of female pointing gun at somebody breaking and entering. Justin Kral/123RF.
tered, but all involve electromyographic (EMG)
measurement of eyeblink amplitude following
typically involve explicit recall of emotional verbal material, al- a loud (eg, 90 dB) burst of noise (Figure 2). The affective com-
though other more implicit measures of memory have been ponent of this task is typically induced through presentation
used, including facial affective priming26 and anagram solv- of emotive picture stimuli or through expectation of an elec-
ing.27 Self-referent stimuli may be particularly susceptible to tric shock. Increased startle reactivity has been described in
negative bias in depression and many studies have used per- anxiety and is increased following social stress.34 In pharma-
sonality adjectives as stimuli (for example, words such as hon- cological studies, anxiolytic drug treatments have been re-
est, original, or mean). In the ETB, a first stage of encoding is ported to decrease emotion-potentiated startle responses in
used (emotional categorization), where participants are pre- healthy volunteer models.2 Thus, acute administration of di-
sented with personality adjectives and asked whether they azepam16 and mirtazapine31 and 7 days treatment with citalo-

340 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Assessment of emotion Harmer


pram24 decreased startle responses in this paradigm. Agome-
latine administration also led to abolition of the emotion-po-
tentiated startle responses in healthy volunteers, suggestive
of an anxiolytic profile.25
N Use of functional imaging models
The effects of depression and anxiety and their treatment on
emotional processing tasks provide important information
about functional changes that may be involved in etiology and
drug response. These measures can also be complemented
by neuroimaging investigations, based on similar emotional
processing tasks, which can reveal underlying neural mecha-
nisms involved in these emotional changes. The neural circuit-
ry of negative bias in depression is believed to involve interac-
tions between the amygdala, hippocampus, anterior cingulate
cortex, and dorsolateral prefrontal cortex (PFC).3 For example,
increased drive in the amygdala in depression would be ex-
pected to increase responses to and interest in negative stim-
uli and facilitate preferential encoding into memory through
projections to the hippocampus.3 Self-referent memory tasks
also tap into areas involved in self-processing, such as me-
dial PFC and precuneus, while the emotional Stroop test re-
liably activates the anterior cingulate cortex, which is involved
in conflict detection and monitoring.2 These measures can all
be adapted to work well in a functional imaging context, but
the probe used most consistently across studies involves pre-
sentations of facial expressions of emotion.
Studies using this approach in functional magnetic resonance
imaging (fMRI) have revealed increased amygdala reactivity
to fear and/or sad facial expressions in depression, which is
normalized following antidepressant treatment.35-37 These ef-
fects are seen prior to changes in mood or other symptoms
of depression, consistent with the data from behavioral mod-
els reviewed above. Decreased amygdala response to neg-
ative versus positive cues can also be observed in healthy
volunteer models and across different antidepressant drug
classes.2 Further research is needed to isolate those process-
es, which are relevant to antidepressant versus anxiolytic prop-
erties of these drug treatments. Indeed, similar effects have
also been described in the treatment of anxiety disorders. For
example, a recent study by Phan et al (2012) revealed that pa-
tients with generalized social phobia also showed increased
amygdala responses to threatening facial expressions, but de-
creased ventromedial PFC (vmPFC) responses to the same
stimuli.38 The vmPFC plays a key role in the regulation of emo-
tional reactivity, presumably via its connections with the amyg-
dala, and this pattern is therefore consistent with impaired
function of this regulatory network.39 Of particular relevance,
this imbalance in activity was normalized following a 12-week
SSRI treatment.38
The use of fMRI in these investigations therefore has the po-
tential to uncover key mechanisms involved in emotional dys-
function and treatment response. However, it provides a dif-
Assessment of emotion Harmer
FOCUS
ferent profile of advantages and disadvantages to behavioral
testing alone. Ideally, fMRI should be complemented by be-
havioral results to allow any changes in neural response to be
interpreted in light of evidence for impaired or affected pro-
cessing in direct measures of performance. In addition, when
planning a pharmacological fMRI study, it is important to be
mindful of possible drug-induced changes in hemodynamic
response or neural coupling, which can confound the blood-
oxygen-leveldependent (BOLD) outcome measure.40 It is
therefore important to build in appropriate control conditions
and tasks to assess changes in hemodynamic response un-
related to the task of interest or to supplement fMRI assess-
ment with more direct measures of neural activity.40 However,
despite these limitations, the use of these neuroimaging meth-
ods has the potential to uncover key processes and mecha-
nisms for which behavioral results are inconclusive. fMRI can
therefore enhance behavioral measures of emotional process-
ing both in our understanding of illness and its treatment and
in application to drug development and screening of novel
agents for depression and anxiety.
N Mood and subjective experience rating scales
Measures of emotional bias are complemented by a thorough
examination of mood and subjective experience, based on
self-report or clinician-rated scales. To assist in diagnosis and
provide a measure of illness severity, the clinician-rated 17-
item Hamilton Depression Rating Scale (HAM-D41) and the
Montgomery-Asberg Depression Rating Scale (MADRS42)
have been well validated for use in clinical trials and research
studies. The self-report measures such as the Beck Depres-
sion Inventory (BDI)43 and the Patient Health Questionnaire-944
also provide highly relevant information, with the latter being
used as a diagnosis aid in primary care settings. However, it
should be noted that although each scale provides an overall
measure of depression, the emphasis on different symptoms
seen in this disorder is different.1 For example, the HAM-D has
a greater number of items relating to sleep and anxiety than
the MADRS or the BDI, whereas the BDI places more em-
phasis on pessimism and feeling of guilt. It is therefore impor-
tant to consider the different symptom clusters in depression
which might be relevant to a dissection of the cognitive neu-
ropsychological maintaining factors.
In addition to rating scales of depression and anxiety, which
typically ask about symptoms and experiences over a peri-
od of one or two weeks, it is also necessary to have meas-
ures of current mood state which may be more responsive to
pharmacological induced change in healthy volunteer groups.
Again, a variety of measures exist to monitor different aspects
of everyday subjective state. The positive and negative affec-
tive schedules provide information across a period of time set
by the experimenter (ie, over the last week or day or hour)
with two subscales detailing positive and negative experi-
ences.45 The Befindlichkeits Scale (BFS) is widely used in con-
junction with the ETB to provide a measure of change in mood
MEDICOGRAPHIA, Vol 35, No. 3, 2013 341
FOCUS
and energy levels.46 This requires the volunteer to choose be-
tween two adjectives (eg, shy or bold, sluggish or animated)
describing current state and therefore may be more sensitive
to minor changes in state than symptom-based measures.
Anxiety can be assessed by the Spielberger State-Trait Anxiety
Inventory (STAI), which provides two measures, a measure of
phasic (or state) anxiety response in a given situation and a
trait measure of more stable patterns of anxiety across time.47
The STAI has been used across studies to recruit volunteers
with high or low levels of trait anxiety and to index the response
to stressors and pharmacological manipulations. Finally, visual
analog scales are used widely in the field of pharmacological
challenges to monitor side effects and key effects on mood
and anxiety.48 These involve the presentation of a line (typical-
ly 10 cm) with a description at the top (eg, alert) and labels at
each end (running from Not at all to Extremely). Volunteers to treatment response, represents an exciting possibility for
are asked to mark a place on the line which represents how
they feel in relation to the descriptor. These can be used re-
peatedly within the same experimental setting and therefore
provide a more finely grained analysis of subjective state, which
can be applied in healthy volunteers and patient groups.
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Keywords: anxiety; cognitive neuropsychology; depression; emotion; emotional processing

VALUATION DE L MOTION
La dysfonction motionnelle est un aspect essentiel des troubles de lanxit et de la dpression mais qui peut tre
difficile explorer et quantifier pleinement laide des seules chelles cliniques dvaluation. Des progrs signifi-
catifs ont t raliss ces dernires annes dans le dveloppement de paradigmes cognitifs permettant dvaluer
les diffrents aspects des processus de traitement motionnel associs aux facults dattention, dinterprtation et
de mmoire. De tels paradigmes ont t utiliss pour caractriser la dysfonction motionnelle tant sur le plan de la
neuropsychologie cognitive que sur celui de son rle dans la dpression et lanxit, ainsi que pour comprendre lac-
tion thrapeutique psychologique et pharmacologique. Cet article passe en revue les diffrentes mthodes dva-
luation de lmotion utilises dans des tudes chez des volontaires sains et dans des groupes de patients laide de
paradigmes cognitifs appliqus des modles comportementaux et de neuro-imagerie. Ces tudes ont rvl des
effets constants et en partie dissociables de la dpression et de lanxit sur les indicateurs mesurs du processus
motionnel. Ces indicateurs, en outre, sont cibls de faon prcoce au cours de ladministration de traitements anxio-
lytiques et antidpresseurs. De tels effets ont t observs en labsence de modifications de lexprience subjective,
ce qui suggre que ces indicateurs seraient plus sensibles pour indexer les biais et les rponses motionnels. Cette
approche constitue une stratgie utile pour comprendre la dpression et lanxit ainsi quun modle mdical exp-
rimental pour tester des hypothses daction thrapeutique et valuer des molcules nouvelles en dveloppement
sur les troubles comportant une dysfonction motionnelle.

Assessment of emotion Harmer MEDICOGRAPHIA, Vol 35, No. 3, 2013 343


Social exclusion has a pro-
found psychological and physio-
logical impact as it threatens fun-
damental human needs, such as
sense of self-esteem, sense of be-
longing, meaning of existence, and
sense of control. On a cognitive lev-
el, social exclusion may dampen
self-esteem, which, according to
the sociometer theory, is a gauge
that measures the quality of peo-
ples relationships with others and
alerts the individual to the possi-
bility of social exclusion.
Philippe FOSSATI, MD, PhD
GH Piti Salptrire
Service de Psychiatrie
dAdultes & CNRS USR 3246
AP-HP, CR-ICM
Universit Pierre & Marie
Paris-VI, Paris
FRANCE
Address for correspondence:
Philippe Fossati, Service de
Psychiatrie dAdultes, GH Piti-
Salptrire, Pavillon Pinel La Force,
47-83 bd de lHpital,
75013 Paris, France
(e-mail: philippe.fossati@psl.aphp.fr)
www.medicographia.com
344 MEDICOGRAPHIA, Vol 35, No. 3, 2013
U P DAT E
Neurobiology and
neuropharmacology
of emotion
by P. Fossati, France
T
his review focuses on the links between the emotional brain and the so-
cial brain through analysis of the role of the amygdala. The amygdala is
believed to have a key role in detection of salient and personally relevant
stimuli in concert with other regions of the emotional brain. Among salient stim-
uli, social signals are potent sources of emotion as they indicate self-relevant
information in the environment. We describe the role of main neurotransmit-
tersserotonin, norepinephrine, and dopamineon amygdala activity and we
emphasize the role of oxytocin in social function. Evidence from brain imaging
studies show that oxytocin may regulate the salience of social signals through
modulation of amygdala activity.
Medicographia. 2013;35:344-348 (see French abstract on page 348)
motions are defined as episodic and synchronized changes in physiological, be-
E
havioral, and cognitive responses of the organism, reflecting the identification
of salient stimuli in the environment. Emotional episodes are critical to survival
and have a strong and persistent influence on cognitive processes such as percep-
tion, attention, memory, and decision-making. Accordingly, with this persistent re-
lationship between cognitive and emotional processes and the putative dysfunction
of these processes in psychiatric disorders, there is a growing interest in the study
of the neurobiology of emotion. In this paper, we will focus on findings about the neu-
roimaging and neurochemistry of emotion with a special emphasis on the links be-
tween emotion, social behaviors, and the amygdala.
Emotional brain and social brain
Animal studies, brain lesions in human, and more recently, neuroimaging studies
have contributed to the definition of the so-called emotional brain. The emotional
brain is a highly distributed set of cortical, subcortical, and limbic regions organized
into several subsystem networks (Figure 1).1,2
The emotional perception network is composed of cortical and subcortical struc-
tures, including sensory cortices, and the amygdala, anterior cingulate cortex, in-
sula, basal ganglia, and orbitofrontal cortex. This system is associated with the de-
tection and evaluation of emotional stimuli.
The emotional regulation network comprises the ventro- and dorsolateral prefrontal
cortex, the rostral anterior cingulate cortex, the dorsomedial prefrontal cortex, the
posterior cingulate cortex, the precuneus, and the hippocampus. These regions are
Neurobiology and neuropharmacology of emotion Fossati

involved in contextualization of emotion and emotional regula-
tion, the ability to dampen or increase response to emotional
stimuli. A subset of these regions (ie, medial prefrontal cortex,
hippocampus, posterior cingulate cortex, precuneus) consti-
tutes the default-mode network (DMN). The DMN has been
related to prospection, autobiographical memory, self-referen-
tial processing, and theory of mind, a common set of cogni-
tive processes devoted to projecting oneself into worlds that
differ mentally, temporally, or physically from ones current ex-
perience.
Several stimuli can activate the emotional brain. Among these
stimuli, social stimuli such as faces, persons, or social feed-
back (ie, social criticism or approbation) are major sources
of emotion. It is now well admitted that there is a large over-
lap between the emotional brain and the social brain.3
The amygdala and processing of self-relevant
stimuli
Major evidence for such overlap between the emotional and
the social brain comes from studies on the amygdala. The
amygdala is a major component of the emotional perception
network and it receives input from the sensory cortices and
thalamus. The amygdala has strong reciprocal connections
with other regions of the emotional brain, such as the ventro-
medial prefrontal cortex and the orbitofrontal cortex. More-
over, the amygdala has widespread projections to the basal
forebrain, striatum, nucleus accumbens, hippocampus, and
sensory cortices.4
The amygdala is usually associated with fear processing and
is involved in threat detection and fear learning.5,6 Brain imag-
ing studies have challenged the specific role of the amygdala
in fear processing by showing that both negative emotion and
positive emotion activate the amygdaloid complex.7
The amygdala is also sensitive to social signals, such as faces,
gaze direction, intention, and trustworthiness.8 Consistent with
a putative role of the amygdala in social processes, patients
with amygdala lesions showed not only abnormal fear re-
sponse, but also impaired social behaviors. Amygdala lesions
are associated with increased social approach and difficulties
to monitor interpersonal distance.9 Likewise, mental disorders
with major social impairment such as autism and schizophre-
nia show abnormal functioning of the amygdala, character-
ized by increased reactivity in response to social stimuli.
SELECTED ABBREVIATIONS AND ACRONYMS
5-HT2C serotonin 2C
DMN default-mode network
fMRI functional magnetic resonance imaging
OT oxytocin
SSRI selective serotonin reuptake inhibitor
Neurobiology and neuropharmacology of emotion Fossati
U P DAT E
Regulation network: Self-regulatory processes
and cognitive regulation of emotion
Perception network: Detection and evaluation
of emotionally relevant stimuli
Figure 1. Emotional brain organized into perception and regulation
networks.
The emotional brain is a highly distributed set of cortical and subcortical re-
gions organized into two main networks: a ventral perception network involved
in the detection and evaluation of emotional stimuli, and a dorsal regulation net-
work involved in self-regulatory processes and cognitive regulation of emotion.
To take into account both emotional and social roles of the
amygdala, Sander et al10 suggested that the amygdala imple-
ments processes related to the detection and evaluation of
the self-relevance of stimuli. According to this proposition, the
specificity and differentiation of emotion mostly relies upon the
cognitive evaluation of the meaning and the consequences
of a relevant external event within a specific context and rela-
tionship to ones own goals.10 Self-relevance relates here to
goals, needs, and concerns. This could explain why the amyg-
dala response is preferential for some stimuli over others in
specific contexts, depending on the subjects motivation. For
instance, response to food stimuli in the amygdala would in-
crease if participants are hungry.11
Social signals and self-relevance
The detection, monitoring, and evaluation of social signals are
essential for individuals to navigate the social world and so-
cial signals may indicate the presence of self-relevant stimuli
in the environment. For instance, negative social signals, such
as social exclusion, are associated with intense emotional re-
sponses and behavioral changes. To be socially excluded is
to be rejected, ignored, or devaluated by others. Social exclu-
sion may result from several social situations including, for in-
stance, forced separation from a loved one, loss of a job, or
being ostracized or criticized. Most people have experienced
episodes of social exclusion in their lives.
A seminal functional magnetic resonance imaging (fMRI) study
has illustrated that social exclusion literally induces psychic
pain with activation of the ventrolateral prefrontal cortex, an-
terior insula, and anterior cingulate cortex, regions classically
MEDICOGRAPHIA, Vol 35, No. 3, 2013 345
U P DAT E
involved in physical pain.12 In this study, the authors used a
Cyberball paradigm, in which participants were led to believe
that they were participating in a ball game with real individ-
uals over the Internet, whereas the actions of the other two
players were preprogrammed to exclude the participant after
a few throws.13 Several studies have replicated these results
on social exclusion and a recent meta-analysis by our group
(Rotg et al, in preparation) showed that social exclusion in-
duced by the Cyberball task mainly activates the subgenual
cingulate cortex, a region involved in the production of nega-
tive emotion and the pathophysiology of major depression.
Social exclusion has a profound psychological and physiolog-
ical impact, as it threatens fundamental human needs, such
as sense of self-esteem, sense of belonging, meaning of exis-
tence, and sense of control.14 On a cognitive level, social exclu-
sion may dampen self-esteem, which, according to the socio-
meter theory, is a gauge that measures the quality of peoples
relationships with others and alerts the individual to the pos-
sibility of social exclusion.15 Consistent with this formulation,
in a recent fMRI study in which subjects received feedback
from peers on how they were liked or disliked, Somerville et
al16 showed that the level of self-esteem modulated reactivi-
ty of the ventromedial prefrontal cortex and amygdala to pos-
itive and negative social feedback. Decreased self-esteem
induced by social exclusion may affect self-evaluation and in-
crease self-focused attention (Am I likable? Why dont others
like me?). The by-product of self-evaluation may subsequent-
ly increase peoples need to pay more attention to others in or-
der to detect self-relevant stimuli and to reconnect with others.
Overall, this emphasizes the importance of social inclusion
and social acceptance for emotional well-being.
Neuropharmacology of emotion
The discovery of drugs such as imipramine and iproniazid,
which elevate mood in patients with depression, revolutionized
the treatment of mood disorders. Antidepressant drugs and
their mechanisms of action on two principal neurotransmit-
ters, ie, serotonin and norepinephrine, contribute to the devel-
opment of research on the chemistry of mood and emotion.17
Beyond their abilities to correct depressive symptoms in pa-
tients with major depression, antidepressants modulate the
processing of emotional stimuli in healthy subjects. In a sem-
inal study, Harmer et al18 showed in healthy volunteers that a
single dose of the selective serotonin reuptake inhibitor (SSRI)
citalopram enhanced the recognition of happy and fearful
faces. One-week administration of the same drug in healthy
volunteers facilitated the processing of positive emotional in-
formation with a better memory for self-related positive per-
sonality traits. In this study, the authors used a memory task
where subjects encoded positive and negative personality
traits while making a self-referential judgment on these words.
Citalopram also induced a decrease in recognition of negative
346 MEDICOGRAPHIA, Vol 35, No. 3, 2013
facial expressions. The short-term emotional effects of citalo-
pram occurred without any changes in mood. Several stud-
ies have replicated these findings with other SSRIs or using
different antidepressant drugs with different mechanisms of
action. For instance, reboxetine, a selective norepinephrine re-
uptake inhibitor, and venlafaxine, a serotonin-norepinephrine
reuptake inhibitor showed slightly similar effects on emotion
processing in healthy subjects.19 According to a recent review,
serotoninergic agents may target negative emotion whereas
noradrenergic agents target positive emotion.20
Harmer et al21 have suggested that pharmacological antide-
pressant interventions and manipulation of serotonin and/or
norepinephrine may exert their therapeutic effects through
the correction of emotional biases of depression. Two emo-
tional biases have been described in major depression: (i) the
tendency to prioritize the processing of negative emotional
stimuli and (ii) increased self-focus, the tendency to relate to
ones self emotional or neutral stimuli. The early correction of
these emotional biases and exposure to environmental stim-
ulation would over time and experience reduce depressive
symptoms.22 This effect of antidepressants, such as SSRIs,
on the processing of emotion mirrors the effect of serotonin
depletion on sadness.23
In both healthy and depressed patients, self-focus involves the
medial prefrontal cortex, whereas the processing of negative
information mainly involves the amygdala.24,25 SSRIs in healthy
subjects modulate the medial prefrontal cortex and amygdala
regions, an effect consistent with the distribution of serotonin-
ergic receptors in limbic pathways.26
There is renewing interest in the effects of antidepressants on
anhedonia, a loss of positive emotion and a core feature of de-
pression.27 It is now well established that dopamine is asso-
ciated with reward processing and learning. Long-term treat-
ment with nearly all antidepressants increases responsiveness
to dopaminergic stimulation, perhaps due to enhanced signal-
ing through dopamine D2 or D3 receptors.28 However, it has
been suggested that long-term treatment (ie, more than two
months) with an SSRI may induce a blunted response to pos-
itive and negative emotional stimuli, likely explained by dop-
amine depletion.29
Agomelatine is a new antidepressant and a potent agonist of
melatonergic receptors MT1 and MT2 and an antagonist of the
serotonin 2C (5-HT2C ) receptor.30 This antagonistic action on
5-HT2C receptors facilitates dopamine release in the prefrontal
cortex, without effect on extracellular levels of serotonin, indi-
cating that agomelatine may show selective effects on pos-
itive emotion. It has also been demonstrated recently that the
melatonergic part of agomelatine is necessary for the en-
hancement of dopamine neurotransmission.31 In healthy vol-
unteers, Harmer et al32 showed that 7 days administration of
agomelatine improved memory for self-encoded positive emo-
Neurobiology and neuropharmacology of emotion Fossati

tional words. These results are consistent with clinical stud-
ies indicating beneficial effects of agomelatine in anhedonia
during treatment of major depression.33
The hedonic component of reward at the time of delivery of
rewarding stimuli involves endogenous opioids. Endogenous
opioids are a family of neuropeptides including endorphins,
enkephalins, dynorphins, and orphanin FG, as well as their
various receptor subtypes.34 Endogenous opioid receptors are
distributed in cortical and subcortical regions, including the
dorsal anterior cingulate cortex, the ventromedial prefrontal
cortex, the orbitofrontal cortex, and the amygdala. Opioid pep-
tides are major players in the experience of pleasure and pos-
itive emotion. Moreover, drugs derived from morphine are
sometimes prescribed for treating psychic pain in severe de-
pressed patients with melancholic features. It is noteworthy
that genetic polymorphisms of opioid receptors modulate psy-
chic pain and brain responses to social exclusion, suggest-
ing that morphine might be used for remediation of distress
induced by social separation.35
Oxytocin and social behaviors
We have emphasized that basic social stimuli (ie, gaze) or
more complex social stimuli (ie, social approbation or criticism)
are potent sources of emotion and that these stimuli signal
self-relevant information in the environment. Can we modulate
with pharmacological agents the tight relationships between
social stimuli processing and emotional responses?
It is well known that oxytocin (OT) is a hormone with a unique
role in parturition, milk letdown, and protection against in-
truders. Recent findings have emphasized the OT effect on
the brain and its major role in social cognition.36 fMRI studies
combining cognitive or emotional tasks with intranasal admin-
istration of OT demonstrate that OT exerts its effect on social
function through the modulation of amygdala response to so-
cial and emotional stimuli. For instance, Domes et al37 demon-
strated that intranasal OT reduced the right amygdalas ac-
tivation in response to angry, happy, or fearful facial expression.
Moreover, OT has been shown to dampen amygdala activity
when faces display a more socially salient (and self-relevant)
signal, such as direct gaze compared with averted gaze.38
Likewise, OT increases gaze to the eye region of human faces,
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Keywords: amygdala; emotional brain; neuropharmacology; oxytocin; self-relevance; social brain; social signals

NEUROBIOLOGIE ET NEUROPHARMACOLOGIE DE L MOTION

Cet article examine les liens entre le cerveau motionnel et le cerveau social en analysant le rle de lamygdale.
Lamygdale a probablement un rle cl dans la dtection des stimuli principaux et individuels pertinents en coo-
pration avec les autres rgions du cerveau motionnel. Parmi les principaux stimuli, les signaux sociaux sont
des sources puissantes dmotion car ils donnent une information auto-pertinente dans lenvironnement. Nous
dcrivons le rle des principaux neurotransmetteurs, srotonine, noradrnaline et dopamine, sur lactivit de
lamygdale et nous insistons sur le rle de locytocine dans la fonction sociale. Les tudes dimagerie crbrale
montrent que locytocine peut rguler limportance des signaux sociaux en modulant lactivit de lamygdale.

348 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Neurobiology and neuropharmacology of emotion Fossati
 A TOUCH
OF VIENNA
ienna, the glittering capital

V of the Habsburg Empire,

was in decline at the end of
the 19th century. Yet it remained
hailed as the Mecca of medicine,
thanks to the likes of Rokitansky,
Virchow, and Freud. Three artists
offer a controversial interpretation
of that period: Messerschmidt, with
his strangely modern sculpted
Medical developments
Character Heads, Klimt, with the
much-decried eroticism that per-
vaded his monumental allegory
in the 19th century:
of Medicine, and Schnitzler, who
satirized the Viennese medical es-
tablishment in his works.
the Vienna Clinical School
I . Pe r c e b o i s , F ra n c e

Page 350

Emoticons in marble and

bronze: Messerschmidts
intriguing character heads
P. Po u l l a l i , F ra n c e

Page 362
 A TOUCH OF VIENNA

iennese medicine in the 19th

V century excelled not only in

its technical prowess and
innovations, but also in its ideolo-
gy, therapeutische Nihilismus (ther-
apeutic nihilism). The method de-
Medical developments
fined the Second Vienna School
under the leadership of Carl von
Rokitansky and Josef koda. The
in the 19th century:
First School had laid the founda-
tions of the method at the end of
the 18th century thanks to the re-
the Vienna Clinical School
forms of Gerard van Swieten and
the emphasis on diagnosis.

b y I . Pe rc e b o i s , Fra n c e

I
sabelle Percebois is Professeur Agrge in Comparative Literature, PhD thesis (Paris IV-Sorbonne University,
France): Scientific Writings in the European Fantastic Imaginary (1816-1894). Specializes in fantastic literature and
the interactions between science and literature. Main publications (in French): Vienna the scientific at the end
of the 19th century. Germanica. 2008;43:75-84; From tale of marvel to tale of fantasy: the forest in Mrimes Lokis.
Otrante. 2010;27-28:113-120; The cadaver in fantastic literature: place of the body in M. Shelleys Frankenstein and
K. S. Gjalskis Doctor Miics
Dream. Frontires. 2011;23-2:7-13; Mary Shelley: the young girl and science; the im-
print of scientific discourse in Frankenstein. In: Weber AG, Thoizet E, Wanlin N. Literary and
Savant Pantheons: 19th-20th Centuries. Arras, France: Artois Presses Universit; 2012:143-
156. Influence of Pseudo-science in Fantasy Literature: a Scientific Chimera of the 19th Cen-
tury. Oral communication presented at the Symposium: Sciences, Fables, and Chimeras:
Crossings, organized by Toulouse University, 3 June 2011. Proceedings accepted for publi-
cation by Cambridge Scholars Publishing. In English: Humorous duplicity: ironic distance and
fantastic tension in Villiers de lIsle-Adams Claire Lenoir Fastitocalon. 2013;3. In press.

I
n the 19th century, the heart of medical science beat strongest in Vienna,
Isabelle PERCEBOIS, PhD
described by the anatomist Rudolf Virchow as the Mecca of medicine.
Its university exerted international influence thanks to talent drawn from
all corners of the Habsburg Empire. This period was the high point of the Sec-
ond Vienna School, personified by Carl von Rokitansky and Josef koda, who
drilled the imperial capital in the doctrine of therapeutic nihilism. Their ap-
proach sought to reinvent medical knowledge from the bottom up. It went hand
in hand with a distrust of the pharmaceutical remedies available at the time,
which they dismissed as ineffective. Although they attracted criticism and
were accused of favoring science over their patients, Rokitansky and koda
were the key contributors to the Schools renown, along with Theodor Billroth
who laid the foundations of modern surgery in the city. But Vienna offered lit-
tle welcome to certain other innovators, forcing Franz Anton Mesmer, the in-
ventor of animal magnetism, into exile, attacking the work of Sigmund Freud,
the father of psychoanalysis, and driving Ignaz Semmelweis, the founder of
hospital hygiene, to an early death. Spanning the spectrum between light and
darkness, Viennese medicine was also an inspiration to writers and artists, in
particular to the former doctor Arthur Schnitzler, and a recurrent reference
for the paintings of Gustav Klimt. Pioneering, bold, and riven by scandal, the
Address for correspondence:
Isabelle Percebois, 8 rue des Fosss,
Second School made Vienna the scientific capital of Mitteleuropa.
77000 Melun (e-mail: Medicographia. 2013;35:350-361 (see French abstract on page 361)
percebois.isabelle@wanadoo.fr)

www.medicographia.com

350 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Medical developments in the 19th century: the Vienna Clinical School Percebois
 A TOUCH OF VIENNA

Joseph-
inum,
founded by
Emperor
Joseph II
(1741-1790).
Built in
1783-1785.
It was the first
medical-surgi-
cal academy in
Vienna; today it
houses the In-
stitute of Med-
ical History, the
Medical Univer-
sity of Vienna,
and other insti-
tutes. Engraving
on copper,
1825.
akg/Imagno.

s the capital of the Habsburg Empire, Vienna was the

A de facto capital of 19th-century Europe, playing host

in 1814 to the monarchs and diplomats tasked with
drawing up a new geopolitical order after Napoleons defeat.
The entire world looked to this Mitteleuropa city that stood
center stage in the political arena up to the First World War
and the collapse of the Austro-Hungarian Empire: For one
century, more than ever, the history of Central Europe was
reflected in that of this city which commanded its fate.1(p115)
The Vienna of the time exerted unprecedented influence as
the embodiment not only of the artistic avant-garde, but also
of scientific progress, thanks to its renowned university. Its star
shone with a special brightness in medicine, to the extent that
none other than the Berlin anatomist Rudolf Virchow labeled
it the Mecca of medicine. The pagan Mecca, visited by pil-
grim physicians from all over the world, played host to a suc-
cession of the most eminent practitioners of modern medicine.

The Mecca of medicine

N From therapeutic nihilism to major strides in morbid
anatomy and surgery
Viennese medicine reached a pinnacle in the 19th century. It
was the embodiment of the Habsburg Empire and drew its
strength from the Empires multicultural base. Its leading fig-
uresthose writ large in its historyconverged on the capi-
tal from the four corners of the Empire to endow the School of

Hygieia: detail of Medicine, itself one of the three

University of Vienna Ceiling Paintings by Klimt, commissioned
by the University (see page 358).
1900-1907, oil on canvas. Hygieia was the Greek goddess of health,
daughter of Asclepius, god of medicine, and Epione, goddess of soothing
of pain. akg-images/Erich Lessing.

Medical developments in the 19th century: the Vienna Clinical School Percebois MEDICOGRAPHIA, Vol 35, No. 3, 2013 351
View of Vienna, by G. Vietto (1860). akg/De Agostini Picture Library.
Gerard van Swieten. akg-images - Franz Anton Mesmer. akg-images
Carl von Rokitansky. akg/Imagno - Jsef Dietl. National Archive in Krakow
Josef koda. akg/Imagno - Ignaz Semmelweis. akg-images
Hermann von Helmholtz. akg-images - Rudolph Virchow. akg-images
Theodor Billroth. akg-images - Sigmund Freud. akg/Imagno

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A TOUCH OF VIENNA

The Viennese medicine of the 19th century

excelled not only in its technical prowess
and innovations, but also in its ideology,
which became so characteristic of its prac-
titioners that it served as their signature.
Known as therapeutische Nihilismus (ther-
apeutic nihilism), the method defined the
Second Vienna School under the leader-
ship of Carl von Rokitansky and Josef
koda. The First School had laid the foun-
dations of the method at the end of the
18th century thanks to the reforms of Ger-
ard van Swieten and the emphasis on di-
agnosis. The influence of Schopenhauers
Naturphilosophie was also visible in the
deep skepticism expressed by the Vien-
nese physicians toward the pharmaco-
logical treatments available at the time.
Instead, they advocated nonintervention,
Wax anatomical model, by Clemente Michel-Angelo Susini, of Florence (1754-1814). trusting in Natures powers of recovery. This
Emperor Joseph II commissioned a set of more than 1000 wax models, sculpted be- shifted the therapeutic vocation of medi-
tween 1781 and 1786. cine temporarily into the background, in
They were carried by several hundred mules to Vienna and were exhibited at the Josephinum, where they
can still be seen, at the Museum of the Medical University of Vienna. Medizinische Universitt Wien.
favor of an overriding concern to first un-
derstand how the human body worked
Medicine with international influence. Jean-Paul Bled summed before seeking to heal it. The words of Jzef Dietl, a pioneer
up the concentration of minds in his History of Vienna: Bohe- urologist and fervent advocate of therapeutic nihilism neatly
mia and Moravia contributed the pathologist Carl Rokitan- sum up the change in emphasis: While the old school car-
sky and the internist Joseph koda.The obstetrician Ignaz ried on therapy before engaging in research, the new school
Philipp Semmelweis came from Hungary, and Jzef Dietl from began researching in order to be able to understand therapy
Galicia. The great surgeon Theodor Billroth arrived from Prus- Our strength lies in knowledge, not in action.4(p122) Up until the
sia one year after Sadowa; the psychiatrist Theodor Meynert,
a precursor of Freud, came from Dresden.1(pp379-380) This por-
trait gallery emphasizes the quality of a medical training that
attracted students to Vienna from all over Europe, whether
already established figures or unknowns such as the young
Arthur Conan Doyle who came to improve his knowledge of Sir Arthur
ophthalmology. All flocked to the city to seek inspiration from Conan Doyle,
the worlds greatest specialists and attend daring and innova- the Father of
Sherlock
tive surgery. In 1841, the German physician Carl August Wun-
Holmes, was
derlich reported that there was always something to learn in also a physi-
Vienna; you saw things there that you would have looked for cian who stud-
in vain elsewhere.2 The image of Viennese excellence leap- ied medicine in
frogged frontiers, in particular into France where the physi- Edinburgh, did
a brief stint as
cian Thophile de Valcourt published his Impressions of a
ship surgeon
traveling physician in the Gazette Mdicale de Paris: Every on a ship
educated Frenchman should prepare for the future by learn- bound for the
ing German and getting to know Germany; in our current cir- West African
cumstances, should we not be giving preference to the Vien- Coast, wrote
a thesis on
na School and requiring French students to undertake part
tabes dorsalis
of their training there?3 Although this view was somewhat (syphilis), and
one-sided, in so far as both Paris and Berlin could claim to studied oph-
challenge the hegemony of the Vienna School, it reflected the thalmology in
historic rise of the capital of Mitteleuropa that within a few Vienna in 1890.
Photo taken
decades had become a mandatory stop on every aspiring in 1930.
physicians career trajectory. akg-Imagno.

354 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Medical developments in the 19th century: the Vienna Clinical School Percebois
 A TOUCH OF VIENNA

Stages of gastric resection, by Christian Billroth (1829-1894)

who carried out the first successful ablation of gastric cancer in 1894.
Paradoxically, advances in surgery were a direct consequence of
therapeutic nihilism. Wellcome Library, London.

Age of Enlightenment, diagnosis had been based mainly on

Hippocratic signs and symptoms. In the 19th century, it was
dethroned by the modern science of morbid anatomy that in-
troduced radical change by shifting the physicians gaze from
the bedside to the autopsy room. Rokitansky was said to have
performed around 85 000 autopsies by 1844 when a chair of
morbid anatomy was established in Vienna.

The names of Viennese physicians live on in eponymous con-

ditions such as Mayer-Rokitansky-Kster-Hauser (MRKH) syn-
drome (Mllerian agenesis) in gynecology. But at the time,
they were celebrated primarily for their doctrine of therapeu-
tic nihilism, as described by William M. Johnston in The Aus-
trian Mind: by 1850 skepticism toward traditional therapy had my and skepticism toward drugs.5(p227) Billroth was a pioneer
so taken root that the only medicament used in the General in the history of surgical science, performing the first total la-
Hospital was cherry brandy. For fear of distorting symptoms, ryngectomy and undertaking a number of cancer resections
doctors refused to prescribe any remedies.5(p224) It may be sur- that had never previously been attempted, such as partial cys-
prising that the most eminent specialists should have con- tectomy via a suprapubic approach. His prodigies on the op-
centrated less on the patient than on building up a body of erating table helped push back the frontiers of human knowl-
knowledge, but their approach served the purpose of medical edge and caused the Vienna School to shine ever more brightly
progress as it sought to shake off the traditional remedies that in the scientific firmament.
had been in use for centuries with nothing but unquestioning
belief in their favor: A profusion of clinical evidence, including
the rarest maladies, encouraged Viennas physicians to exploit
observation as a tool for exploding medical myths.5(p227) How-
ever, even in the 19th century, the proponents of therapeutic
nihilism themselves came under attack, in particular from two
celebrated figures: the biologist Ernst Haeckel and physiolo-
gist Hermann Helmholtz. The latter was scathing in his crit-
icism of the cruelty of Josef koda, whom he accused of in-
strumentalizing patients for the greater good of science: And
one degraded the patient who was, after all, a human being,
and disgraced him, as if he were a machine.6(p30) Even foreign
observers were taken aback by his insensitivity, as shown in
the Journal de Mdecine, de Chirurgie et de Pharmacologie
published by the Brussels Society of Medical and Natural
Sciences in 1858: Rarely, if ever, has medicine seen as ab-
solute or as fervent a doubter.On the 28 sick in his care
or rather on his long-suffering patientshe deploys a succes-
sion of all the most traditional and vaunted medicines, and do
you know to what end?... With the sole intention of demon-
strating to his students that all these medicines are in every
case completely ineffective.7(pp284,285)

Although therapeutic nihilism came to be called into question

in the second half of the century, it remained intimately asso-
ciated with the Vienna School, characterizing the fields not
only of clinical medicine and morbid anatomy, but also of sur-
gery, whose undisputed champion was Theodor Billroth. Ac-
cording to the father of modern surgery, reliance on excising
a diseased part accorded with stress on pathological anato-
Surgeon binding up womans arm after bloodletting.
Oil painting (50.439.9 cm, on copper) by Jacob Toorenvliet (1666).
Probably the most popular form of treatment for centuries, Joseph Dietl (1804-
1878), one of the fathers of therapeutic nihilism waged a successful battle
against the then prevalent recourse to bloodletting as cure for pneumonia.
The Wellcome Library, Wellcome Images.

Medical developments in the 19th century: the Vienna Clinical School Percebois MEDICOGRAPHIA, Vol 35, No. 3, 2013 355
A TOUCH OF VIENNA
N Illustrious pariahs: Mesmer, Freud, Semmelweis
While the Academy showered some physicians with honors,
it cast others into the wilderness for their novel and anticon-
formist ideas. The history of Viennese medicine is also that of
the celebrated pariahs whose names remain as intimately as-
sociated with the imperial capital as those of their glorious
colleagues, along with a strong whiff of scandal. Franz Anton
Mesmer remains without doubt the most scandalous of these
physicians. On his death in 1815, at the dawn of the 19th cen-
tury, he left behind the foundations of a new discipline, at the
interface between the science of the occult and psychology,
which was to spread across the whole of Europe.
Before becoming the disruptive prophet of magnetism and the
darling of Paris salons, Mesmer had made every effort to ob-
tain the recognition of his peers. When he defended his doc-
toral dissertation at Vienna Universitys Faculty of Medicine on
27 May 1766, he did so before a committee chaired by the
celebrated Gerard van Swieten, the Dutch physician whom
Empress Maria Theresa had brought in to reorganize med-
ical education. Mesmer thus placed himself under the pro-
tection of the father of the First Vienna School, obtaining the
seal of his scientific authority for the ideas expounded in De
planetarum influxu in corpus humanum (On the influence of
the planets on the human body). This physico-medical work
on the influence of the planets heralded his subsequent re-
search direction, but it wasnt until the end of the century that
Mesmer established the doctrine of animal magnetism, stat-
ing that man possesses properties similar to that of mag-
356 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Medical developments in the 19th century: the Vienna Clinical School Percebois
Anton Mesmer
(1734-1815) ex-
ercising his hyp-
notic skills
(right), while pa-
tients try out the
effects of his
famed tub or
baquet (no, its
not a table!).
This was a oak tub
containing iron filings
that delivered mag-
netic rays which
Mesmer claimed
would cure any num-
ber of ailments. En-
graving, 1780. Biblio-
thque Nationale de
France. akg-im-
ages.
nets.8(p6) This prompted his break from the Vienna School
whose physicians poured scorn on his miracle cures and
compared his treatments to conjuring shows. Mesmer was
deeply bitter in 1777 on leaving faithless Vienna for libertarian
Paris; two years later, on looking back over this painful period
in his Mmoire sur ses Dcouvertes, he described himself as
the victim of jealous colleagues: The first cures achieved in
some patients regarded as incurable aroused envy and even
produced ingratitude, such that many physicians banded
together to bury or at least pour scorn on the discoveries that
I made in this field: I was accused on all sides of being an im-
postor.8(pp9,10) Mesmer was to spend his life trying to achieve
scientific status for his doctrine, and continued to express
his need for recognition by presenting himself as a Doctor of
Medicine from the Faculty of Vienna.
Sigmund Freud offers a similar instance of the mixed attrac-
tion and repulsion aroused by the city of Vienna in someone
faced with the hostility of his peers. The Austrian capital may
well pride itself today on having been the birthplace of psy-
choanalysis, but it was not always so welcoming to Freuds
theories and showed its hostility on several levels: in infancy,
it was Vienna that dragged him away from the green para-
dise of Freiberg; in adolescence, it exposed him to anti-Se-
mitic hostility; during his engagement, it kept him back from
Martha in Hamburg; during his years of research, it withheld
the scientific recognition he craved.9(p199) Freud was at univer-
sity in the second half of the 19th century in an era when the
Medical School was personified by koda, Rokitansky, and

Sigmund Freud (1856-1939) in his study in Vienna in 1935.
Doctorate of medicine in Vienna in 1881, appointed professor in
neuropathology at the University of Vienna in 1902.
Created psychoanalysis, a clinical method based on treating patients through
dialogue rather than drugs. akg/Imagno.
Billroth. Although he too went through a period of therapeutic
nihilism in his youth while training in the various departments
of Viennas General Hospital, he was to develop his approach
to the treatment of mental disorders in opposition to the pre-
vailing orthodoxy. At a time when psychiatric patients were
condemned to trepanation or to confinement in the Fools Tow-
er, Freuds preference for a talking cure over the trephine led
to him being outcast by his colleagues.
His fate bears astonishing resemblance to that of Mesmer
in that it was in Paris that he too sought refuge from the
sustained hostility. In Vienna, Freuds professor Theodor
Meynert, who headed the department of psychiatry, looked
down on his work, whereas in the Parisian medical world,
Freud found fresh prospects beckoning. In 1885, he trained
in hypnosis under Jean-Martin Charcot at the Salptrire
Hospital and began translating his works for the benefit of
his compatriots. Yet when he returned to Vienna the follow-
ing year and presented a report on male hysteria to the so-
ciety of physicians, he found himself once again the butt of
criticism and ridicule. As a man of science, he experienced
frustration on two levels: not only were his innovative theo-
ries treated with scorn, but he was kept pinned down to the
Medical developments in the 19th century: the Vienna Clinical School Percebois
A TOUCH OF VIENNA
Statue of Ignaz Semmelweis (1818-1865) who elucidated the
cause of puerperal (childbed) feverdoctors unwashed hands
but earned only postmortem gratitude from his peers.
They ridiculed him during his lifetime, to the point that he was committed to an
insane asylum, where he died from beatings inflicted on him by the guards.
Semmelweis Memorial, marble, in Budapest, Erzsbet Square, by Alajos Strbl
(1906). akg-images/Grard Degeorge.
post of Dozent, unable to advance higher up the university
ladder. Freud also took it as evidence of the anti-Semitism
rife throughout the Medical School, scathingly portrayed on
stage by Arthur Schnitzler in Professor Bernhardi, and that
was eventually to drive him into exile in 1938.
Freud managed to survive Vienna and his colleagues hostil-
ity, but not everyone in the 19th century was so lucky. Despite
revolutionary discoveries that were to transform clinical prac-
tice and the history of medicine, Ignaz Semmelweis fell vic-
tim to the city. His fate was sealed in 1846 when as a young
master of surgery he joined Professor Johann Kleins depart-
ment of obstetrics at the General Hospital. He was astonished
to observe that the mortality of young mothers was much high-
er in this department than in the adjoining department of Pro-
fessor Bartsch. He eventually worked out why. After various
experiments, he established that it was the medical students
training under Professor Klein who were passing fatal infections
on to the patients: by going straight from the autopsy room to
the labor ward, they were spreading the puerperal fever that
caused the young mothers to flee the hospital, sometimes
MEDICOGRAPHIA, Vol 35, No. 3, 2013 357
A TOUCH OF VIENNA

358 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Medical developments in the 19th century: the Vienna Clinical School Percebois

even to deliver in the street. By making the students wash their
hands in chlorinated lime solution, Semmelweis significantly
decreased the mortality rate. Yet his colleagues remained skep-
tical and maintained that his handwashing protocol was too
restrictive in practice. But in reality, just as with Mesmer and
Freud, Semmelweis was challenging the doctrine of thera-
peutic nihilism, thereby blocking all hope of future promotion.
Even the support he received from his fellow Hungarian, Josef
koda, proved of no avail in preventing his disgrace.
Following this bitter failure, Semmelweis left Vienna for Buda-
pest, entrusting his colleague Professor Ferdinand von Hebra
with the job of publishing his research in the Journal de la So-
cit Impriale et Royale de Mdecine, which the professor
duly did, not without some errors. It was only in 1861 that
Semmelweis himself put pen to paper to lay the foundation
of modern aseptic technique in his book Die Aetiologie, der
Begriff und die Prophylaxis des Kindbettfiebers (Etiology, con-
cept and prophylaxis of childbed fever).10 In 1862, in an open
letter to professors of obstetrics in Vienna, he gave vent to his
anger and bitterness: I would be committing a crime if I kept
silent any longer and did not publish the results of my expe-
rience. I have the intimate conviction that since 1847 thou-
sands of women and children have died who would still be
alive had I not kept silent.11 Semmelweis succumbed to de-
pression and mental illness before dying in 1865 in an asy-
lum close to the city of Vienna that had rejected him. Modern
history books often refer to Semmelweis as a Viennese ob-
stetrician, but it is important to remember that he paid for
this title with his life.
Medicine in Viennese art and literature
N Gustav Klimt and his ill-fated university mural Medicine
Vienna was without doubt one of the cultural capitals of 19th-
century Europe, standing at the forefront not only in science,
but also in literature in the shape of the Jung-Wien (Young
Vienna) group and the graphic arts represented by the Se-
zessionsstil (Vienna Secession) movement. As the bedrock
of Viennas reputation, medical science also permeated the
arts, as shown in the early work of Gustav Klimt, who epito-
mized art nouveau and the Vienna Secession. In 1888, Klimt
started work on a portrait of Carl von Rokitansky for a painting
of the Burgtheater auditorium, famous for having premiered
Left page: Gustav Klimt (1862-1918) was commissioned to
paint three ceiling muralsthe University Paintingsfor the Great
Hall of the University of Vienna: Philosophy, Medicine, and Juris-
prudence.
Medicine was presented in March 1901 at the Tenth Secession Exhibition.
The goddess Hygieia (middle, bottom) holds the snake of Asclepius and a cup
with water from the river Lethe in Hades. Above her, a laughing skeleton clutch-
es the corpse of a woman shrouded in dark muslin. A column of nude figures
extends on the right symbolizing life, while a provocatively exposed nude woman
is featured on the left, with a newborn infant at her feet. Medicine and the
two other ceiling paintings, judged pornographic, were never displayed on
the ceiling and were eventually destroyed by retreating German troops in May
1945 at Immendorf Castle, Lower Austria. 430300 cm. Photo and : Archive
Leopold Museum, Vienna.
Medical developments in the 19th century: the Vienna Clinical School Percebois
A TOUCH OF VIENNA
at least three of Mozarts operas. This was officially commis-
sioned by the Vienna city council with a view to immortaliz-
ing the old theater before its replacement. In this painting for
which he was awarded the Emperors Prize, Klimt portrayed
the capitals leading figures in such a striking gallery of char-
acters that everyone in high society fought for a place in the
group portrait.12(p16) Behind the silhouette of Rokitansky, Gus-
tav Klimt paid tribute to Viennese medicine as a whole; by re-
moving the anatomist from the dissection room and plung-
ing him into a high society setting, he lifted science out of the
University to share in its splendor.
Medicine was also intertwined with a key moment in Klimts
career in so far as his early work on the Ringstrasse interior led
to him being selected in 1896 to paint the ceiling of the Great
Hall of the University. This commission marked the conse-
cration of Klimt, but caused scandal within the sacrosanct
Viennese institution. The history of this abortive work is that of
a vision, for which only some preparatory drawings now re-
main, testimonies to the power of Klimts art in this period. The
vision originated in 1900, when Klimt exhibited Philosophy,
the first of the three compositions commissioned for the Great
Hall. The university authorities were expecting a classical work.
Instead, Klimt represented philosophy as an enigmatic fe-
male sphinx surging out of a star-lit sky. The symbolist style
of this painting unsettled the general public, but the scan-
dal only increased when Klimt delivered his second compo-
sition, entitled Medicine, at the Vienna Secession exhibition in
1901. In this painting, the Greek goddess of health Hygieia
stands disdainful before the onlooker, brandishing the phallic
symbol of a serpent. Reinforcing the eroticism of the scene is
the presence, opposite the entwined shades of the sick and
dying, of a sensuously pregnant woman whose flagrant nu-
dity appeared profoundly shocking to the conservative pro-
fessors. These reactionary forces organized an anti-Klimt ca-
bal that recruited popular scientific periodicals such as the
Medizinische Wochenschrift to exert pressure on the city au-
thorities and have the official commission cancelled. Yet Klimt
managed to capture the very essence of Viennese medicine
in this painting, with its intimate juxtaposition of death and
life, and its transformation of the gruesome autopsy room into
a place of serious study. However, Medicine was never to find
a home in the University, any more than Philosophy or Juris-
prudence. In the late 1930s, all were seized from their Jewish
owners and moved for protection to Immendorf Castle, which
was set alight in 1945 by retreating SS, in final and uninhib-
ited consummation of the professorial condemnation half a
century earlier.
N Arthur Schnitzler: a doctor fictionalizes Viennese medicine
In Vienna, art thus interacted with medicine. Artists regarded
the men of science with an eye that was both admiring and
critical, a duality particularly apparent in the writings of Arthur
Schnitzler, whose approach was not dissimilar to that of the
Vienna Secession master in that he too sought to expose
MEDICOGRAPHIA, Vol 35, No. 3, 2013 359
A TOUCH OF VIENNA

the erotic depths beneath Viennese Phaeaceanism.5(p145) To
understand the scientific character of this Young Vienna writer,
we need to go back to his upbringing in the shadow of his fa-
ther. As one of Viennas most celebrated laryngologists, Jo-
hann took a poor view of his sons literary inclinations and
forced him to complete his medical education. In his autobi-
ography, Schnitzler was to complain of the stifling aridity of the
for example, Schnitzler studied the origin of certain neuroses,
in the person of a dying mother who attempts to explain the
violent behavior of her son by admitting she had tried to kill
him when he was a child: Do we conserve blurred memo-
ries from the first hours of our lives that we have become un-
able to interpret but that do not disappear without leaving a
trace?14(pp219,220) His writing reflects the influence of his men-
tors, in particular his professor, the psychiatrist
Theodor Meynert. Despite feeling a certain an-
tipathy for the man, Schnitzler owed him his fas-
cination with dreams and hypnosis. This also
accounts for the close relationship between his
writings and the work of Sigmund Freud, who
had also been Meynerts student and consid-
ered Schnitzler his Doppelgnger.

Schnitzlers style was all about stripping his char-

acters bare and studying their psyche. He was
a master of the internal monologue which he
used to expose inner conflicts to the readers
gaze. He resorted to the same technique to han-
dle the subjects of death and loss of a loved
one. These represent a leitmotif in his work, in
particular in Ein Abschied (1896) and Die Toten
schweigen (1897), two complementary short
stories that together form a veritable case his-
tory. However, even as he retained his physi-
Arthur Schnitzler (1862-1931). Physician and prolific author (plays, short stories, cians eye, Schnitzler never used medical sci-
novels). His father, Johann Schnitzler, was a pioneer of modern laryngology.
akg/Imagno.
ence as a pretext for long disquisitions, but only
as a plot driver: he never sought to impress with
medical curriculum. He described the internal conflict beset- the superiority conferred upon him by his medical skills.
ting a young student, or rather budding author, torn between Almost always a simple allusion would suffice to illuminate
pen and scalpel: I was undecided and vacillating, and these the story, without weighing it down or inserting blunt or unpre-
were my feelings about medicine too. Being forced to study possessing details.15(p199) Thus, his short stories, novels, and
medicine at times aroused in me a particularly violent re- plays were not texts of medical vulgarization, but snapshot
pulsion towards it, while at other times drawing me to it and reconstitutions of the scientific city atmosphere that reigned
moving me to the very roots of my being.13(p189) In May 1885, in 19th-century Vienna.
Schnitzler qualified as a doctor and used his talents to help
his father in Viennas Poliklinik. When several years later he In the final analysis, it was in his plays that Arthur Schnitzler
decided to give up his medical career, he found it impossible was most critical of medicine, as in Paracelsus (1899) where
to detach himself from the medical environment that he knew he described the European fascination for the hypnotism that
so well and was to carry over into his fiction. was ridiculed by the Vienna School. By recounting the ca-
bal mounted against the physician Paracelsus, accused of
One reason why Viennese medicine is so central to Schnit- charlatanism, Schnitzler transposed into 16th-century Basel
zlers work is that he was describing its golden age, even to the attacks that he himself suffered in his youth when he prac-
the extent of prefiguring Freudian psychoanalysis. He drew ticed hypnosis: [Some] slyly put about the rumor that I staged
inspiration from his experience of medicine and enjoyed blur- shows at the Poliklinik, the immediate effect of which was to
ring the frontier between autobiography and fiction by sub- stop me conducting my experiments in front of a large au-
titling some of his early stories, such as Mein Freund Ypsilon dience, although I continued them for a while in front of re-
(1887), Pages from a doctors notebook. He thus drew his duced numbers.13(p319) Schnitzler adopted a more humoristic
readers into a tantalizing web of masks and doubles, depicting tone in Professor Bernhardi (1912), a play that immersed the
himself under a variety of fictional avatars, such as Dr Merano reader-spectator in a hospital not dissimilar from the Poliklinik
in Die Weissagung (1902). The stories resemble consulting of Johann Schnitzler, featuring a medley of white-coated car-
rooms in which the reader eavesdrops on a series of psycho- icatures: from the preposterously-named Hochroitzpointner,
logical disturbances and mental illnesses. In Der Sohn (1889), a heel-clicking student capable of the basest of behavior in

360 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Medical developments in the 19th century: the Vienna Clinical School Percebois
 A TOUCH OF VIENNA

order to get ahead, to kindly Cyprian, the honest and sen-
tentious professor, via the stubborn 60s-style liberal protest-
er, the unscrupulous careerist, the personification of vanity ob-
sessed with letters after his name, and the dedicated man of
science.15(p121) Beneath its superficial levity, the play describes
the disgrace of a man reproached less for his professional
failings than for his religious convictions. It was Schnitzlers
way of stigmatizing the rise of anti-Semitism in the Austro-
Hungarian Empire while satirizing the medical establishment
that contributed to the Empires fame.
The legacy of the Viennese school
Throughout the 19th century, world medicine centered on
Vienna and the prestige of figures such as Rokitansky, koda,
and Billroth. Even if Vienna was sometimes fickle and failed
to recognize and justly reward some of its most strikingly in-
novative minds, it epitomized scientific progress and was an
inspiration for artists. The name of the Vienna School remains
written in gold in the history of medicine and its star never
ceased to shine, even after the decline of the Habsburgs and
the downfall of the Empire. I

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Paris, France: Didier; 1966.

LA MDECINE L HEURE VIENNOISE : LCOLE DE VIENNE AU XIXE SICLE

Au XIX e sicle, le cur de la science mdicale bat Vienne, que lon surnomme la Mecque de la mdecine , selon
lexpression de lanatomiste Rudolf Virchow. Son universit connat un rayonnement international et bnficie des
talents venus de toutes les provinces de lempire des Habsbourg. Cest l'apoge de la Seconde cole viennoise, in-
carne par Carl von Rokitansky et Josef koda, qui imposent dans la capitale la mthode du nihilisme thrapeu-
tique . Cette mthode vise refonder le savoir mdical et va de pair avec une mfiance lgard des traitements
mdicamenteux de leur temps, jugs inefficaces. Bien que critiqus et accuss de dlaisser leurs patients au profit
de la science, Rokitansky et koda participent la gloire de cette cole, tout comme Theodor Billroth qui y pose les
bases de la chirurgie moderne. Mais la ville de Vienne rejette aussi des esprits novateurs : elle pousse lexil l'inven-
teur de la doctrine du magntisme animal, Franz Anton Mesmer, elle sattaque aux travaux du pre de la psychana-
lyse, Sigmund Freud, et elle entrane le fondateur de lhygine hospitalire, Ignaz Semmelweis, jusque dans la tombe.
Entre ombre et lumire, cette mdecine viennoise inspire aussi les crivains et les artistes : elle est recre sous la
plume dArthur Schnitzler et jalonne lexistence du peintre Gustav Klimt. la fois pionnire, audacieuse et scanda-
leuse, elle fait de Vienne la capitale scientifique de la Mitteleuropa.

Medical developments in the 19th century: the Vienna Clinical School Percebois MEDICOGRAPHIA, Vol 35, No. 3, 2013 361
 A TOUCH OF VIENNA

esserschmidt maintained

M that there are 64 different

expressions or grimaces
that express all the proportions of
the head and, by extension, of the
human body. The series of heads
Emoticons in marble
was intended to review and fix for-
ever these 64 versions of the pro-
portions. In truth, careful analysis
and bronze: Messerschmidts
of the heads shows that Messer-
schmidt used his own mirrored ex-
pressions to compose the heads.
intriguing character heads
The face contorts because the
body is pinched, and the artist
models each bulging muscle, each
furrow induced by the contortion
of features.
b y P. Po u l l a l i , Fra n c e

W
ho are these characters who laugh and weep, sing and yell, moan
and gnash their teeth, who shudder and shake and wince in the eter-
nal silence of the Belvedere in Vienna, of the Slovak National Gallery
in Bratislava? Self-portraits perchance? One and the same man, his counte-
nance frozen in myriad expressions? Or, in the spirit of the Enlightenment, a
scientific study of expressions of the soul? Did the artist seek to give form to
All rights reserved

his woes, to free himself from inner demons? He plays with the principle of se-
ries, with repetition, molding a strange and somber materialmetallic, yield-
ing, elasticinto heads so true to nature that they could be mistaken for life
masks. These are the creative choices of a modernist. Yet the sculptor of these
Pascal POULLALI, MA baffling and unfathomable heads, Franz Xaver Messerschmidt, was born near-
Servier International ly three hundred years ago.
DTC Medical Publications
Division, 50 rue Carnot Medicographia. 2013;35:362-371 (see French abstract on page 371)
92284 Suresnes Cedex
FRANCE (e-mail:
pascal.poullali@fr.netgrs.com)
Oh, the most violent Paradise of the furious grimace!
Arthur Rimbaud, Parade. In: Illuminations, 1873-1875

ranz Xaver Messerschmidt was born into a family of sculptors in 1736 in Wiesen-

F steig, in the Swabian Alps. His uncle, Johann Baptist Straub, one of the mas-
ters of the Rococo style in Bavaria, took him on as a 10-year-old apprentice
after the death of his father. Franz Xaver continued his apprenticeship under three
other uncles, the Straub brothers Philipp Jakob and Johann Georg, and then Joseph
with whom Messerschmidt perfected the astonishing mastery of wood sculpture
which would later so dazzle his fellow students in Vienna and Rome. When six-
teen, Messerschmidt began training at the Academy of Fine Arts Vienna under the
renowned 18th century masters Matthus Donner and Jakob Schletterer, studied
with the sculptor Balthasar Ferdinand Moll, and developed his metalworking tech-
nique using an alloy of lead and tin.

Life and works

Left page: The Yawner. The rector of the Academy of Fine Arts Vienna, the painter Martin van Meytens, sup-
Sculpture by Franz Xaver ported Messerschmidt, who received his first commissions from 1760, after which
Messerschmidt. his reputation grew. From the outset, Messerschmidt executed with great skill
Szpmuvszeti Mzeum (Museum works remarkable in their majesty and attention to detail. This was the beginning
of Fine Arts), Budapest.
of a rich artistic decade. Messerschmidt made imperial busts and larger-than-life
statues of Empress Maria Theresa, (2 meters high) and of her husband Francis I,
www.medicographia.com the Holy Roman Emperor (2.16 meters), the most remarkable statues of the age in

Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali MEDICOGRAPHIA, Vol 35, No. 3, 2013 363
A TOUCH OF VIENNA
Central Europe. David Chatelle, an artillery captain in the can-
non foundry of the imperial arsenal, devised a special alloy,
essentially tin plus some copper, to cast these two statues.
This alloy was easy to work and cast, and gave the sculp-
tures a silvery gleam that was much appreciated at the time.
Messerschmidt used it for all his metal sculptures.
In 1765, Messerschmidt spent a year working and studying
in Rome, and then four years later, once again with the sup-
port of Meytens, obtained a teaching post at the Academy
of Fine Arts in Vienna. Messerschmidt was thirty-three years
old and at the peak of his career. With the proceeds of plen-
tiful commissions Messerschmidt bought a house and gar-
den near the home of one of his patrons, Dr Franz Anton Mes-
mer, the founder of the theory of animal magnetism. Mesmer
commissioned Messerschmidt to make his bust and a foun-
tain for the garden in which he treated patients with his famous
magnetic healing. There is nothing though to substantiate the
legend that Messerschmidt befriended Mesmer and stayed
at his house for two years upon his return from Rome, or that
Mesmer used magnetic healing to treat Messerschmidt when
364 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali
The Ill-Humored Man. Sculpture by Franz Xaver
Messerschmidt. Muse du Louvre, Paris.
RMN-Grand Palais (Muse du Louvre)/Ren-Gabriel Ojda.
in 1771 he fell victim to a mysterious and to this
day unelucidated mental instability. This breakdown
seems to have triggered Messerschmidts work on
the heads, to which he devoted the whole of the
next decade.
Modern interpretations of Messerschmidts men-
tal breakdown vary. Using historical accounts and
analysis of the works, Ernst Kris, the Austrian psy-
choanalyst and art historian, concluded that Messer-
schmidt was schizophrenic. Rudolf and Margot
Wittkower, the German art historians, saw him as
an eccentric who was paranoid at certain times of
his life.
The flow of commissions dwindled and Messer-
schmidt found himself isolated. During this period
of alienation Messerschmidt did, however, receive
a commission for a bust of Gerard van Swieten,
the Dutch-Austrian physician, and another, recent-
ly discovered, of Joseph Wenzel, Prince of Liecht-
enstein. Yet lacking exhibitions and sales, his pe-
cuniary situation became untenable, and he had
to sell his house. On 19 May 1774, old Professor
Jakob Schletterer died. Contractually, the profes-
sors post should have gone to Messerschmidt, but
over the previous three years the word was that
he sometimes seems to lose to his mind, and
though his health had improved since the break-
down, he still manifested some brain problems
and from time to time showed signs of a morbid imagina-
tion. Messerschmidt was passed over for the professorship.
Two official documents dated 1774 allude to this deteriora-
tion in the sculptors health: a report by the academic council
of the Academy of Fine Arts Vienna and a letter Prince Kaunitz
sent to Maria Theresa. The empress was advised that the
afflicted artist should be given a modest pension and could
perhaps work for the imperial buildings, but Messerschmidt
refused the pension, particularly as no commissions were at-
tached. He resigned from the Academy, left Vienna on 8 May
1775, and went to the Bavarian village of Wiesensteig, his
birthplace, to live with his mother, taking with him the first five
heads. The situation though was unbearable as his mother
had sold the house to her son-in-law. So Messerschmidt set
up in a hut and resumed work on the heads.
This exile and solitude were short-lived because at the end
of the year he moved to Munich where the Court had prom-
ised him commissions, even a position. Messerschmidt hoped
to present six sculpted heads to the Prince Elector of Bavaria,
to showcase his talent, but nothing came of it.
 A TOUCH OF VIENNA

Bust of Gerard Van Swieten. Sculpture by Franz Xaver Messer- The Archvillain. Sculpture by Franz Xaver Messerschmidt.
schmidt. sterreichische Galerie im Belvedere. akg-images. sterreichische Galerie im Belvedere. akg-images/Erich Lessing.

A Grievously Wounded Man. Sculpture by Franz Xaver Messer- The Beaked. Sculpture by Franz Xaver Messerschmidt. ster-
schmidt. sterreichische Galerie im Belvedere. akg-images. reichische Galerie im Belvedere. akg-images.

Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali MEDICOGRAPHIA, Vol 35, No. 3, 2013 365
A TOUCH OF VIENNA
After this failure, Messerschmidt left Munich in August 1777
and set up house in Pressburg (modern-day Bratislava, the
capital of Slovakia), a flourishing city and the capital of the
government of the Kingdom of Hungary. His younger brother
Johann Adam Messerschmidt, also a sculptor, had a house
and studio there and created living and working space for
Childish Weeping. Sculpture by Franz Xaver Messerschmidt.
Szpmuvszeti Mzeum (Museum of Fine Arts), Budapest.
Franz Xaver. Although the brothers did not see eye to eye, this
arrangement lasted for five years before Franz Xaver moved
into his own house, The Harts Abode, in December 1780.
Messerschmidts main sponsors in Pressburg were Prince Al-
bert of Saxony, Duke of Teschen, and two counts. His repu-
tation for oddness did not hinder the flow of commissions,
and he executed the works in a neoclassical style with a very
hard rendering of the face, which contrasted with the minute
details of the hair and clothes. It was during this period that
Messerschmidt produced most of his heads. And it was the
heads that made his name. Men of letters and travelers pass-
ing through wished to meet the artist and discover his work.
366 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali
Birth of a legend
The German writer Christoph Friedrich Nicolai left us an ex-
ceptional record of his visit to Messerschmidt in 1781. Full of
anecdotes, his account should, however, be viewed with cir-
cumspection. Nicolai presents Messerschmidt as a singular
man and artist, a solitary genius in the grip of attacks by evil
spirits from which he could only escape by pinch-
ing himself hard under the lowest right rib. He
observes himself, grimaces into the mirror All
the heads represent his image. I saw him work on
the 61st head. He looked at himself in the mirror
every thirty seconds and carefully pulled the faces
needed. As works of art, these are genuine mas-
terpieces.
According to Nicolai, it was in Vienna (through Mes-
mer?) that Messerschmidt entered into relations
with Freemasonry, Rosicrucianism, and secret sects
conversing with the spirits and claiming access to
the secrets of the universe. Messerschmidts fas-
cination with the esoteric theories of these secret
societies is attested by his interest in the art of An-
cient Egypt, his allusions to the god Thoth, the ibis-
headed man of the Egyptian pantheon of deities,
and a sketch of an armless Egyptian statue that he
stuck on his window.
This interest in things Egyptian was not solely philo-
sophical, but also artistic, as witnessed by his bust
entitled A Seriously Injured Person, which we know
of thanks to a plaster copy made in the 19th centu-
ry and whose hair irresistibly suggests an Egyptian
headdress.
Nicolai speaks of Messerschmidts belief in the
apotropaic magic of the heads, of the chasing away
of evil spirits, notably the Spirit of Proportion, which
frightened and plagued him at night and who, he
felt, was jealous of his remarkable learning, and of
the fact that he had uncovered the secret of the
proportions. He who, wrote Nicolai, has always
lived chastely, suffers from painful sensations in
the lower belly and thighs when he sculpts a part of the face
that corresponds to a certain part of the nether regions of the
body. The vital talismanic purpose of these works is attest-
ed by the fact that Messerschmidt refused to sell the heads,
even though he claimed to want to make even more beauti-
ful ones if he found a taker.
Critical fortune and modernity
Sixty-nine heads were found in the artists house upon his
sudden death at age 47, apparently of pneumonia. Fifty-three,
in wood, alabaster, wax, and lead, were preserved. Ten years
later, in 1793, an exhibition at the Citizens Hospital in Vienna
displayed 49 heads, which were seen as freakish works rep-
 A TOUCH OF VIENNA

resenting monstrosities or caricatures of human expres-
sions. An anonymous brochure soon dubbed them Charac-
ter Heads. Each was given an illustrative title which, natural-
ly, bore no relation to the artists intentions. Messerschmidt
himself called them head pieces (Kopfstcke), and saw
them as a means of expressing the whole range of human
expressions, which he believed numbered 64.
ment park in Vienna. Still more could be seen in a hat shop
window, and three decorated a wine bar in the Hungarian
town of Esztergom. Once aroused, the elites interest in the
Character Heads never waned. Picasso owned a set of im-
ages of the heads, and Ludwig Wittgenstein kept a copy of
The Simpleton on his desk.

We have a visual record of the 49 heads thanks to

Matthias Rudolph Toma (see cover), who published
a lithograph, based on an earlier drawing, four years
after they were first exhibited in 1835 by their own-
er Josef Jttner, who showed them again in 1853.
One commentator wrote: Messerschmidt, this ex-
pert of the esthetic of the ugly, can with good rea-
son be considered the Hogarth of sculpture. Ir-
remediably dispersed at an auction in 1889, the
49 heads have over the years been tracked down
using Tomas famous lithograph.

Camillo Sitte, a renowned Viennese architect, was

the first who tried to collect the Character Heads,
and at the 1889 auction bought a large number
both privately and above all as director of the
Staatsgewerbeschule (state industrial school) for
an educational exhibition. It is thought that Egon
Schiele discovered Messerschmidts works at this
exhibition.

From this moment on there was a veritable reha-

bilitation and artistic and scientific reappraisal of
Messerschmidts work. In particular, Emil and Berta
Zuckerkandl, ardent defenders of the paintings of
Gustav Klimt, did much to reunite the Character
Heads. Emil Zuckerkandl was an eminent physi-
cian, professor of anatomy, and author of numerous
studies on the anatomy of the head and particu-
larly the nose. His wife, Berta, who had trained with
Albert Ilg, one of the first historians to rediscover
Baroque art and the author of the first serious study
An Intentional Jester. Sculpture by Franz Xaver Messerschmidt. sterreichische
of Messerschmidt in 1885, throughout her life ran Galerie im Belvedere. akg-images.
brilliant literary and intellectual gatherings where
artists were able to discover these highly original sculptures. From shooting ranges at the Prater, Messerschmidt returned
Around 1905-1906, some of the Character Heads were pre- to the world of the museum, through exhibitions of his Char-
sented to the public by the playwright Richard Beer-Hofmann, acter Heads, but also by inspiring major contemporary artists
who had been a member of Young Vienna (Jung Wien), a so- like the Austrian Arnulf Rainer, the British sculptor Tony Cragg,
ciety of writers who met in Viennas coffeehouses in the 1890s. the British painter Tony Bevan, and the French artist Bernard
Against the backdrop of the movement of the Vienna Seces- Crespin and his series of self-portraits. Messerschmidt is in-
sion and the Vienna of Freud, the Character Heads intrigued, dissociable from modernity in the minds of museum cura-
fascinated, and inspired painters, writers, and doctors. tors. The Louvre in Paris presented the Character Heads with
sculptures by Tony Cragg in 2011, and the J. Paul Getty Mu-
Others found a more mundane use for the heads. Right up seum in Los Angeles in 2012 staged an exhibition entitled
until the 1960s, copies cast in molds taken from originals Messerschmidt and Modernity, which presented sculp-
served as targets on shooting ranges or were used to com- tures by Messerschmidt and works by contemporary artists
pose freakish and parodic scenes at the Prater, an amuse- who draw inspiration from his work.

Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali MEDICOGRAPHIA, Vol 35, No. 3, 2013 367
A TOUCH OF VIENNA

Self-Portrait after Messerschmidt. Tony Bevan, 2009, Bad Guys. Tony Cragg, 2005, bronze, 120100110 cm,
acrylic and charcoal on canvas, 9980 cm. Tony Bevan/ photographer Lothar Schnepf. Tony Cragg. With kind per-
Galerie Vidal-Saint Phalle. With kind permission. mission.

Der Strichstricker. Arnulf Rainer,1970s (After Messerschmidt. Ricordo #10. Bernard Crespin, 2010/2011. Pigment print on
Der Heftige Geruch - The Strong Smell), ca 60.747.5 cm, paper (unique prooof), 102.5x82.5 cm. Bernard Crespin.
lead pencil on photo. Arnulf Rainer. With kind permission. With kind permission.

368 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali
 A TOUCH OF VIENNA

The legend under the scrutiny of stylistic

interpretation
Of 49 heads catalogued in 1793, a total of 38 orig-
inals are accounted for today, plus six variants that
were not part of the set of 49. These heads sustain
the romantic myth of the mad, solitary genius, but
a stylistic analysis puts these heads squarely in
the esthetic and philosophical context of their time.
This analysis reveals a virtuoso artist, recognized,
sought after throughout Eastern Europe, scion of
a family of famous sculptors, welcomed in the stu-
dios of the greatest artists of his time. Although
Messerschmidt trained in the Rococo tradition of
sculpture, he is the harbinger of the movement of
art toward the classicism of antiquity. Sickly it is
true, aggressive and uncouth with those around
him, Messerschmidt was nonetheless aware of the
philosophical and artistic movements of his time:
Enlightenment ideas, esoteric knowledge, the mag-
netism of Franz Anton Mesmer, pathognomonic
analysis, the Swiss Johann Kaspar Lavaters phys-
iognomy, the somnambulism induced by A. M. J.
Chastenet de Puysgur.

Messerschmidts stylistic evolution can be detached

from the psychological crisis of 1771, insofar as
his art presents perceptible changes from the piv-
otal period between 1767 and 1769 when he re-
ceived the commission for the bust of van Swieten.
This stylistic and esthetic progression was consol-
idated with the realization circa 1780 of the spectac-
ular lead-tin cast of the head known as Capuchin.

From the outset, then, Messerschmidt proved in-

novative and distanced himself from the official Ro- The Enraged and Vengeful Gypsy. Sculpture by Franz Xaver Messerschmidt.
coco style, a tendency that quickly became marked sterreichische Galerie im Belvedere. akg-images.
in his portraiture. Messerschmidt abandoned the
bust, which was a pretext for spectacular and dramatic ef- edge of the sculpture and art of Ancient Egypt. This quest
fects of draped clothing or for decorative and symbolic ele- for the ideal does not break completely with a sensual ren-
ments like medals, jewelry, symbols of the subjects power dering, which preserves something of the Baroque spirit. Re-
and status. Instead, he used a frontal representation of a bare markably for the time, the Character Heads were not com-
head, in contrast to the official portraits of that time in which missioned and none was sold during the artists lifetime,
the subjects were bewigged. despite attractive financial offers. Messerschmidt, at Press-
burg, made extremely costly marble busts for wealthy clients,
Messerschmidt refused to idealize or to embellish portraits and not to mention the sale of alabaster medallions which he en-
made them as realistic as possible, seeking to translate their trusted to his servant and which gave the artist a certain where-
intemporal truth, in contrast to the Baroque, which sought to withal and allowed him to pursue his work on the heads. This
translate movement and the ephemeral. is an extremely modern approach.

Messerschmidt was the only artist to propose neoclassical
portraits uncompromised by the triumphal Baroque style of
the era. This stylistic evolution has no equivalent among
Messerschmidts peers. He drew inspiration from the frontal
and realistic portraits of the end of the Roman Republic that
he discovered during his stay in Rome, and from his knowl-
The legend rides the winds of change
One should not forget the philosophical and esoteric world
in which artists moved or Mesmers theories and treatments,
which were familiar to Messerschmidt. Some critics interpret
the gag, the rope around the forehead or neck of certain heads
as the magnetics or accessories that Mesmer attached to his

Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali MEDICOGRAPHIA, Vol 35, No. 3, 2013 369
A TOUCH OF VIENNA
patients to stimulate the flow of magnetic fluid. Nicolai reports
another, more tormented, explanation given by Messerschmidt
himself: Man must completely draw in the red of his lips,
because no animal shows it. The artist was convinced that
animals were superior to humans in the perception of a good
many things, notably the spirits, the absence of obvious lips
in animals being the explanation, whence the effacement of
lips on his heads.
The mystery remains: the problems of series
Messerschmidt maintained, once more according to Nicolai,
that there are 64 different expressions or grimaces that ex-
press all the proportions of the head and, by extension, of the
human body. The series of heads was intended to review and
fix forever these 64 versions of the proportions. In truth, care-
ful analysis of the heads shows that Messerschmidt used his
own mirrored expressions to compose the heads, but also se-
lected items already sculpted. This is not snapshot mimicry of
expressions the virtuoso artist fixed in alabaster or in a lead-
tin cast. Rather, Messerschmidt assembles and reassembles
graphic elements (eyes, mouths, chins, eyebrows, and so forth)
in shaping a head, which is therefore in no way naturalistic.
The paradox of this work lies in its principle: the series. In ap-
pearance, the rendering is hyperrealistic. The face contorts
because the body is pinched. The artist models each bulging
muscle, each furrow induced by the contortion of features.
But this rendition is not unique (there are variations of some
heads) and is part of a repetitive, serial approach which ne-
cessitates the abandonment of naturalistic or realistic inter-
pretation for a more formal and esthetic probing. The series
annihilates veristic representation and propels us toward ab-
stract questioning.
Further reading :
Ptzl-Malikov M, Scherf G, Bostrm A, Lambotte MC. Franz Xaver Messer-
schmidt 1736-1783. Paris, France: Louvre Editions & Milan, Italy: Officina Li-
braria; 2011.
Bostrm A, Scherf G, Lambotte MC, Ptzl-Malikov M. Franz Xaver Messer-
schmidt 1736-1783; From Neoclassicism to Expressionism. Milan, Italy: Officina
Libraria, 2010.
Bckling M. Die Phantastischen Kopfe des Franz Xaver Messerschmidt. Munich,
Germany: Hirmer Verlag GmbH; 2007.
Bckling M, Fanta R, Keleti M, Krapf M, Krapf-Weiler A, Husler W. Franz Xaver
Messerschmidt 1736-1783. Ostfildern, Germany: Hatje Cantz Verlag; 2002.
Keleti M, Thevenon L, Loubet C, Forneris J, Crou G. Franz Xaver Messerschmidt
(1736-1783), Sculpteur baroque, Ttes de caractre. Nice, France: Palais Mass-
na, Muse dArt de dHistoire; 1993.
Bostrm A. Messerschmidt and Modernity. Los Angeles, CA: J. Paul Getty Mu-
seum: 2012.
Gudron M. LArt de la Grimace. Paris, France: Hazan: 2011.
Clair J, Comar P, Faroult G, Gugan S. Mlancolie: Gnie et Folie en Occident.
Paris, France: Runion des Muses Nationaux/Gallimard; 2008.
370 MEDICOGRAPHIA, Vol 35, No. 3, 2013 Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali
Moreover, the strange illusionism of these heads is not devoid
of anatomical implausibilities. So the Character Heads are
neither naturalistic self-portraits (some heads have features
that differ completely from those of the rest of the series) nor
a scientific attempt to describe the outward display of the
souls inner workings, manifestations which would anyway
be hard to pin down (from laughing to weeping, from pain to
pleasure).
The importance of, not to say obsession with, the mouth,
which is reminiscent of that of the painter Francis Bacon,
leads to spectacular and complete misshaping of the whole
head in the two heads called The Beaked, in which the face
ends in a birdlike beak. These two heads terrorized the artist.
Nicolai relates that: [The spirit] pinched him again and again
until the faces saw daylight. He [Messerschmidt] thought Ill
get the better of you yet, but admitted that he had almost
died in the attempt. However we interpret the series, these
heads are not the artists inner, intangible self portrayed through
a glass, darkly.
Everlasting modernity
Historical facts, their interpretation, dismantle the fascinating
legend of Messerschmidt as the damned artist, the mad ge-
nius who withdrew to Pressburg, sculpting fearfully in a des-
perate fight against his inner demons and the Spirit of Propor-
tion. What remain are his heads, larger than life, so precisely
and convincingly fashioned that their creator has earned an
everlasting presence through his works. The force of this work
is such that its mystery is preserved and lasting and all mus-
ings and interpretations are permitted It is perhaps just
this which explains the beauty, the vitality, the modernity of
Messerschmidts Character Heads. I
Le Brun C. Expressions des Passions de lme: Reprsentes en Plusieurs Testes
Graves dAprs les Dessins de Monsieur Le Brun. Paris, France: GLM; 1956.
Cyroulnik P, Crespin B. Visages Dcouverts - Pratiques Contemporaines de
lAutoportrait. Montbliard, France: Le 19 - Centre Rgional dArt Contemporain;
2005.
Bouttemy MF, Van Hoeke N, Hattori C, Tapi A. Goya: Les Caprices & Chapman,
Morimura, Pondick, Schtte. Paris, France: Palais des Beaux-Arts de Lille, So-
mogy; 2008
Baudry MT. Sculpture: Mthode et Vocabulaire. Paris, France: Monum, Ed du
Patrimoine, Imprimerie nationale; 2000.
Faraut C, Faraut P. Modelage de Portraits en Argile: Anatomie et Expressions du
Visage. Paris, France: Eyrolles; 2010.
Bajac Q. Fleur de Peau: Le Moulage sur Nature au XIXe Sicle. Paris, France:
Runion des Muses Nationaux; 2001.
Courtine JJ, Haroche C. Histoire du Visage: Exprimer et Taire ses Emotions (du
XVIe Sicle au Dbut du XXe sicle). Paris, France: Payot; 2007.
http://www.charleslebrun.com.
http://www.textesrares.com.
 A TOUCH OF VIENNA

MOTIONS DE MARBRE ET DE BRONZE :

MESSERSCHMIDT ET SES TROUBLANTES TTES DE CARACTRES
Lgende et vrit inextricablement mles, sculptures authentiques et copies indiffremment exposes, luvre
de Franz Xaver Messerschmidt (1736-1783), depuis deux sicles quelle a t redcouverte et rhabilite, fait tou-
jours lobjet dinterrogations et dinterprtations contradictoires Artiste rput la cour des Habsbourg, sculp-
teur des clbres ttes dexpression , luvre de Messerschmidt, aprs avoir t mprise et raille dans les ba-
raques foraines du Prater, a connu un regain dintrt dans la Vienne fin de sicle qui ne sest plus jamais dmenti.
Aujourdhui encore, comme si Messerschmidt tait toujours vivant parmi nous, les plus grands muses du monde se
battent pour acqurir les dernires ttes en mains prives et les exposent le plus souvent en compagnie des uvres
que Messerschmidt a inspires aux artistes contemporains les plus rputs. Etonnant destin que celui dun sculp-
teur que la lgende a voulu faire passer pour un fou solitaire et qui ne cesse dintriguer et de fasciner grand public,
critiques dart, artistes et mdecins. Au-del dune vie dont les pripties sont difficiles expliquer, au-del dune
interprtation historique ou dune interprtation psychiatrique et psychanalytique, la dcouverte des ttes de ca-
ractre de Messerschmidt provoque, par-del le temps, un vritable choc et une trange fascination.

Emoticons in marble and bronze: Messerschmidts intriguing character heads Poullali MEDICOGRAPHIA, Vol 35, No. 3, 2013 371
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