Académique Documents
Professionnel Documents
Culture Documents
REVIEW ARTICLE
1
VA Palo Alto Health Care System, Palo Alto, California, USA
2
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California, USA
For the first time in 20 years, the American Psychiatric Association (APA) updated the psychiatric diagnostic system for
mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Perhaps one of the
most notable changes in the DSM-5 was the recognition of the possibility of mixed symptoms in major depression and
related disorders (MDD). While MDD and bipolar and related disorders are now represented by 2 distinct chapters, the
addition of a mixed features specifier to MDD represents a structural bridge between bipolar and major depression
disorders, and formally recognizes the possibility of a mix of hypomania and depressive symptoms in someone who has
never experienced discrete episodes of hypomania or mania. This article reviews historical perspectives on “mixed states”
and the recent literature, which proposes a range of approaches to understanding “mixity.” We discuss which symptoms
were considered for inclusion in the mixed features specifier and which symptoms were excluded. The assumption that
mixed symptoms in MDD necessarily predict a future bipolar course in patients with MDD is reviewed. Treatment for
patients in a MDD episode with mixed features is critically considered, as are suggestions for future study. Finally, the
premise that mood disorders are necessarily a spectrum or a gradient of severity progressing in a linear manner is argued.
Downloaded from https://www.cambridge.org/core. University of New Orleans, on 06 Oct 2017 at 18:00:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000256
156 T. SUPPES AND M. OSTACHER
was naturalistically observed by such individuals as Depression Collaborative to identify those with MDD and
Kraepelin and Weygandt.2,3 The 6 proposed mixed states some degree of hypomanic symptoms.18 These large data
as Kraepelin defined them are well-known: depressive or sets, in concert with new European datasets including the
anxious mania, excited depression, mania with thought Bipolar Disorder: Improving Diagnosis, Guidance and
poverty, mania with stupor, depression with flight of Education (BRIDGE) study, supported the possibility of
ideas, and inhibited mania. MDD depression episodes presented with mixed symp-
While there was a limited focus on mixed states in the toms. Further studies as well as the BRIDGE study, such as
mid-20th century, perhaps in part due to greater focus the National Comorbidity Study - Replication (NCS-R) and
on psychoanalytic versus biologic considerations, work the Munich study, and a reanalysis of baseline NIMH
by Himmelhoch and others in the 1970s and 1980s Depression Collaborative Study data, opened the way
increased awareness that mania and depression did not to consideration of mixed symptoms during a MDD
exist in only polar isolation, and raised the importance of episode of depression.10,17–19 The Munich study provided
assessing mixed states not only as an important modifier strong evidence in a somewhat younger population that
of disease course and treatment response, but as a subthreshold hypomanic symptoms were present in a
distinct subtype of bipolar disorder.4,5 While the DSM-5 substantial number of MDD episodes without the subjects
recently modified the definition of mixed states, it was necessarily converting to a full bipolar diagnosis over a
recognized early on that the DSM-IV definition of a 10-year observation period.19 In this longitudinal study,
mixed state, as only when a full episode of mania and depending on how symptom count was done, based on
depression co-occurred, had limitations that did not 1 hypomanic symptom, 40% of the population observed
adequately capture clinical experience.6 Debate con- from an earlier age reported MDEs with some degree of
tinues on the best definition of mixed states, as well as mixity. While re-examination of the NIMH Depression
which definitions should rule the day and are the most Collaborative found that those subjects presenting at
clinically relevant.7–10 baseline with a depression episode and 3 or more
hypomanic symptoms had a significant likelihood of
converting to bipolar disorder, evidence also suggested
DSM-5 and Differential Diagnosis
that not all subjects with a degree of subthreshold
While DSM-IV made advances in characterizing the mood hypomania went on to develop bipolar disorder.18 Both
disorder range of presentation, including bipolar II the NCS-R, an epidemiologic replication study, and the
disorder for example, the definition of mixed states was multinational BRIDGE study demonstrated a broad range
limited to full mixed episodes, requiring a full manic of presentations, including subthreshold bipolarity among
episode and a full depressive episode to be simultaneously many patients with MDD, as well as frank bipolar disorder
present. There was no consideration of the possibility of often missed.10,17 It should be noted these studies
more complex and less well-delineated presentations, such specifically tested a hypomanic checklist in consideration
as mixed hypomania or mixed depression in bipolar of the idea that MDD and BD exist on a continuum.
disorder—presentations which are quite familiar to clini- The confluence of these findings suggests that the
cians but are not formally codified in the nomenclature. No clinical features that distinguish bipolar disorder from
consideration was formally given to the possibility of MDD “pure” MDD are very similar to the distinguishing
mixed depression, though the European literature has features for those patients with MDD and a depressive
already included discussion of these more complex episode with mixed features. Cross-cultural studies
presentations.11–13 reinforce findings of increased suicidality, increased
More recent publications both before and during the family history of bipolar disorder, and earlier onset of
development of DSM-5 provided a range of evidence illness noted for those with MDD in a depressive episode
supporting the more frequent presentation of mixed with mixed features versus a depressive episode without
symptoms over pure euphoria mania in bipolar disorder mixed features.20 Despite the different definitions of
and mixed symptoms during depression in patients with mixed features, these cross-cultural and cross-national
bipolar disorder.14–16 These and other studies clarified not findings overall, given the numbers of patients
only that euphoric presentations may be the minority, but described, draw a picture of a potential intermediate
also that in bipolar disorder a mixed presentation may phenotype. This phenotype has yet to be fully defined,
herald a more severe course of illness.17 given that a significant percentage fitting this profile
During the development of DSM-5, the consideration may develop bipolar disorder illness over time.
was raised that mixed symptoms might also be present There has been much discussion differentiating MDD
during major depressive episodes in those with MDD but and bipolar disorder (BD), with mixed features patients
lacking any history of hypomanic or manic episodes. particularly highlighted as those potentially on the road
Active discussion led to new analyses of older data sets, to developing BD. However, such features as early onset,
such as the National Institute of Mental Health (NIMH) increased recurrences, family history, and temperament
Downloaded from https://www.cambridge.org/core. University of New Orleans, on 06 Oct 2017 at 18:00:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000256
MIXED FEATURES IN MAJOR DEPRESSIVE DISORDER 157
have been suggested as distinguishing features for MDD and for a noticeable amount of time, though which
with and without mixed features.21,22 In particular, the symptoms present can vary. Three of the following
notion that MDD with mixed features may be less symptoms are required:
responsive to antidepressants has not been firmly
∙ Elevated or expansive mood
established. In one retrospective study (STAR*D), those
∙ Inflated self-esteem or grandiosity
patients evidencing at least 2 mixed symptoms actually
∙ More talkative than usual or pressure to keep talking
were more responsive to antidepressants.23 This,
∙ Flight of ideas or subjective sense that thoughts are
however, continues to be an active area of debate as to
racing (This symptom must be distinguished from
whether patients exhibiting MDD with mixed features
anxiety and anxious thoughts.)
are more severely ill and less likely to be responsive to
∙ Increase in energy or goal-directed activity
usual antidepressant treatments.24–26
∙ Increase or excessive involvement in activities that
Importantly, the clinical observation of increased
have a high potential for painful consequences
suicidality with mixed symptoms during depressive
∙ Decreased need for sleep
episodes has been reported across a range of study
designs.9,10,24,27 While increased suicidality is certainly Additional factors would include that the mixed
not only observed during periods of mixed symptoms, symptoms are observable to others and represent a
given the periodic increased energy sometimes seen change from usual behavior, and that mixed symptoms
during mixed depression and the consequent lower are not better explained by a medical condition or
threshold to action in many cases, caution and careful substance use. (For this second qualifying condition, one
observation are warranted. example could be depression with mixed symptoms
attributable to a recent period of using cocaine.)
There is debate as to whether 2 versus 3 symptoms is
Diagnosis as Defined by DSM-5
the correct threshold to consider for meeting the mixed
In consideration of developing a specifier that would features specifier. This issue was considered in the
apply to patients diagnosed with either bipolar or major development of the DSM-5 Mixed Features Specifier,
depression and related disorders, what to include or and it was decided that in the absence of more extensive
exclude was reviewed by the DSM-5 committee. In prospective data, a conservative decision of requiring 3
particular, in the interests of clarity, discussion included non-overlapping symptoms for the specifier should be
whether to use all of specific symptoms at either pole and made.1,6,12,28 There is a range of views on this topic;
to exclude only those symptoms that often overlap in some argue that the bipolar spectrum supports consider-
depression, hypomania, and mania. These overlapping ing 1 symptom during depression as consistent with a
symptoms included irritability, agitation, or distractibility. mixed profile, though there is concern for the precision
Given that irritability is a common symptom regardless of and limits of our measurement ability.7,9,10,17 The
the presence of mixed features, it was viewed as more requirement of 3 symptoms of a non-overlapping nature
nonspecific and therefore more difficult to ascertain if the may indeed be too stringent and bias the likelihood of
irritability related to a mixed picture or simply one of illness patients meeting this specifier condition with MDD more
generally. Similar discussion led to the removal of these likely to be those who later go on to develop a full
overlapping symptoms. This conclusion was also reached in hypomanic or manic episode, thus changing the diag-
the recently released position paper on mixed states by the nosis to bipolar disorder.18 This debate speaks to the
International Society of Bipolar Disorders.27 limits of our notions around mixity, and further
While the DSM-5 committee decided to exclude over- prospective, biologic, and clinical treatment data are
lapping symptoms from the definition of mixed specifiers, needed to fully inform this debate.
these excluded symptoms are important gateways to
suggest to the clinician that further evaluation for mixed What Do Treatment Reports Suggest About
symptoms should be considered for both the diagnosis and
Mixed Depression?
treatment choices.10,16,17,28–30 In particular, while these
symptoms are present at both poles and across mood At this time there are no medications approved by the US
disorders in general, they serve as red flags to look deeper; Food and Drug Administration (FDA) for treatment of
recent analyses suggest that when other mixed symptoms MDD depression episode with mixed features. There is
are present, these 3 excluded symptoms, particularly some concern as to the specificity of this diagnosis, and
irritability and agitation, are likely to be present.16,31 further studies will be needed to resolve this issue. The
The current criteria for major depressive episode with question of whether the medications that patients respond
mixed features are defined as meeting full episode to during a MDE with mixed features are different than
criteria for a depression episode, and in the last 2 weeks those for a MDE without mixed features will await future
some degree of the following symptoms at least every day studies. Such studies are needed to directly address both the
Downloaded from https://www.cambridge.org/core. University of New Orleans, on 06 Oct 2017 at 18:00:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000256
158 T. SUPPES AND M. OSTACHER
question of specificity of this subcategory of MDD spectrum? Developing biologic data suggest that our
and to posit a possible approach to distinguishing categories may not reflect what the brain is experiencing
differences from BD II or “other specified.” While some in terms of how symptoms are clumping together in
studies suggest no negative impact of antidepressants on comparison to the relatively arbitrary categories imposed
those with MDE with mixed features, others suggest the by DSM-5 and other similar systems of diagnosis.34
opposite. In particular, the question remains whether We hope that the developing biological literature will
greater treatment resistance is conferred by mixed features inform the discussions on mood spectrum from the
as defined by DSM-5.7–9,17,23,26 purely observational approach currently utilized to
There is a range of definitions of mixed depression, address these questions.1
including the elements that were viewed as “over- One of our usual assumptions diagnostically is that the
lapping” in DSM-5, but that are viewed as essential in development of bipolar disorder is a one-way road. The
the conceptualization and assessment of frequency implication of this is that once a patient has experienced
during any mixed depression.8,13,25,29,30,32 It is of a hypomanic (or manic) episode, the lifetime diagnosis
interest to consider the 1 study to date that examined changes to bipolar II disorder regardless of future course
the treatment response of patients with MDD currently of illness, or similarly once a patient has a manic episode,
in an episode with mixed features.29 his or her diagnosis changes to bipolar I and never falls
In this study of a newer atypical antipsychotic, back to MDD or BDII regardless of future course. The
lurasidone, for MDD with mixed symptoms, inclusion limitation to this one-way road is that our approach to
criteria were modified to allow entry and randomization treatment changes from “treatment for MDD” to
in this monotherapy, placebo-controlled study based “treatment for BD.” It has been observed that patients
on 2 or 3 symptoms of the mixed specifier, though experiencing MDD who have a MDE with mixed features
overlapping symptoms of irritability, distractibility, and respond poorly to antidepressants, though more formal
agitation were excluded.29 (The study was designed and testing of this hypothesis is needed. On the other end of
undertaken prior to the final version of DSM-5.) The this spectrum, no one would advocate more monother-
study found benefit for lurasidone versus placebo for the apy antidepressants in BDI (although it is unclear what
defined group over the 6-week study; the authors report the right treatment is, for example, for a currently
on which symptoms were most frequently observed. depressed 60-year-old patient whose last manic episode
About two-thirds of patients met the entry criteria of was at age 22). What, however, is the correct approach to
2 mixed symptoms, while the remainder otherwise met depression in BPII? There is indication that some
DSM-5 criteria for the mixed feature specifier. Of all patients with BDII with or without rapid cycling do
patients (n = 209), about 67% reported flight of ideas, nearly as well on antidepressants as on lithium.35–37 Do
61% pressured speech, 41% decreased need for sleep, these results imply that one group of patients with mixed
28% increased energy or activity, 18% elevated or features with only to-date subsyndromal hypomania,
expansive mood periodically, 16% increase in impulsive such as those with MDD, may not do well on antidepres-
behavior, and 7% inflated self-esteem or grandiosity. By sants, but those potentially seen as further along this
comparison for overlapping symptoms, 57% reported one-way road in fact do fine on antidepressants? What
irritability, 59% distractibility, and 37% agitation. would these results imply about the concept of the
This study of a newer atypical antipsychotic provides “spectrum” that is currently the predominant approach
the most thorough prospective treatment response data to to mood disorders?
date of subjects who approximate the mixed specifier for There are other unconsidered paradigms besides a
MDE in MDD. Of particular note is that the overlapping simple spectrum or continuous gradient of severity.
symptoms excluded from the mixed features specifier in The assumption of a one-way road to modeling
DSM-5 occur almost as often as the 2 most frequent mood disorders probably should be questioned.
symptoms included in DSM-5: flight of ideas and If all those with MDD with mixed features do not
pressured speech. Thus, while excluded to bring greater in fact develop bipolar disorder over time, and some of
clarity to the newly proposed specifier bridging MDD and these individuals do less well on antidepressants than
BD, it is important to note that these symptoms may be some patients with bipolar II disorder, this argues for
key to alerting the clinician and the patient that further discrete symptoms making up a set of disorders versus a
treatment and assessment are needed beyond the usual continuum. Rather than the ongoing assumption that
approach to a major depressive episode. the only paradigm to model bipolar and major depression
and related disorders is a spectrum, it is to be hoped
that the developing biologic information will more
Alternative Considerations for Diagnosis
appropriately define whether this is a continuous or a
What are our assumptions about mood disorder spec- discontinuous process requiring other approaches than
trum, and should we consider whether it really is a a spectrum.
Downloaded from https://www.cambridge.org/core. University of New Orleans, on 06 Oct 2017 at 18:00:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000256
MIXED FEATURES IN MAJOR DEPRESSIVE DISORDER 159
Downloaded from https://www.cambridge.org/core. University of New Orleans, on 06 Oct 2017 at 18:00:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000256
160 T. SUPPES AND M. OSTACHER
16. Miller S, Suppes T, Mintz J, et al. Mixed depression in bipolar 27. Swann A, Lafer B, Perugi G, et al. Bipolar mixes states: an
disorder: prevalence rate and clinical correlates during naturalistic International Society for Bipolar Disorders task force report of
follow-up in the Stanley Bipolar Network. Am J Psychiatry. 2016; symptom structure, course of illness, and diagnosis. Am J
173(10): 1015–1023. Psychiatry. 2013; 170(1): 31–42.
17. Angst J, Azorin J, Bowden C, et al. Prevalence and characteristics of 28. Koukopoulos A, Sani G. DSM-5 criteria for depression with mixed
undiagnosed bipolar disorders in patients with major depressive features: a farewell to mixed depression. Acta Psychiatr Scand. 2014;
episode. Arch Gen Psychiatry. 2011; 68(8): 791–799. 129(1): 4–16.
18. Fiedorowicz J, Endicott J, Leon A, Solomon D, Keller M, Coryell W. 29. Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the treatment of
Subthreshold hypomanic symptoms in progression form unipolar major major depressive disorder with mixed features: a randomized,
depression to bipolar disorder. Am J Psychiatry. 2011; 168(1): 40–48. double-blind, placebo-controlled study. Am J Psychiatry. 2016;
19. Zimmermann P, Brückl T, Nocon A, et al. Heterogeneity of DSM-IV 173(4): 400–407.
major depressive disorder as a consequence of subthreshold 30. Benazzi F, Koukopoulous, Akiskal H. Toward a validation of a new
bipolarity. Arch Gen Psychiatry. 2009; 66(12): 1341–1352. definition of agitated depression as a mixed state (mixed
20. Liu X, Jiang K. Should major depressive disorder with mixed features depression). Eur Psychiatry. 2004; 19(2): 85–90.
be classified as bipolar disorder? Shanghai Arch of Psychiatry. 2014; 31. Benazzi F. Reviewing the diagnostic validity and utility of mixed
26(5): 294–296. depression (depressive mixed states). European Psychiatry. 2008;
21. Perlis R, Uher R, Ostacher M, et al. Association between bipolar 23(1): 40–48.
spectrum features and treatment outcomes in outpatients 32. Benazzi F, Akiskal H. Delineating bipolar II mixed states in the
with major depressive disorder. Arch Gen Psychiatry. 2011; Ravenna-San Diego collaborative study: the relative prevalence
68(4): 351–360. and diagnostic significance of hypomanic features during major
22. Serra G, Koukopoulos A, De Chiara L, et al. Features preceding depressive episodes. J Affect Disord. 2001; 67(1–3): 115–122.
diagnosis of bipolar versus major depressive disorders. J Affect 33. Clementz B, Sweeney J, Hamm J, et al. Identification of distinct
Disord. 2015; 173: 134–142. psychosis biotypes using brain-based biomarkers. Am J Psychiatry.
23. Perlis R, Cusin C, Fava M. Proposed DSM-5 mixed features are 2015; 173(4): 373–384.
associated with greater likelihood of remission in out-patients with 34. Williams L. Precision psychiatry: a neural circuit taxonomy
major depressive disorder. Psychol Med. 2014; 44(7): 1361–1367. for depression and anxiety. Lancet Psychiatry. 2016; 3(5):
24. McIntyre R, Soczynska J, Cha D, et al. The prevalence and illness 472–480.
characteristics of DSM-5-defined “mixed feature specifier” in adults 35. Altshuler L, Sugar C, McElroy S, et al. Switch rates during lithium
with major depressive disorder and bipolar disorder: results from the monotherapy, sertraline monotherapy and lithium/sertraline
International Mood Disorders Collaborative Project. J Affect Disord. combination therapy for the acute treatment of bipolar II
2015; 172: 259–264. depression: a randomized double-blind comparison.
25. Smith D, Forty L, Russell E, et al. Sub-threshold manic symptoms in Am J Psychiatry. 2017; 174(3): 266–276.
recurrent major depressive disorder are a marker for poor outcome. 36. Amsterdam J, Shults J. Efficacy and safety of long-term fluoxetine
Acta Psychiatr Scand. 2009; 119(4): 325–329. versus lithium monotherapy of bipolar II disorder: a randomized,
26. Balázs J, Benazzi F, Rihmer Z, Rihmer A, Akiskal KK, Akiskal HS. double-blind, placebo-substitution study. Am J Psychiatry. 2010;
The close link between suicide attempts and mixed (bipolar) 167(7): 792–800.
depression: implications for suicide prevention. J Affect Disord. 37. Suppes T. Is there a role for antidepressants in the treatment of
2006; 91(2–3): 133–138. bipolar II depression? Am J Psychiatry. 2010; 167(7): 738–740.
Downloaded from https://www.cambridge.org/core. University of New Orleans, on 06 Oct 2017 at 18:00:08, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1092852917000256