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International Journal of Neuropsychopharmacology (2014), 17, 491–495.

© CINP 2013 TRENDS AND


doi:10.1017/S1461145713001107
PERSPECTIVES

Clinical staging: a necessary step in the


development of improved animal models
of mood disturbance?

Frederick Rohan Walker1,2*, Morgan H. James1,2, Ian B. Hickie3 and Patrick D. McGorry4
1
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
2
Centre for Translational Neuroscience and Mental Health Research, Hunter Medical Research Institute, NSW, Australia
3
Brain and Mind Research Institute, The University of Sydney, Camperdown, NSW, Australia
4
Department of Psychiatry, ORYGEN Youth Health Research Centre, University of Melbourne, VIC, Australia

Abstract
Recently, it has been suggested that the clinical staging approach be considered a serious alternative framework
for conceptualising mood related psychopathology. The fundamental difference between clinical staging and the
now dominant categorical diagnostic framework is that the entire illness trajectory becomes relevant, as opposed
to simply the end-stage. The concept of disease trajectory has significant implications for animal models of psy-
chopathology, and particularly for animal models of depression. This article will introduce and discuss the impli-
cations of the clinical staging approach for those undertaking research using animal models of mood disturbance.

Received 11 April 2013; Reviewed 13 May 2013; Revised 26 August 2013; Accepted 26 August 2013;
First published online 16 October 2013
Key words: Animal models of depression, clinical staging, depression, mood disorders.

Clinical staging: implications for animal models of the clinical staging approach is that the entire illness
trajectory becomes relevant, as opposed to simply the
The recent release of the 5th edition of Diagnostic and
end-stage – which remains the primary focus of existing
Statistical Manual of Mental Disorders (DSM-5) has pro-
diagnostic approaches (McGorry et al., 2006). The clinical
voked considerable debate on the strengths and weak-
aim of the staging concept is to guide the deployment
nesses of our traditional approaches to clinical and
of stage-appropriate (and often early-phase) interventions
research diagnoses. One of the strongest themes to
that have the potential to slow or halt progression to more
emerge is the view that existing diagnostic criteria are
advanced stages.
fundamentally limited by three major factors. First, they
By its nature, a clinical staging approach endorses a
are based largely on symptoms presented only by those
more dimensional view of psychiatric illness, adding the
with severe or persisting illness. While these ‘end-stage’
variables of time course and disease progression to the
phenotypes are representative of a subset of patients,
traditional dimension of illness severity. A significant
they may have very limited application outside of
feature of the staging approach is the recognition that
highly-specialised clinical settings. Second, little con-
the initial stage of major psychotic and mood disorders
sideration is given to those early and often sub-threshold
is phenotypically similar (Hafner et al., 2005). Indeed,
symptoms that are more characteristic of the onset
because of the degree of phenotypic overlap it has been
phase rather than the persistent course of an illness.
suggested that the initial phase of illness be considered
Third, the validity of the proposed links between the vari-
as a ‘pluripotential’ rather than disease-specific ‘at risk’
ous symptom-sets and any underlying or differentiating
stage (McGorry, 2011). While the clinical utility of adopt-
pathophysiologies remains largely unresolved (McGorry
ing this approach is being evaluated (McGorry, 2008),
et al., 2006).
the broad implications that it has for development of
An alternative view proposed independently by
relevant animal models for mood disturbance need to
McGorry et al. (2006) and Insel (2007) contends that a
be considered. To date, most animal models of mood
clinical staging approach is essential for both enhanced
disturbance have been designed without giving serious
clinical practice and the development of more meaning-
consideration to neither what stage of illness has been
ful clinical and basic research. A fundamental difference
modelled nor the fact that different phenomena may
emerge at different stages of illness. Indeed, a poor fit
between the stage of illness and the stage captured by
* Address for correspondence: Dr F. R. Walker, Room MS306, Medical
the animal model may have contributed to the clinical
Sciences Building, University of Newcastle, Callaghan, NSW 2308,
Australia.
failure of several compounds that had exhibited signifi-
Tel.: +61 2 4921 5012 Fax: +61 2 4921 5141 cant promise during pre-clinical testing (Cryan and
Email: Rohan.Walker@newcastle.edu.au Slattery, 2007).
492 F. R. Walker et al.

Animal models of mood disturbance – what stage are condition. Many working within the field consider it to
they at? be critical that animals exposed to a particular model
also respond in a manner that approximates the way in
There are now a large number of experimental models which patients respond to medication in clinical settings.
of depression in rodents. The central feature of almost For example, the validity of a given animal model of
all of these models is their reliance on repeated exposure depression is predicated not only on its ability to elicit
to aversive experiences. Amongst the most commonly ‘depression-like symptoms’, such as anhedonia, but on
used models are: repeated social defeat (Berton et al., whether animals display a marked reduction in this and
2006; Tsankova et al., 2006), repeated social disruption other symptoms when treated with a selective serotonin
(Herzog et al., 2009), repeated corticosterone adminis- reuptake inhibitor or serotonin-noradrenalin reuptake
tration (Gregus et al., 2005; Zhao et al., 2008), repeated inhibitor (or another accepted antidepressant). Consistent
restraint stress (Tynan et al., 2010; Hinwood et al., 2012) with this thinking, there are now many dozens of articles
and chronic mild stress (Bortolato et al., 2007; Goshen attesting to the fact that the behavioural disturbances
et al., 2008). Each of these models in turn can be combined exhibited by animals who have been subjected to a stan-
with developmentally earlier interventions to model early dard model of depression exhibit a marked reduction in
life and adulthood interactions (Hodgson et al., 2001; these symptoms following treatment with a conventional
Gardner et al., 2005). Many of these models are considered, antidepressant, such as a selective serotonin reuptake
in the presence of appropriately supportive data, to pro- inhibitor (Christiansen et al., 2011; Razzoli et al., 2011;
vide valid approximations of the human condition as Gumuslu et al., 2013).
they produce a symptom set that is highly analogous Significantly, however, we could not find any clinical
to that seen individuals with diagnosable depression. literature describing the use of anti-depressants during
Although all symptoms are not routinely measured in all the pre-diagnosable early stage of what would become
experiments, there are numerous instances in the literature major depression. Therefore it is not clear that a reduction
where any of the aforementioned models can be shown in symptoms when treated with an accepted antidepress-
to produce robust levels of anhedonia, psychomotor re- ant is in actual fact a measure of end-stage illness. It is
tardation, working memory deficits, anorexia and disturb- possible that such a reversal may also occur in early
ances in sleep (Willner, 1997, 2005; Yan et al., 2010). stage illness. To be certain that the behaviour(s) exhibited
Despite the undeniable ability of standard pre-clinical by an animal following exposure to a standard experimen-
models of mood psychopathology to elicit what are rou- tal model of depression are genuinely analogous to those
tinely referred to as ‘depression-like’ symptoms, it is not seen in individuals with depression, evidence should
totally clear that this interpretation is as straightforward also be available demonstrating that the clinical and pre-
as it seems. Specifically, some interpretational uncertainty clinical pre-diagnosis phase of the disorder do not
arises because numerous clinical studies have demon- respond in a similar way to antidepressants. Obtaining
strated that many symptoms present in patients that are such evidence at the present time represents a major chal-
diagnosed with depression (anhedonia, sleep disturb- lenge, as metrics capable of effectively discriminating
ance, irritability, and cognitive disturbance) are also between stage progressions have yet to be developed.
present in the prodromal (pre-diagnosis) stage of the
condition.
The need to develop indices of stage progression
The concept of consistent prodromal symptoms is not
new, and has been extensively investigated, principally The development and introduction of metrics or decision
due to interest in using prodromal symptoms to predict matrices that would allow researchers to determine how
the emergence of subsequent illness (Hetrick et al., 2008; far a disorder had progressed would be enormously ben-
Kovacs and Lopez-Duran, 2010; Szklo-Coxe et al., 2010; eficial. Perhaps the best outcome would be that each
Fusar-Poli et al., 2013). Particularly notable amongst this stage, from moderate behavioural perturbation through
literature is Fava’s (1990) early study highlighting the to a diagnosable condition, could be uniquely and categ-
consistency with which general anxiety, loss of interest, orically discriminated from the next, or in lieu of this, a
impaired work performance, fatigue and insomnia probabilistic estimate could be ascribed to stage pro-
appear in individuals that subsequently go on to develop gression. Unfortunately, without extensive experimental
depression. If features such as anhedonia are present in work it is difficult to know what the best indicators of
the pre-diagnosis and the post-diagnosis phase of major stage progression will be. Clearly, evaluating the extent
depression, the critical question for those using standard to which commonly used and well understood metrics
pre-clinical models and measuring anhedonic behaviour (e.g. sucrose preference) show graduated, intensity-
is: which phase of the disorder is this measured symptom dependent changes is an obvious place to begin investi-
actually occurring in? gations. Ideally, if sucrose preference did change in a
The mere presence of certain behavioural changes graduated intensity-dependent manner, it may be poss-
is not the only reason that current animal models are ible to ascribe particular stages to certain changes in
considered to be approximations of the diagnosable preference scores.
Clinical staging for animal models 493

Alternatively, in terms of developing stage metrics may be more appropriate, models that focus more on the
capable of differentiating prodromal-like behaviour application of specific risk or time-limited factors (e.g.
from diagnosable-like behaviour, it may be useful to acute stress, sleep deprivation, shifting circadian timing,
look at the approach taken with clinical diagnosis. exposure to infection) or manipulation of quite specific
One of the key aspects of clinically diagnosing the pres- developmental, pharmacological or other biological
ence of major depression is to identify the continued pres- pathways. The challenge, however, inherent with the
ence of certain debilitating symptoms for a given period introduction of ‘early-stage’ models is that the emergent
of time (DSM-IV-TR; APA, 2000). At present, the vast symptoms may only be loosely associated (pheno-
majority of animal models assess symptom severity either typically) with major depression in humans. Further
during the application of aversive experience or immedi- complicating matters, and mirroring clinical reality,
ately after its termination. We could find very few studies early-stage models could produce symptoms of mood
that tracked how persistent the depression-like symptoms disturbance that may in fact be linked equally to other
were following the cessation of aversive experiences. psychiatric syndromes (McGorry, 2011).
While the suggestion may carry some anthropomorphic
bias, it does not seem unreasonable to expect that if a Conclusion
diagnosable condition is being modelled then symptoms
should not rapidly resolve following the removal of the Perhaps the greatest utility of animal models to date has
aversive stimulus. If rapid symptom dissipation was been their role in testing the potential therapeutic capacity
observed using standard models it may be taken to of novel pharmacological agents. It is now apparent that a
suggest that they elicit more prodromal-like behaviour. range of compounds that appeared to have therapeutic
While speculative, a straightforward response to this situ- value in animal models of depression has not translated
ation would be to employ repeat cycles of aversive experi- well into the clinic (Cryan and Slattery, 2007). There are
ence, arguably providing a more accurate representation a variety of possible explanations for this phenomenon,
of the life history of those that do eventually develop but one that has not been widely considered may well
depression (Kendler et al., 1993; Chapman et al., 2004). be a poor fit between the stage of illness in most human
One of the most significant issues in terms of moving subjects (i.e. chronic or recurrent illness) and the stage
forward with the development of metrics capable of captured by the animal model.
detecting modest behavioural disturbances is sample Fortunately, a firm platform for clinical research
size. Much of the work undertaken thus far using animal in major mood disorders based on the clinical staging
models of mood disturbance has made use of group sizes approach has now been established (McGorry et al.,
of between 6 and 10 animals per group. This modest 2006). The implications of the staging model for the sub-
number reflects the fact most studies have only been pow- sequent development of relevant animal models of
ered to detect relatively large between-group differences. depression, and potentially other mood disorders, are
Given the typical variability observed in studies of animal profound. It will be necessary, first, to state what stage
behaviour, it is likely that sample size will have to be of illness (and observed behaviour or physiological
increased significantly in order to robustly identify change) is produced in response to a given risk factor
small differences in behaviour that may occur during and, second, what types of therapeutic strategies are rel-
early phases of disease progression. evant to the various stages of illness progression.
Whatever ‘stage-metrics’ are eventually employed, Importantly, without the development, introduction and
hopefully they will confirm, as many have long assumed, evaluation of stage metrics it will be difficult to fully
that existing animal models of psychopathology, and par- understand how representative the information is that is
ticularly animal models of depression, are reasonable currently being generated from existing animal models
models of the end-stage clinical condition. We must, how- of mood disturbance. Ultimately, continued development
ever, be open to the possibility that existing models may of the staging concept in the field of pre-clinical models
represent earlier stages of disease progression than we of mood disorders has the potential to increase the chance
had originally anticipated. of successful translation of therapies from the lab to
personalised clinical practice.

Are new models required or can existing models be Acknowledgments


repurposed to accommodate the staging concept?
This work was supported by project grants from
Application of the staging concept to preclinical model- the National Health and Medical Research Council of
ling of mood disorders raises questions about what Australia and the Hunter Medical Research Institute.
models should be used. Can existing models of mood
disturbance, such as the repeated restraint stress model,
Statement of Interest
be pressed into service by simply evaluating change
earlier in the environmental insult process? If not, it F.R.W. currently receives research support from the
may be the case that specific early (or later) stage models National Health and Medical Research Council of
494 F. R. Walker et al.

Australia (NHMRC). M.H.J. has no interests to declare. social defeat: focus on serotonergic systems. Neuroscience
I.B.H. Sits on the National Advisory Council on Mental 136:181–191.
Health, which reports to the Federal Minister for Mental Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T,
Health, is a member of BUPA Australia and a Headspace Weidenfeld J, Ben-Hur T, Yirmiya R (2008) Brain interleukin-1
mediates chronic stress-induced depression in mice via
board member. I.B.H. was previously chief executive
adrenocortical activation and hippocampal neurogenesis
officer and clinical adviser of Beyondblue, an Australian
suppression. Mol Psychiatry 13:717–728.
National Depression Initiative. He has led projects for Gregus A, Wintink AJ, Davis AC, Kalynchuk LE (2005) Effect
health professionals and the community supported by of repeated corticosterone injections and restraint stress on
governmental, community agency and drug industry part- anxiety and depression-like behavior in male rats. Behav Brain
ners (Wyeth, Eli Lily, Servier, Pfizer, Astra-Zeneca) for the Res 156:105–114.
identification and management of depression and anxiety. Gumuslu E, Mutlu O, Sunnetci D, Ulak G, Celikyurt IK,
He has served on advisory boards convened by the drug Cine N, Akar F (2013) The effects of Tianeptine, Olanzapine
industry in relation to specific antidepressants, including and Fluoxetine on the cognitive behaviors of unpredictable
nefazodone, duloxetine, and desvenlafaxine and has par- chronic mild stress-exposed mice. Drug Res (Stuttg)
ticipated in a multi-centre clinical trial of agomelatine doi: 10.1055/s-0033-1347237.
Hafner H, Maurer K, Trendler G, an der Heiden W,
effects on sleep architecture in depression. I.B.H. is also
Schmidt M (2005) The early course of schizophrenia
supported by a National Health and Medical Research
and depression. Eur Arch Psychiatry Clin Neurosci
Council Australian Medical Research Fellowship. He is 255:167–173.
a participant in a family-practice-based audit of sleep Herzog CJ, Czeh B, Corbach S, Wuttke W, Schulte-Herbruggen O,
disturbance and major depression, supported by Servier, Hellweg R, Flugge G, Fuchs E (2009) Chronic social
the manufacturers of agomelatine. Research studies instability stress in female rats: a potential animal model
done by I.B.H. are mainly funded by NHMRC project for female depression. Neuroscience 159:982–992.
and programme grants. Hetrick SE, Parker AG, Hickie IB, Purcell R, Yung AR,
P.M. Currently receives research support from the McGorry PD (2008) Early identification and intervention
NHMRC and the Colonial Foundation. in depressive disorders: towards a clinical staging model.
Psychother Psychosom 77:263–270.
Hinwood M, Morandini J, Day TA, Walker FR (2012) Evidence
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