466185

2013

JOP27510.1177/0269881112466185Journal of PsychopharmacologyHendrie and Pickles

Commentary

The failure of the antidepressant drug

discovery process is systemic
Journal of Psychopharmacology
27(5) 407416
The Author(s) 2013
Reprints and permissions:
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DOI: 10.1177/0269881112466185
jop.sagepub.com

Colin Hendrie1 and Alasdair Pickles2

Abstract
Current antidepressants are crude compared with the ideal and patents on most have expired. There are therefore strong clinical and commercial
pressures for new drugs to replace them. The prospects for this are, however, now markedly reduced as several major pharmaceutical companies have
abandoned work in this area whilst many others have sharply decreased their research investment. These changes and the lack of progress over such a
long period are indicative of a catastrophic systems failure which, it is argued, has been caused in large part by a logical flaw at the animal modelling
stage. This tautology has served to lock the current antidepressant drug discovery process into an iterative loop capable only of producing further
variations of that which has gone before. Drugs produced by this approach have proved to be only poorly effective in the context of the clinically
depressed population as a whole. Hence, the inevitable failure of the current antidepressant drug discovery process has left little behind that can be
salvaged. Therefore, it is suggested that this be urgently reformulated on more rational grounds using more appropriate species in new animal models
based upon a thorough understanding of the behavioural expressions of depression in the clinic.

Keywords
Animal models, antidepressant, depression, drug discovery, MDD

Introduction
Depression is a widespread disorder that accounts for approximately 12% of the total burden of non-fatal global disease (stn
et al., 2004). In the developed world around 25% of people can
expect to experience this at some point in their lives (Blazer, 2000;
WHO, 2002). Females are up to three times more vulnerable than
males (Burt and Stein, 2002). First line treatments for depression
are mostly drugs based (Hollon et al., 2002), with antidepressants
being the third most commonly prescribed medication in the
United States (Mojtabai and Olfson, 2011).
Whilst their use is on an upward trajectory throughout the
developed world (Lin et al., 2011) the utility of these drugs is
nonetheless restricted because not all patients respond to them
(e.g. Bielski and Friedel, 1976; Brown et al., 1994; Fava and
Davidson, 1996; Moncrieff, 2007). Indeed, these response rates
may be as low as 4050% (e.g. Trivedi et al., 2006), even after
several years of treatment (e.g. Colman et al., 2011). This is not
greatly higher than the response rate to placebo (Walsh et al.,
2002). A further cause for concern are meta-analyses including
negative findings submitted to the FDA but not published in the
scientific literature that show that even these low figures are exaggerated by publication bias (Piggot et al., 2010; Turner et al.,
2008).
There are reviews indicating that small numbers of severely
(but not mild or moderately) depressed patients respond to these
drugs (e.g. Fournier et al., 2010) but these must be viewed in the
light of this publication bias. There is also a marked tendency for
the strength of reported drug effects to be related to the age of the
publication (Papakostas and Fava, 2009), which has been suggested to reflect the larger amount spent on advertising whilst
these drugs were still in patent (Lacasse and Leo, 2005; Leo and
Lacasse, 2008).

In addition to concerns about the large number of patients who

cannot be treated using these drugs, currently available antidepressants are crude compared with the ideal and have several very
serious shortcomings. Relapse rates are high (e.g. Geddes et al.,
2003), there is a dangerous therapeutic lag of several weeks (e.g.
Skolnick, 1999) that leaves even those who do eventually respond
feeling temporarily even more depressed (Jick et al., 2004; Mller
and Volz, 1996) and side effects remain an issue even though these
are reduced in second generation antidepressants compared with
first (e.g. Dording et al., 2002).
In consequence official policies no longer recognise drugsbased antidepressant therapies as the panaceas they once did (e.g.
Hughes and Cohen, 2009; Middleton et al., 2005; NICE, 2004) and
significant numbers of depressives reject these treatments in favour
of self-medication, with alcohol and/or other non-prescription
drugs (e.g. Garland et al., 2012; Hendrie et al., 1998).
There are therefore strong clinical and ethical pressures
towards the development of a new generation of antidepressants
and the commercial rewards for doing so are potentially enormous. It is deeply paradoxical then that so many of the major
players in the pharmaceutical industry have declared that they are

1Institute

of Psychological Sciences, University of Leeds, Leeds, UK

of Membranes and Systems Biology, University of Leeds,
Leeds, UK

2Institute

Corresponding author:
Colin Hendrie, Institute of Psychological Sciences, University of Leeds,
Woodhouse Lane, Leeds LS2 9JT, UK.
Email: c.a.hendrie@leeds.ac.uk

408
no longer going to vigorously pursue this goal (Miller, 2010). The
aim of the present paper is to explore the reasons why this hiatus
has occurred and ways in which this knowledge can be used to
help inform efforts to get the antidepressant drug discovery process moving forward once again.

Dissecting the process

Animal models
The drug discovery process seeks to produce drugs that are both
efficacious and safe (Paul et al., 2010). Whilst clinical trials are
often given a higher profile (e.g. Lipsky and Sharp, 2001) this
fails to take into account the pivotal role animal models play in
the process leading up to this phase. That is, preclinical models
provide information that helps determine whether drugs should
move into Phase 1 clinical trials (Herrling, 2005; Verkman,
2004) and, where appropriate, fulfil the regulatory obligation for
efficacy to be shown before they are allowed to do so (e.g.
Woodcock and Woosley, 2008). That said, the utility of animal
models of depression is often not immediately obvious to nonspecialists because they tend not to be based on a direct mapping
of homologous responses between species (as would be the case
with, say, hypertension), their end points often bear no resemblance to the disorder they are seeking to model (see below) and
the level of translation between these models and clinical efficacy is low (Harmer et al., 2011).
In this context, animal models of depression should ideally
be based on a common aetiology in both animals and man. They
are not and so pharmacological validity has been used as the
defining characteristic instead. That is, all potential new drugs
are measured against existing compounds in models that have
been developed solely on the basis of their sensitivity to these
standards (e.g. Kudryavtseva et al., 1991; Porsolt et al., 1977;
Song and Leonard, 2005; Steru et al., 1985; Willner, 1997).
These models have in consequence remained mechanistic and
are now frequently referred to as assays in recognition of their
lack of any obvious relationship with clinical depression (e.g.
Krishnan and Nestler, 2008).
There are a plethora of such models (for reviews see
McArthur and Borsini, 2006; Willner, 1984, 1997) and one of
the main reasons for this is that it is impossible to reject particular tests once they have satisfied the sensitivity to known antidepressants criterion. This point also extends to those more
recent genetically based models (e.g. Cryan and Holmes, 2005;
Cryan and Mombereau, 2004). Hence, use of these assays has in
recent times become a matter of preference and taste rather than
utility, since they have all been developed on essentially the
same definitional lines.
Commonly used models of depression include tail suspension
(Cryan et al., 2005; Steru et al., 1985), forced swim (Porsolt et al.,
1977), mouse killing (e.g. Song and Leonard, 2005), chronic
social defeat (e.g. Keeney and Hogg, 1999; Kudryavtseva et al.,
1991) and chronic mild stress (e.g. Monleon et al., 1995; Willner
et al.,1987).

Logical flaw
Attempting to identify new compounds as potential antidepressants by testing them in animal models of depression that have

Journal of Psychopharmacology 27(5)

been defined as such solely on the basis of their sensitivity to
existing antidepressants is logically flawed, a tautology (of the
form A=B therefore B=A). Thus the argument it is an antidepressant because it has effects in animal models of depression that are
animal models of depression because they are sensitive to the
actions of antidepressants is in context no different in form from
the statement God exists because the Bible says he does and the
Bible is the infallible word of God.
This basic error was built into the current antidepressant drug
discovery process from its inception (e.g. Chessin et al., 1956;
Loomer et al.,1957) and the problems inherent with this approach
have become compounded at each stage. Hence the current situation, where first generation antidepressants put on the market
before FDA regulations required efficacy to be shown (Goodrich,
1963) were used as templates for a second generation of drugs
that we now know to be only poorly effective in the context of the
clinically depressed population as a whole (Colman, 2011; Piggot
et al., 2010; Trivedi et al., 2006).
This situation has become further confounded in more recent
times by the propensity to blur the conceptual differences between
stress and depression and to erroneously use these terms more
or less interchangeably (Dias et al., 2009). Further, many of the
models currently in use are open to alternative explanations for
effects seen in them. For example the end-points used to indicate
antidepressant action in the forced swim test could also be the
product of effects on learning and memory (e.g. West, 1990).
Effects on sucrose consumption in the chronic mild stress model
can be accounted for by the food deprivation component of this
procedure alone (Forbes et al., 1996) and chronic social stress
models where animals are exposed to attack from an aggressive
conspecific (e.g. Keeney and Hogg, 1999) could equally be measuring factors that influence the activation of the endorphin system
(e.g. Rodgers and Hendrie, 1983; Siegfried et al., 1987) and/or the
well documented analgesic actions of the antidepressants themselves (e.g. Mic et al., 2006; Wattiez et al., 2011)
In consequence, the vast majority of researchers in this area
operate on the de facto working definition of depression as that
which responds to existing antidepressants (e.g. Cryan et al.,
2002; Cryan and Holmes, 2005; Deussing, 2006; Kelly et al.,
1997; Krishnan and Nestler, 2008; Samuels et al., 2011; Song
and Leonard, 2005; Willner, 1984; Wong and Licinio, 2004) in
any species, including yeast (e.g. Chen et al., 2012) and regardless of the mechanisms underlying these effects or the end-points
employed.

False assumptions
If the first flawed premise of the current antidepressant drug
discovery process is that existing drugs are suitable templates on
which to base the development of new treatments, the second is
that rats and mice are suitable species on which to (almost
exclusively) base the animal models these drugs are tested in
(e.g. Cryan and Holmes, 2005; Krishnan and Nestler, 2008;
Porsolt et al., 2001).
Were the antidepressant drug discovery process to have been
developed along rational lines, rats and mice would have been
selected because of special characteristics that make them particularly suitable for use in these models. They do not, however, have
such characteristics (Dias et al., 2009; Hendrie and Pickles, 2009)
and there are indeed strong arguments against their continued use

Hendrie and Pickles

409

Table 1. False assumptions underlying the current antidepressant drug discovery process. The resulting practices have led to inappropriate
species being used in animal models that have been developed solely on the basis of their sensitivity to drugs that are now known to be only poorly
effective in the context of the clinically depressed population as a whole. This tautological reasoning locked the drug discovery process into an
iterative loop capable only of producing further variations of that which had gone before and made systems failure inevitable.
Assumption

Practice

Issue

Consequence

Existing drugs are effective

Animal models developed on basis

of sensitivity to existing drugs
Animal models defined by
sensitivity to existing drugs

Existing drugs not effective in

5060% of depressed population
Logically flawed
Tautology

Heavy reliance on rats and mice

Depression most likely species-specific

and not present in rats or mice

Candidate drugs struggle to

outperform placebo
Process locked into iterative loop
Capable only of producing
more me-toos
Rats and mice not suitable species
for use in this context

Animal models must be

sensitive to existing drugs
Depression can be studied
in any species

in this context (Hendrie et al., 2011; Hendrie and Pickles, 2009).

Further, little consideration has been given to species differences
between rats and mice except for perhaps, occasionally, their size.
Hence there are rat (Detke et al., 1995) and mouse (Porsolt et al.,
1977) forced swim tests; rat (Rygula et al., 2005) and mouse
(Keeney and Hogg, 1999) social defeat models; rat (Willner et al.,
1987) and mouse (Yalcin et al., 2005) chronic unpredictable mild
stress models and rat (Chermat et al., 1986), mouse (Steru et al.,
1985) and gerbil (Varty et al., 2003) tail suspension tests, etc.
There are nonetheless important differences between rats and
mice and their significance cannot be ignored. Laboratory rats
are derived from Rattus norvegicus. These are colonial animals
that live together relatively peaceably under laboratory conditions (e.g. Barnett, 1963; Rodgers and Hendrie, 1982), within
which significant levels of full-blooded aggression are seen
under only the most unusual of conditions (e.g. Rodgers et al.,
1983). Laboratory mice (Mus musculus) are by contrast strongly
territorial and show high levels of intra-male aggression whenever they are group housed. Cages of male mice (the sex that is
most frequently used) are in consequence a mixture of dominant
and subordinate animals that vary greatly in terms of behaviour,
physiology and immune functioning (Berry, 1970; Brain, 1971;
Hendrie et al., 1996) and this is, at least, a major source of
variance in all studies using this species.
Rats and mice are, it seems, used extensively in the field of
depression research because there has been no serious consideration that things should be otherwise (e.g. Borsini, 2012; Hendrie
et al., 2011; Nestler and Hyman, 2010) and the lumping together
of findings made using rats, mice and/or other species as rodent
models (e.g. Castagn et al., 2011; Duman, 2010; El Yacoubi and
Vaugeois, 2007; Krishnan and Nestler, 2011; McArthur and
Borsini, 2006; Nestler and Hyman, 2010) ignores the potential
importance of these species differences. This is also a very high
risk strategy that assumes depression to be a general mammalian
feature that can be modelled in any animal of this class.

Systems failure
The ease with which me-same compounds could be produced in
the 1960s, 70s and to a certain extent the 80s (e.g. Domino, 1999;
Geddes et al., 2000) once gave this flawed antidepressant drug
discovery process an aura of rationality. However, serendipity
remained at its base, the illusion could not be maintained indefinitely and the paucity of this approach has now been fully exposed.

The glacial rate of progress over the past 60 years has provided
improvements in tolerability but not efficacy (Hindmarch, 2001).
The most frequently prescribed antidepressants are now more than
20 years old and out of patent (Ciprani et al., 2009). There is little
in the pipeline to replace them and only poor prospects of there
being progress in the near future now that many of the worlds
leading pharmaceutical companies have to a greater or lesser
degree reduced their investment in this area (Blier, 2010). There
has been what can only be described as a catastrophic systems
failure and this has left little behind that can be salvaged.

Taking stock
With the benefit of hindsight it is apparent that even a cursory
consideration of the species used in these models would have
raised serious questions about the models themselves. Asking
what species? inevitably raises the question why? and any
rational answer to that demands a level of understanding about
depression itself that we do not currently possess. The emphasis
would thus have been on developing that understanding of depression rather than continuing down the line of making high levels of
investment in drug-led approaches that have not proved successful. The result of this omission has been an antidepressant drug
discovery process that is tautologically locked into an iterative
loop capable only of producing further variants of that which has
gone before. This error has become critical now the proportion of
the clinical population that cannot be treated with these drugs has
become clear. There can be no more potent demonstration of the
moribund state of the current antidepressant drug discovery process than the growing clinical interest in the Class C street drug
ketamine (e.g. Berman et al., 2000; Morgan and Curran, 2012).

Moving forward
The need to develop a greater understanding of clinical depression
and to apply that knowledge to the development of new animal
models for use in a reformulated drug discovery process highlights one further difficulty that needs to be addressed before that
process can begin: that of resolving the different approaches taken
by psychiatrists and pre-clinicians so that findings from each can
be integrated. The prevalent approach in the clinic has been
nosological, with an emphasis on interview and questionnaires
that themselves concentrate heavily on mood state (such as those
originally developed by Hamilton (1960) and Beck and colleagues

410

Journal of Psychopharmacology 27(5)

(1961)). These methods are clearly not available to those that

work with animals. Hence, although there is no widespread tradition of behavioural assessment in psychiatry (e.g. van Praag et al.,
1987; van Praag, 2010) a full characterisation of the behavioural
expression of depression in the clinic is nonetheless required.

Importance of the ethological approach

Ethological analysis was first applied to laboratory animals in
the 1960s (e.g. Grant and MacKintosh, 1963) and has gained use
particularly in the fields of anxiety (e.g. Cole and Rodgers, 1993;
Holmes et al., 2000, Smolinsky et al., 2009) and depression (e.g.
Hendrie and Starkey, 1998; Pickles et al., 2012).
The most important aspects of the ethological approach are
Tinbergens four principal questions (Tinbergen, 1963). These
questions relate to form (what does it look like?), function (what
does it do?), ontogeny (how does it change over a lifetime?) and
phylogeny (what does it look like and do in other species?) and
can be applied to all levels from molecular to societal to give
insights that are not obtainable by any other means.
In the context of depression this approach has recently led to
an analysis that suggests that this is an adaptation mediated via
events in the third ventricle (Hendrie and Pickles, 2010). This has
been concluded because the behavioural cluster associated with
depression (e.g. hunched posture, avoidance of eye contact,
reduced competition for food/sex and sleep disruption) is defensive in nature. This cluster in turn serves to reduce an individuals
attack provoking stimuli and so allows them to remain within
social groups that have become hostile to their presence.
Depression is most commonly seen in adults and the nature of the
adaptation indicates that it would only have developed in those
species with a similar social need to our own. The third ventricle
is implicated because the hypothalamus lies at one end, the pineal
at the other and major pathways from the amygdala and hippocampus pass through it (Hendrie and Pickles, 2009, 2010).
The opportunity to test this hypothesis experimentally has not
presented itself as yet and so it may not be supported. Nonetheless,
its proposal serves to illustrate the potential significance of the
guiding principles of ethology in this context and the value of the
pioneering work that has already been done on the behavioural
characterisation of human psychiatric illness (e.g. Dixon, 1986;
Dixon et al., 1989; Troisi et al., 1990; Troisi, 1999).

3.

These new models must also be constructed on the basis

of a full understanding of the natural histories of the
species to be used in them. Since it is postulated that
depression is a species-specific adaptation developed in
response to particular social circumstance this adaptation
will only be seen in those species with similar social
needs to our own (Hendrie and Pickles, 2009, 2010). The
social organisations of rats and mice do not predict that
they are amongst the group of species to have developed
this adaptation (Hendrie and Pickles, 2009). Mongolian
gerbils (Meriones unguiculatus) are, however, a strong
candidate in this context (e.g. Pickles et al., 2012) and
other species will no doubt be found once they are
looked for.

Lastly, the purpose of the drug discovery process is to produce

drugs that are both efficacious and safe and the process needs to
be shaped to meet those goals, not the other way round. Hence, if
rats and mice are not suitable for use in this context then concerns
about using different species in new animal models must be set to
one side. The continued use of current animal models of depression cannot be justified only on the grounds that they fit in with
other aspects of the drug discovery process and the process must
evolve to accommodate that.

Conclusions
The annus horribilis suffered by European neuroscience in 2010
as the result of GSK, AstraZeneca, Pfizer, Merck and Sanofi all
announcing significant reductions in their research efforts into
traditional drug discovery for the treatment of neuropsychiatric
disorders has been well documented (Nutt and Goodwin, 2011).
The catastrophic failure of the antidepressant drug discovery
process has undoubtedly been a contributing factor and there are
hence pressing clinical, ethical and commercial reasons why this
process must be quickly built anew.

Conflict of interest
None declared.

Funding
This research received no specific grant from any funding agency in the
public, commercial, or not-for-profit sectors.

Reformulating the process

The failure of the current antidepressant drug discovery process
has been contingent upon a number of avoidable factors and it is
imperative that these mistakes are not repeated. It is beyond the
scope of this paper and the position of those authoring it to suggest
in detail how the antidepressant drug discovery process should be
reformulated but there are a few general principles that clearly
need to be adhered to:
1.

2.

Ethology must be at the heart of this new process, to provide the required ethological description of clinical depression in all its various stages and to enable homologies
between animals and man to be identified as they emerge.
New animal models need to be developed on the basis of
this knowledge and designed to allow full integration of
data generated in animals and man.

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Beating the recession in

preclinical measures of
antidepression: A response
to: The failure of the
antidepressant drug discovery
process is systemic (Hendrie
CA and Pickles AR)
S Clare Stanford

Hendrie and Pickles paint a gloomy picture of the state of preclinical psychopharmacology. They argue that behavioural models that
are used to develop antidepressants have constrained, rather than
enabled, progress. We will never know whether these tests have
filtered out any compounds that would have worked well had they
reached the clinic (false negatives). However, there is a great deal
of concern about the failure of promising candidates at the translation stage (false positives). These are expensive mistakes and it is
unfortunate, to say the least, that the few attempts to break into
new pharmacological territory have burnt industrial fingers.
It is true that imipramine has proved unbeatable on measures of
efficacy. It is also true that there has been little progress in helping
non-responsive patients. Hendrie and Pickles believe that preclinical tests are culpable because they comprise a self-validating loop
that merely produces families of similar compounds. However, the
strong, cautious focus on drug candidates that were most likely to
succeed (i.e. anything that will augment monoamine transmission)
is a contributing factor. Even so, clinicians must agree that the
greater tolerability and safety of younger compounds, especially in

413
overdose, were important steps in the right direction. This could
not have been achieved without the behavioural tests that many
people now assert have let us down so badly.
This is not the first time that behavioural tests in rodents
have been blamed for translational failures and for the withdrawal of investment in preclinical psychiatry. We are even
beginning to question whether preclinical models are equivalent
to the Emperors sartorial hoax. This crash in confidence has
arisen partly because behavioural procedures that are described
as models of depression have been confused with those that are
merely predictive screens for antidepressant drugs, which is
completely different. Even a test that looked for drugs that make
mice whistle the national anthem would have predictive validity
if they all turned out to be antidepressants in humans, but it
would not be a model of depression. Similarly, it is most unlikely
that rodents are depressed during a brief bout of tail suspension
or enforced swimming but it is clear that these tests have found
many antidepressants. This might be because they reveal a druginduced increase in motor motivation, which would be helpful
in some depressed patients. Other screens will pull out different
elements of antidepression: for example, reversing social defeat
in rodents/low self esteem in humans; reduced sucrose preference in rodents/anhedonia in humans. In other words, it is likely
to be the combination and scope of screens in the battery of tests,
not the individual tests, that determines predictive validity for
antidepression, which must require a broad spectrum of actions.
Some procedures do cause long-lasting, complex changes in
behaviour that are prevented, or reversed, by antidepressants and
so are arguably more valid as models of depression. Learned
helplessness is a case in point. However, it is not at all clear
whether this behavioural deficit emulates depression or posttraumatic stress disorder, or whether it is a learned motor
response, which makes a big difference when interpreting the
effects of psychotropic drugs on this behaviour. What is certain is
that the nature of the aversive stimulus (repeated electric shock)
and its context (inescapable enclosure) raise questions about the
type of human experience that is being studied and when, if ever,
it is ethical or relevant to replicate them in other animals.
To resolve such problems, Hendrie and Pickles argue in favour
of developing preclinical tests that are based on ethological measures and contexts that are equivalent to those of depressed humans.
They are optimistic that the study of more naturalistic behaviour
would help to drag us out of the doldrums. The approach they suggest could be invaluable in complementing existing drug screens
provided we avoid anthropomorphic assumptions, such as the
behaviour looks defensive. They would also need to deal with the
complication that depression is not a stable, homogenous disorder
with a single sign that is amenable to measurement. How would
we distinguish different combinations of negative emotions such
as low self-esteem, melancholia and suicidality, for instance?
Until these difficulties are resolved, I predict that it will be hard to
convince sceptics that the validity of ethological tests is any better
Department of Neuroscience, Physiology and Pharmacology,
University College London, London, UK
Corresponding author:
S Clare Stanford, Department of Neuroscience, Physiology and Pharmacology,
University College London, Gower Street, London WC1E 6BT, UK.
Email: c.stanford@ucl.ac.uk

414
than that of existing procedures or that they will improve successful translation.
Meanwhile, we need new drug targets as well as reliable preclinical tests. We seem to be pinning our hopes on finding those
targets in human studies (experimental medicine and a search for
biomarkers) but their development will still involve an iterative
process of backtranslation/retranslation that cannot short-circuit
the preclinical phase. To ensure that a therapeutic breakthrough
does not slip through the net, Hendrie and Pickles warn that we
should be refining and strengthening the preclinical research
base rather than dismantling it. It is impossible to disagree with
that. The process will be difficult and expensive but the potential
benefits to quality of life, life expectancy and sheer cold-lightof-day economics make it hard to justify giving up unless those
in charge of drug discovery and development (the accountants)
have decided that the antidepressants we use at present are good
enough.

Can a single animal model

ever provide a valid
approach to study clinical
depression? A response
to: The failure of the
antidepressant drug discovery
process is systemic (Hendrie
CA and Pickles AR)
Emma Robinson

Hendrie and Pickles provide a critical review of the approach

taken in the development of antidepressant drugs and highlight
the limitations associated with an (over)reliance on animal models
such as the forced swim test (FST) and tail suspension test (TST)
to predict clinical efficacy. They propose that the use of such
models has limited our search for novel drug targets due to their
bias towards detecting drugs which enhance monoamine neurotransmitters. They also make a compelling case that, without
urgent re-evaluation of how we model depression in animals, the
development of new antidepressants will only further stagnate.
Their suggestion is to move outside our traditional rodent models
of mice and rats and look to alternative species, and ethological
approaches, to develop models which can better represent the
behavioural expressions of depression in the clinic.
The term animal model of depression is somewhat confusing
as it is used as a general term referring to methods to both assay
antidepressant-like behaviour or induce a depression-like phenotype. The FST, as originally reported, described a method to test

Journal of Psychopharmacology 27(5)

for antidepressant efficacy based on evidence of predictive validity. It made no claims that it was a model of the human syndrome
of depression although is now widely used in studies investigating
depression-like phenotypes in animals. Hendrie and Pickles highlight the limitations of these models in terms of only identifying
drugs with similar mechanisms of action, as well as the lack of
specificity of these tests to anti-depressant and pro-depressant
manipulations. There have undoubtedly been costly examples
where animal models have failed to accurately predict antidepressant and pro-depressant effects in man. For examples, the NK1antagonist aprepitant failed in clinical studies despite exhibiting a
positive effect in animal models. The CB1-antagonist rimonabant
has been shown to exhibit an antidepressant profile in some animal studies but subsequently was found to have pro-depressant
side effects in man. Given these costly failures, it is not surprising
that confidence in current animal models has declined, but the
FST and TST were a crucial part of the development of antidepressants with much improved side effect profiles, if not improvements in efficacy.
In general, it is perhaps not the tests which are the major failure but the way in which they are used and the results subsequently interpreted. Perhaps we need to be more realistic about
what exactly animal models of depression do and do not tell us
about the clinical condition. Hendrie and Pickles make a very
important point when they argue that the FST and TST may be
restricted in terms of moving outside the area of monoamine neurotransmitters and these tests are likely to be limited in terms of
their validity for studies into the basic neurobiology of depression
and identifying novel, non-monoaminergic targets. Given our
increasing knowledge about genetic predisposition, environmental factors which precipitate depressive episodes and cognitive
neuropsychological features of depression, new approaches are
desperately needed, but how do we achieve validity for these?
Perhaps it is a necessary evil associated with developing animal
models in psychiatry as a whole that we still rely heavily on
sensitivity to known therapies in order to provide validity and in
doing so create the problems highlighted in this article. Without
good biomarkers or clear evidence for a biological substrate
underlying the disease, what other approach do we have? The
authors raise an interesting point when they suggest that rat and
mouse are not the best species, and animals with a more comparable social structure may make a more appropriate alternative.
Several studies have looked at social manipulations, including the
gerbil model described here, but also the tree shrew and rat
models, such as maternal separation. Looking towards the evolutionary basis for depression and taking an ethological approach
offers a very interesting route into understanding more about the
disease and identifying the most appropriate species for nonclinical investigations, although making the case that these have
validity remains a major challenge.
Perhaps an interesting way of looking at depression and modelling this highly complex disease is to look first to the human. Could

University of Bristol, Physiology and Pharmacology, School of Medical

Sciences, Bristol, UK
Corresponding author:
Emma Robinson, University of Bristol, Physiology and Pharmacology,
School of Medical Sciences, Bristol BS8 1TD, UK.
Email: Emma.S.J.Robinson@bristol.ac.uk

Hendrie and Pickles

a human model of depression meet our animal model criteria? If
we look at the DSM-IV criteria for diagnosis, it is clear that this is
a heterogeneous disease where only a number of symptoms need to
be present to meet the diagnosis. So what are we trying to model in
our animals? Would we not be better to focus our efforts on developing and validating good assays in animals to study key symptoms of the disease? If this approach were taken, then different
species may well be found to offer advantages over others, depending on the measure. The physiological and hormonal effects of
social separation, behavioural despair in the FST/TST and anhedonia in the SPT all have shown potential in terms of the respective
symptoms they propose to replicate in animals. Cryan and Holmes
(2005) reviewed the use of mouse models of depression and produced an interesting map of different rodent assays against the
DSM-IV criteria. They also make the point that symptoms such as
rumination of negative thought, suicidal ideation and mood
changes can never be modelled in animals because of their subjective nature. Maybe the key to moving forward with non-clinical
depression research is a better integration of basic and clinical sciences into depression. Whilst we inevitably blame the rodent models and animal methodology, perhaps we also need to consider how
we quantify depression in patients and look to assess depressive
illness in patients by using methods which can also be taken to the
bench and used in animal studies. To some extent, this has already
started with evidence from clinical studies that neuropsychological
measures of emotional behaviour can predict vulnerability to
depression and acute effects with antidepressant and pro-depressant drug treatments (Pringle et al., 2011). Cognitive affective
behaviours have recently been evaluated in animals by using an
approach designed to replicate aspects of the cognitive impairments associated with mood disorders (Mendl et al., 2010). If we as
animal researchers look to the neuropsychological literature, we
can see a number of opportunities for reverse translation and perhaps this is also a way we can move forward with non-clinical
research into depression and developing novel treatments.

References
Cryan JF and Holmes A (2005) The ascent of mouse: Advances in modelling human depression and anxiety. Nat Rev Drug Discov 4: 775-790.
Mendl M, Burman OH and Paul ES (2010) An integrative and functional
framework for the study of animal emotion and mood. Proc Biol Sci
277: 2895-2904.
Pringle A, Browning M, Cowen PJ, et al. (2011) A cognitive neuropsychological model of antidepressant drug action. Prog Neuropsychopharmacol Biol Psychiatry 35: 1586-1592.

Concluding reply
We present the argument that the current antidepressant drug discovery process is fatally flawed and hence not fit for purpose. Our
conclusion is that the nature of these flaws are such that there is
little to be salvaged and no option but to begin again from scratch.
Drs Stanford and Robinson offer thoughtful and considered
responses to these contentions and for that we thank them.
Both commentators give close attention to our criticism of the
existing animal models. Dr Stanford says, This is not the first

415
time that behavioural tests in rodents have been blamed for
translational failures. Dr Robinson reminds us that these test for
antidepressant efficacy based on evidence of predictive validity
and should not be reprimanded for failing to model the human
syndrome.
Animal models are central to the antidepressant drug discovery process and hence included in any criticism of that process.
However, our main concerns are the logical flaw that underpins
these models and the disconnection between preclinical and clinical psychopharmacology/psychiatry that has allowed them to
develop superstitiously. The resolution of these issues is crucial to
any successful reformulation of the antidepressant drug discovery
process and any criticism of current models is secondary to this.
With regard to new model development Dr Robinson concludes that perhaps it is a necessary evil associated with developing animal models in psychiatry as a whole that we still rely
heavily on sensitivity to known therapies in order to provide
validity. Dr Stanford suggests that even a test that looked for
drugs that make mice whistle the national anthem would have
predictive validity if they all turned out to be antidepressants in
humans even though it would not be a model of depression.
We argue that the whole approach to animal modelling must be
changed and that predictive validity (e.g. Willner, 1984; Willner
and Mitchell, 2002; Markou et al., 2009) should be discarded as a
concept in this context. Defining models in this way (i.e. determining that a model of depression is a model of depression solely
on the basis of its sensitivity to the actions of existing antidepressants) is logically flawed, a tautology (of the form A=B therefore
B=A) and all the term predictive validity does is restate that tautology. This error is further compounded by predictive validity
being used to give justification for the continued use of a wide
range of animal models in the absence of any clear evidence to
demonstrate there is purpose in doing so.
The consideration of how to develop new models also brings
the disconnection between preclinical psychopharmacology and
psychiatry into sharp relief. Dr Stanford asks how would we
distinguish different combinations of negative emotions such
as low self-esteem, melancholia and suicidality, for instance?
Dr Robinson cites Cryan and Holmes (2005) to make the similar
point that symptoms such as rumination of negative thought,
suicidal ideation and mood changes can never be modelled in
animals because of their subjective nature.
Our views on these issues have already been given but, in
brief, whilst the prevalent approach in the clinic has been
nosological, with an emphasis on mood state, these methods are
not available to those seeking to develop animal models. Hence,
although there is no widespread tradition of behavioural assessment in psychiatry a full characterisation of the behavioural
expression of depression is nonetheless required. This is an
essential component of our proposals for a new approach to the
modelling of depression mentioned above and in the main body
of the paper.
Dr Robinson reiterates this point, urging better integration of
basic and clinical sciences into depression and suggests, as we
do, that there is a need to consider how we quantify depression
in patients and look to assess depressive illness in patients by
using methods which can also be taken to the bench and used in
animal studies. Dr Stanford concurs with our arguments in
favour of developing preclinical tests that are based on ethological measures and contexts that are equivalent to those of

416
depressed humans but warns that these are only of use provided
we avoid anthropomorphic assumptions, such as the behaviour
looks defensive.
Ethology asks questions to do with form, function, ontogeny
and phylogeny and one of its founding principles is the avoidance
of anthropomorphism. This is built into the methodology. The
behavioural cluster associated with depression includes sleep disturbance, a loss of appetite for food and sex, social withdrawal,
avoidance of eye contact, and a hunched posture. The behavioural
cluster hence has a form that can be described and quantified.
Function is inferred from this. The link with defence is clear
enough to have also been seen by others (e.g. Price et al., 1998),
although not the implication this carries with it that depression is
an adaptation rather than a pathology. The third ventricle hypothesis (Hendrie and Pickles, 2010) is also the first to integrate these
behaviours with the brain areas mediating them and to propose a
likely mechanism, an inflammatory (possibly cytokine) agent
released into the third ventricle.
As a final point we would like to add our voices to Clare
Stanfords remarks directed at those in charge of drug discovery
and development and to also remind them that given current
response rates of only 4050%, the market for more effective

Journal of Psychopharmacology 27(5)

antidepressant drug treatments is potentially 23 times the size
it is now. Hence, it is difficult to understand how the pressing
clinical, ethical and commercial reasons to build a reformulated
antidepressant drug discovery process can continue to be ignored
or to see how any substantive progress can be made without this
being done.

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