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JOP27510.1177/0269881112466185Journal of PsychopharmacologyHendrie and Pickles


The failure of the antidepressant drug
discovery process is systemic
Journal of Psychopharmacology
27(5) 407–416
© The Author(s) 2013
Reprints and permissions:
DOI: 10.1177/0269881112466185

Colin Hendrie1 and Alasdair Pickles2

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.

Animal models, antidepressant, depression, drug discovery, MDD

Depression is a widespread disorder that accounts for approximately 12% of the total burden of non-fatal global disease (Üstün
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 40–50% (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.,
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; Möller
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


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


Corresponding author:
Colin Hendrie, Institute of Psychological Sciences, University of Leeds,
Woodhouse Lane, Leeds LS2 9JT, UK.

Krishnan and Nestler. Chen et al. Monleon et al. 2011). 1999. Were the antidepressant drug discovery process to have been developed along rational lines. Whilst clinical trials are often given a higher profile (e. Willner. 2009).g. That said. however. 1997. Song and Leonard. 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. 2010. 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’.1957) and the problems inherent with this approach have become compounded at each stage. 1984. Cryan and Holmes. Dissecting the process Animal models The drug discovery process seeks to produce drugs that are both efficacious and safe (Paul et al.g. They are not and so ‘pharmacological validity’ has been used as the defining characteristic instead. 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..... Trivedi et al..g. 1997). 2004) and. Cryan and Holmes.. 1983.g..408 no longer going to vigorously pursue this goal (Miller..g. Micó et al. Woodcock and Woosley.. 2008). 2005. 2010). 2005. 1985.. 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. 2006. say. Deussing. 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. Hendrie and Pickles. 2008. 2011.1987). That is. Kudryavtseva et al. 2012) and regardless of the mechanisms underlying these effects or the end-points employed..g.. Keeney and Hogg. Verkman. forced swim (Porsolt et al. Song and Leonard. 1991. West. Cryan and Mombereau. 2004).g.. Keeney and Hogg. This basic error was built into the current antidepressant drug discovery process from its inception (e.g.g. Hence. Kudryavtseva et al. Kelly et al. 1984. 2001) this fails to take into account the pivotal role animal models play in the process leading up to this phase. 2009. 2010). 1987) and/or the well documented analgesic actions of the antidepressants themselves (e.. 2004) in any species. 2011. Piggot et al. 2006. including yeast (e. 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... Wattiez et al. Willner. There are a plethora of such models (for reviews see McArthur and Borsini. 1956. Wong and Licinio. Song and Leonard. 2005. rats and mice would have been selected because of special characteristics that make them particularly suitable for use in these models. Cryan et al. 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. 2005). 2005.g. 2011) In consequence. Siegfried et al. Lipsky and Sharp.g. Porsolt et al. 2002. 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. preclinical models provide information that helps determine whether drugs should move into Phase 1 clinical trials (Herrling. 1990). 2009) and there are indeed strong arguments against their continued use . animal models of depression should ideally be based on a common aetiology in both animals and man.g.g. Willner et al. many of the models currently in use are open to alternative explanations for effects seen in them. Further. They do not. 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... where appropriate. 2008). Krishnan and Nestler. 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. Hence the current situation.g. 1995..g.g. Willner. 2005. 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. 2005. In this context. This point also extends to those more recent genetically based models (e.. chronic social defeat (e. 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. Samuels et al. Commonly used models of depression include tail suspension (Cryan et al. use of these assays has in recent times become a matter of preference and taste rather than utility. 1985). 1977). 2006.. Steru et al. 2005. a tautology (of the form A=B therefore B=A). hypertension). 1996) and chronic social stress models where animals are exposed to attack from an aggressive conspecific (e. 1977. 2006). where first generation antidepressants put on the market before FDA regulations required efficacy to be shown (Goodrich. 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. fulfil the regulatory obligation for efficacy to be shown before they are allowed to do so (e... 2001). Chessin et al. Cryan and Holmes. 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.. Loomer et al. since they have all been developed on essentially the same definitional lines. Steru et al.. Porsolt et al. mouse killing (e.. Rodgers and Hendrie. have such characteristics (Dias et al. That is. 2008. Krishnan and Nestler. 1991) and chronic mild stress (e. 1999) could equally be measuring factors that influence the activation of the endorphin system (e. 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.

. 1982). Systems failure The ease with which ‘me-same’ compounds could be produced in the 1960s. their size. Domino. rat (Willner et al. mouse (Steru et al..g. Nestler and Hyman. Berman et al. used extensively in the field of depression research because there has been no serious consideration that things should be otherwise (e. 2009). The most frequently prescribed antidepressants are now more than 20 years old and out of patent (Ciprani et al. 2007. rat (Rygula et al. The glacial rate of progress over the past 60 years has provided improvements in tolerability but not efficacy (Hindmarch. 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. Brain.g. 2009). ’70s and to a certain extent the ’80s (e. Further. 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 50–60% 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-too’s 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. Nestler and Hyman. 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. 2011..g. Hendrie et al. 2010) and the lumping together of findings made using rats. 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. 2011. Rodgers et al. 2005) chronic unpredictable mild stress models and rat (Chermat et al. 2012). 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.g. 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 world’s leading pharmaceutical companies have to a greater or lesser degree reduced their investment in this area (Blier. within which significant levels of full-blooded aggression are seen under only the most unusual of conditions (e. Rodgers and Hendrie. These are colonial animals that live together relatively peaceably under laboratory conditions (e.. 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. 1971. Laboratory mice (Mus musculus) are by contrast strongly territorial and show high levels of intra-male aggression whenever they are group housed. Morgan and Curran. a major source of variance in all studies using this species. Duman. it seems. 2011. 2001).. 2010.. 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 .. Hendrie et al. 2005) and mouse (Keeney and Hogg. 1985) and gerbil (Varty et al. little consideration has been given to species differences between rats and mice except for perhaps. 2006. 2010).. Geddes et al. 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. 2000. 1999) social defeat models.g. 1996) and this is. Laboratory rats are derived from Rattus norvegicus. 1963. 1970. This error has become critical now the proportion of the clinical population that cannot be treated with these drugs has become clear. There are nonetheless important differences between rats and mice and their significance cannot be ignored. Castagné et al. 2012. at least. Rats and mice are. Hence there are rat (Detke et al.. El Yacoubi and Vaugeois. False assumptions underlying the current antidepressant drug discovery process. 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. Barnett. mice and/or other species as ‘rodent models’ (e. physiology and immune functioning (Berry. Hendrie and Pickles.. 1986). 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. 1987) and mouse (Yalcin et al. 1995) and mouse (Porsolt et al. Borsini... 1983).. Krishnan and Nestler. 2000) once gave this flawed antidepressant drug discovery process an aura of rationality. serendipity remained at its base. 2011. There has been what can only be described as a catastrophic systems failure and this has left little behind that can be salvaged. 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. occasionally. etc. The prevalent approach in the clinic has been nosological. 2010) ignores the potential importance of these species differences..Hendrie and Pickles 409 Table 1. the illusion could not be maintained indefinitely and the paucity of this approach has now been fully exposed..g. 2003) tail suspension tests. 1999. 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. 1977) forced swim tests. McArthur and Borsini.. However.

g. These methods are clearly not available to those that work with animals. Funding This research received no specific grant from any funding agency in the public.. Beck AT. 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. 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. . J Psychiatry Neurosci 35: 219–220. 2009) and depression (e. Grant and MacKintosh. et al. reduced competition for food/sex and sleep disruption) is defensive in nature. Troisi et al. Lastly. however. Williams and Wilkins. 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. Berman RM. van Praag et al. 2010).. 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. 2010) a full characterisation of the behavioural expression of depression in the clinic is nonetheless required. 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. Ethology must be at the heart of this new process.g. Dixon et al. 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. Cappiello A. Pickles et al. et al. Importance of the ethological approach Ethological analysis was first applied to laboratory animals in the 1960s (e.g. These questions relate to form (what does it look like?). Hence. 1999).g. 1963). 2009. 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. Ward CH. Smolinsky et al. van Praag. 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. Hence. New York: Lippincott.. 1987. ethical and commercial reasons why this process must be quickly built anew. Bielski RJ and Friedel RO (1976) Prediction of tricyclic antidepressant response: A critical review. Holmes et al. References Barnett SA (1963) The Rat: A study in Behavior. hunched posture. 1989. 2010). The catastrophic failure of the antidepressant drug discovery process has undoubtedly been a contributing factor and there are hence pressing clinical. (1961) An inventory for measuring depression. This cluster in turn serves to reduce an individual’s attack provoking stimuli and so allows them to remain within social groups that have become hostile to their presence.. 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. the pineal at the other and major pathways from the amygdala and hippocampus pass through it (Hendrie and Pickles. 2010). 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. although there is no widespread tradition of behavioural assessment in psychiatry (e.g. 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. 2012) and other species will no doubt be found once they are looked for.g. not the other way round. 1986. Mongolian gerbils (Meriones unguiculatus) are. Mendelson M. 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. 2012).g. This has been concluded because the behavioural cluster associated with depression (e. commercial. 2. Pickles et al. 2009). AstraZeneca. The third ventricle is implicated because the hypothalamus lies at one end. 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. 1993. In: Sadock BJ and Sadock VA (eds) Comprehensive Textbook of Psychiatry. 1998. 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UK Corresponding author: S Clare . University College London. 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. Wong ML and Licinio J (2004) From monoamines to genomic targets: A paradigm shift for drug discovery in depression. In other words. Similarly. 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. London. 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. World Health Organization (2002) The World Health Report 2002: Reducing Risks. for instance? Until these difficulties are resolved. Yalcin I. were important steps in the right direction. (1987) Reduction of sucrose preference by chronic unpredictable mild stress. 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. London WC1E 6BT. Switzerland: World Health Organization. Willner P (1997) Validity. and its restoration by a tricyclic antidepressant. Psychopharmacology 93: 358–364. such as ‘the behaviour looks defensive’. that the few attempts to break into new pharmacological territory have burnt industrial fingers. there is a great deal of concern about the failure of promising candidates at the translation stage (false positives). to say the Learned helplessness is a case in point. Gower Street. Ann Rev Med 59: 1–12. 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.e.Hendrie and Pickles Willner P (1984) The validity of animal models of depression. anything that will augment monoamine transmission) is a contributing factor. Woodcock J and Woosley R (2008) The FDA Critical Path Initiative and its influence on new drug development. Aksu F and Belzung C (2005) Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol. that determines predictive validity for antidepression. They argue that behavioural models that are used to develop antidepressants have constrained. We will never know whether these tests have filtered out any compounds that would have worked well had they reached the clinic (false negatives). or whether it is a learned motor response. homogenous disorder with a single sign that is amenable to measurement. not the individual tests. Email: c. It is also true that there has been little progress in helping non-responsive patients. especially in 413 overdose. Physiology and Pharmacology. Hendrie and Pickles believe that preclinical tests are culpable because they comprise a self-validating loop that merely produces families of similar compounds. reversing social defeat in rodents/low self esteem in humans. Nat Rev Drug Discov 3: 136–151. reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation. et al. the strong. Department of Neuroscience. if ever. it is likely to be the combination and scope of screens in the battery of tests. However. However. by antidepressants and so are arguably more valid as ‘models’ of depression. How would we distinguish different combinations of negative emotions such as low self-esteem. but it would not be a model of depression. progress. To resolve such problems. which makes a big difference when interpreting the effects of psychotropic drugs on this behaviour. melancholia and suicidality. This might be because they reveal a druginduced increase in motor motivation. clinicians must agree that the greater tolerability and safety of younger compounds. They would also need to deal with the complication that depression is not a stable. cautious focus on drug candidates that were most likely to succeed (i. The approach they suggest could be invaluable in complementing existing drug screens provided we avoid anthropomorphic assumptions. reduced sucrose preference in rodents/anhedonia in humans. 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. or reversed. These are expensive mistakes and it is unfortunate. complex changes in behaviour that are prevented. Psychopharmacology 134: 319–329. Psychopharmacology 83: 1–16. Willner P. They are optimistic that the study of more naturalistic behaviour would help to drag us out of the doldrums. which is completely different. However. Geneva. It is true that imipramine has proved unbeatable on measures of efficacy. rather than enabled. Eur J Pharmacol 514: 165–174. Even so. Promoting Healthy Life. Physiology and Pharmacology. 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. Sampson D. University College London. Some procedures do cause long-lasting. Other screens will pull out different elements of antidepression: for example. UK. it is ethical or relevant to replicate them in other animals. which would be helpful in some depressed patients. which must require a broad spectrum of actions. This could not have been achieved without the behavioural tests that many people now assert have let us down so badly.stanford@ucl. We are even beginning to question whether preclinical models are equivalent to the Emperor’s sartorial hoax. it is not at all clear whether this behavioural deficit emulates depression or posttraumatic stress disorder. Towell A. I predict that it will be hard to convince sceptics that the validity of ethological tests is any better Department of Neuroscience.

new approaches are desperately needed. the development of new antidepressants will only further stagnate.S. if not improvements in efficacy. to develop models which can better represent the behavioural expressions of depression in the clinic. although making the case that these have validity remains a major challenge. Several studies have looked at social manipulations. 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. Bristol. Their suggestion is to move outside our traditional rodent models of mice and rats and look to alternative species. It is impossible to disagree with that. 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. Given our increasing knowledge about genetic predisposition. University of Bristol. Bristol BS8 1TD. and ethological approaches. 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. To ensure that a therapeutic breakthrough does not slip through the net. UK. 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. UK Corresponding author: Emma Robinson. For examples. such as maternal separation. it is not surprising that confidence in current animal models has declined. Meanwhile. including the gerbil model described here. but the FST and TST were a crucial part of the development of antidepressants with much improved side effect profiles. as originally reported. Physiology and Pharmacology. School of Medical Sciences. the NK1antagonist aprepitant failed in clinical studies despite exhibiting a positive effect in animal models. but also the tree shrew and rat models. In general. Email: Emma. what other approach do we have? The authors raise an interesting point when they suggest that rat and mouse are not the best species. Could University of Bristol. 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. Hendrie and Pickles warn that we should be refining and strengthening the preclinical research base rather than dismantling it. Hendrie and Pickles highlight the limitations of these models in terms of only identifying drugs with similar mechanisms of and animals with a more comparable social structure may make a more appropriate alternative. 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. The process will be difficult and expensive but the potential benefits to quality of life. described a method to test Journal of Psychopharmacology 27(5) for antidepressant efficacy based on evidence of predictive validity.414 than that of existing procedures or that they will improve successful translation.Robinson@bristol. Given these costly failures. it is perhaps not the tests which are the major failure but the way in which they are used and the results subsequently interpreted. non-monoaminergic targets. 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. environmental factors which precipitate depressive episodes and cognitive neuropsychological features of . There have undoubtedly been costly examples where animal models have failed to accurately predict antidepressant and pro-depressant effects in man. without urgent re-evaluation of how we model depression in animals. Perhaps an interesting way of looking at depression and modelling this highly complex disease is to look first to the human. 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. we need new drug targets as well as reliable preclinical tests. as well as the lack of specificity of these tests to anti-depressant and pro-depressant manipulations. 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.J. Physiology and Pharmacology. 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. They also make a compelling case that. School of Medical Sciences. Without good biomarkers or clear evidence for a biological substrate underlying the disease. The FST.

Proc Biol Sci 277: 2895-2904. melancholia and suicidality. depending on the measure. References Cryan JF and Holmes A (2005) The ascent of mouse: Advances in modelling human depression and anxiety. 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. 1984.’ 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. To some extent. 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. Animal models are central to the antidepressant drug discovery process and hence included in any criticism of that process. whilst the prevalent approach in the clinic has been nosological. Prog Neuropsychopharmacol Biol Psychiatry 35: 1586-1592. then different species may well be found to offer advantages over others. with an emphasis on mood state. 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’. urging ‘better integration of basic and clinical sciences into depression’ and suggests. Both commentators give close attention to our criticism of the existing animal models. 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 . The consideration of how to develop new models also brings the disconnection between preclinical psychopharmacology and psychiatry into sharp relief. Nat Rev Drug Discov 4: 775-790. Dr Stanford asks how ‘would we distinguish different combinations of negative emotions such as low self-esteem. in brief.e.. 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. a tautology (of the form A=B therefore B=A) and all the term ‘predictive validity’ does is restate that tautology. 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.g.Hendrie and Pickles a human model of depression meet our animal model criteria? If we look at the DSM-IV criteria for diagnosis. Defining models in this way (i. 2011). for instance?’ Dr Robinson cites Cryan and Holmes (2005) to make the similar point that ‘symptoms such as rumination of negative thought. Dr Stanford says. as we do. Willner. Markou et al. et al. 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. it is clear that this is a heterogeneous disease where only a number of symptoms need to be present to meet the diagnosis. suicidal ideation and mood changes can never be modelled in animals because of their subjective nature. 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. ‘This is not the first 415 time that behavioural tests in rodents have been blamed for translational failures. although there is no widespread tradition of behavioural assessment in psychiatry a full characterisation of the behavioural expression of depression is nonetheless required. 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. We argue that the whole approach to animal modelling must be changed and that ‘predictive’ validity (e. If we as animal researchers look to the neuropsychological literature. The physiological and hormonal effects of social separation. Drs Stanford and Robinson offer thoughtful and considered responses to these contentions and for that we thank them. They also make the point that symptoms such as rumination of negative thought. 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. Browning M. Maybe the key to moving forward with non-clinical depression research is a better integration of basic and clinical sciences into depression. 2002. Concluding reply We present the argument that the current antidepressant drug discovery process is fatally flawed and hence not fit for purpose. 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. Hence. Cowen PJ.. 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.’ Our views on these issues have already been given but. (2011) A cognitive neuropsychological model of antidepressant drug action. these methods are not available to those seeking to develop animal models.. 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. Dr Robinson reiterates this point. Pringle A. Willner and Mitchell. Whilst we inevitably blame the rodent models and animal methodology. 2009) should be discarded as a concept in this context. suicidal ideation and mood changes can never be modelled in animals because of their subjective nature. 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. 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. 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’. Mendl M. 2010). Burman OH and Paul ES (2010) An integrative and functional framework for the study of animal emotion and mood. However. 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.

and a hunched posture. ontogeny and phylogeny and one of its founding principles is the avoidance of anthropomorphism. Gardner R. Sloman L. The link with defence is clear enough to have also been seen by others (e. Willner P (1984) The validity of animal models of depression. Nat Rev Drug Discov 4: 785–790 Hendrie CA and Pickles AR (2010) Depression as an evolutionary adaptation: Anatomical organisation around the third ventricle. Willner P and Mitchell PJ (2002) The validity of animal models of predisposition to depression. Hence. As a final point we would like to add our voices to Clare Stanford’s remarks directed at ‘those in charge of drug discovery and development’ and to also remind them that given current response rates of only 40–50%. Behav Pharmacol 13: 169–188. This is built into the methodology. Function is inferred from this. avoidance of eye contact. . (1998) The social competition hypothesis of depression. Markou A. 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. 2010) is also the first to integrate these behaviours with the brain areas mediating them and to propose a likely mechanism. Med Hypotheses 74: 735–740. (2009) Removing obstacles in neuroscience drug discovery: The future path for animal models.g. function. et al. the market for more effective Journal of Psychopharmacology 27(5) antidepressant drug treatments is potentially 2–3 times the size it is now. The behavioural cluster associated with depression includes sleep disturbance. References Cryan JF and Holmes A (2005) The ascent of mouse: Advances in modelling human depression and anxiety. Br J Psychiatry 164: 309–315. although not the implication this carries with it that depression is an adaptation rather than a pathology. an inflammatory (possibly cytokine) agent released into the third ventricle. Price et al.416 depressed humans’ but warns that these are only of use ‘provided we avoid anthropomorphic assumptions. Geyer MA. a loss of appetite for food and sex. et al. social withdrawal. such as “the behaviour looks defensive”’. Psychopharmacology 83: 1–16. Neuropsychopharmacology 34: 74–89. Price J. Chimmulera C. The behavioural cluster hence has a form that can be described and quantified. Ethology asks questions to do with form. it is difficult to understand how the pressing clinical.. 1998). The third ventricle hypothesis (Hendrie and Pickles.