Documentos de Académico
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2013
Commentary
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).
1Institute
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.
Logical flaw
Attempting to identify new compounds as potential antidepressants by testing them in animal models of depression that have
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
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
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
3.
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.
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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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.
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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
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