1. The authors argue that viewing psychiatric drugs through a "drug-centered model" rather than a "disease-centered model" may better fit the evidence and empower patients. 2. Under the disease-centered model, drugs are thought to correct underlying biological abnormalities causing symptoms. But evidence for this is limited. The drug-centered model views drugs as producing altered psychoactive states that may suppress symptoms. 3. More research is needed on the full range of subjective effects of psychiatric drugs to inform patients' treatment decisions. The drug-centered model encourages periodic rather than continuous use of drugs and shared decision making.

1. ANALYSIS
How do psychiatric drugs work?
Joanna Moncrieff and David Cohen argue that changing our view of the action of psychiatric
drugs would help patients to become more involved with decisions about treatment
Drugs for psychiatric problems are pre­ a neurological syndrome consisting of physi­ and altered sense perception, could have an
scribed on the assumption that they mostly cal restriction and mental symptoms such effect on the symptoms of distress in countless
act against neurochemical substrates of dis­ as cognitive slowing, apathy, and emotional disorders and be distinguished from effects
orders or symptoms. In this article we ques­ flattening, which resembled Parkinson’s dis­ associated with inert placebo.6 Any drug with
tion that assumption, proposing that drugs’ ease.2 These effects also reduced the intensity sedative properties, for example, will modify
action be viewed rather as producing altered, of psychotic symptoms. Thus, ­ xtrapyramidal
e disturbances of sleep and arousal found in
drug induced states, a view we have called effects, and their con­ many psychiatric
the drug centred model of action. We believe joined mental effects, conditions and in
that this view accords better with the avail­ were not regarded the disorder specific
able evidence. It may also allow patients to as side effects but as rating scales used in
exercise more control over decisions about the mechanism by clinical trials.
the value of pharmacotherapy, helping to which the drugs pro­ A second dif­
move mental health treatment in a more duced their intended ficulty has been a
collaborative direction. o
­ utcome.3 paucity of realistic
Inducing overt trials that use active
Assumptions about mode of action parkinsonism has placebos or compare
The widespread use of psychiatric drugs is jus­ long been thought drugs believed to be
tified by the idea that they work by correcting, unnecessary to pro­ disorder specific
or helping to correct, underlying biological duce a therapeutic (according to current
abnormalities that produce particular psy­ effect, yet there has diagnostic classifica­
chiatric symptoms. We have called this view been little consider­ tions or theories) with
the disease centred model of psychiatric drug ation of the mental other drugs known to
action (table). Most drugs used in medicine alterations produced exert some psycho­
can be understood as working according to by neuroleptic drugs active effects. Early
a disease centred model—even analgesics, for and just how these trials comparing
example, work by acting on the physiological might interact with chlorpromazine and
mechanisms that produce pain. In psychia­ psychotic symp­ barbiturates favoured
try, the disease centred model is reflected in toms. Some modern BSIP VEM/SPL
chlorpromazine, but
the names of the major drug classes: antide­ commentators have comparisons with
pressants are believed to reverse biochemi­ suggested that the benzodiazepines give
cal pathways that give rise to symptoms of emotional indifference induced by neurolep­ mixed results,7 and a trial using opium as a
depression and antipsychotics are thought to tics accounts for their therapeutic effects,4 and comparator found no difference.8 However,
act on mechanisms that produce psychotic empirical research supports this position.5 although evidence of the superiority of anti­
symptoms. From this viewpoint, the therapeu­ Overall, the drug centred model suggests psychotics might imply disease specific effects,
tic actions of drugs (their actions on disease looking more closely at how psychological superior effects can also be explained within a
processes) can be distinguished from other alterations produced by psychiatric drugs drug centred framework. This view suggests
effects, accordingly termed side effects. interact with the experiences of distress and that the characteristic psychomotor and emo­
An alternative, drug centred model of drug psychosocial disability that lead people to seek tional restriction induced by antipsychotics is
action, stresses that psychiatric drugs are, clinical help.6 more effective at suppressing psychotic agita­
first and foremost, psychoactive drugs. They tion than other sedatives, as proposed by the
induce complex, varied, often unpredictable Evidence on psychiatric drug action early investigators.2
physical and mental states that patients typi­ Both models help clarify possible mecha­ Drugs not normally considered to be anti­
cally experience as global, rather than distinct nisms of drug action and need not be mutu­ depressants, including antipsychotics, benzo­
therapeutic effects and side effects (table). ally exclusive. However, the neglect of the diazepines, and stimulants, have been found
Drugs may be useful because some altered psychoactive effects of psychiatric drugs has to have comparable effects to antidepressants
states can suppress the manifestations of cer­ made it difficult to establish disease specific in people with depression.9 Comparisons
tain mental disorders. actions. For example, placebo controlled tri­ of lithium with antipsychotics and benzodi­
The disease centred model of drug action als are not designed to distinguish whether azepines have not confirmed its superiority to
developed in the 1950s and 1960s and replaced observed outcomes occur because of the treat mania or affective psychosis.10 Although
a drug centred understanding of how psychi­ drug’s action on an underlying pathological one study suggested some differential effect on
atric drugs worked.1 For example, the early process or as a consequence of being in an particular symptoms,11 others have not.12
investigators of neuroleptic or antipsychotic altered state. ­ sychoactive effects, including
P Biochemical aetiological theories such as
drugs suggested that they worked by inducing sedation, psychomotor slowing, activation, the dopamine theory of schizophrenia or
BMJ | 27 June 2009 | Volume 338 1535

2. ANALYSIS
psychosis and the monoamine hypothesis of ness, but this has not been confirmed.18 How Models of psychiatric drug action
depression seem to support a disease centred they cause suicidal ideation, if they do, is also Disease centred model Drug centred model
view of drug action, although their strongest not established. Similarly, few data exist about
Drugs correct an abnormal Drugs create an altered
support remains the presumed specificity of the subjective effects produced by second brain state physical and mental state
drug treatment. Proponents of the dopamine g
­ eneration ­ ntipsychotics, how they differ
a Therapeutic effects arise Therapeutic effects are a
hypothesis argue that antipsychotics exert their from each other, and whether they are simi­ from the action of drugs consequence of being in an
therapeutic action by correcting an underly­ lar to the effects ­ roduced by older antipsy­
p on an underlying disease altered state
process
ing dopamine dysregulation.13 However, little chotics. Obviously, this information is crucial
evidence suggests that any abnormality of the if people are to make informed choices about Main indication is the Indication is the value of
presence of a particular particular drug induced
dopamine system is specific to psychosis and whether these drugs are likely to improve disease effects
not accounted for by other factors associated their mental state and what price might be
with dopamine activity, such as increased paid in return.
arousal or stress. That some effective antipsy­ More comprehensive volunteer studies are psychoactive substances allows people
chotic drugs such as clozapine have relatively are needed to obtain data on the full range to judge for themselves what sort of drug
weak actions on dopamine receptors also of effects of psychiatric drugs. It is also impor­ induced effects might help them and what
seems to contradict the theory.14 tant to pay attention to patients’ uncensored sort might not. Patients become the ultimate
Evidence for the monoamine hypothesis, accounts of taking psychiatric drugs, avail­ arbiters of the value of taking a particular
which states that antidepressants work by able on the internet, for example. Clinical drug and are encouraged to take an active
countering a deficiency of noradrenaline or trials need to devise ways to explore patients’ role in adjusting drug regimens to suit their
serotonin activity, is also questionable. Many experiences more directly than through clini­ needs.
different investigations of the drugs’ metabo­ cians’ diagnoses and symptom rating scales. In the short term, for example, the cog­
lites and receptors in depressed people and Patients’ views also need to be collected after nitive and emotional suppression described
postmortem examinations have produced no the drugs have been stopped, since many by people who have taken antipsychotic
reliable demonstration of such a deficiency.15 effects may be difficult to identify while in a drugs may bring relief to someone trauma­
Generally, there have been few attempts to drug induced state. tised by intense psychotic experiences and
evaluate the dominant, disease centred expla­ allow ­ eople to engage better with the world
p
nation for drug action in psychiatry because Implications for clinical practice around them.20 However, after recovery from
few people realise that an alternative explana­ Messages conveyed in information leaflets an acute episode, some people may decide
tion exists.1 The little available evidence does and advertising campaigns have persuaded that the costs of continued drug treatment
not yet provide compelling grounds to accept millions of people that mental disorders are are not outweighed by the reduction in the
the disease centred model. caused by chemical imbalances that can be risk of relapse that long term treatment may
rectified by drugs.19 However, given the produce. According to a drug centred model,
Drug centred model in research paucity of the evidence, we suggest that pre­ therefore, non- compliance may be a rational
There has been little systematic exploration scribers should not present the drugs they response to the effects of drugs, which pre­
of the full range of psychoactive and physical prescribe for mental disorders as disease spe­ scribers need to understand and accommo­
effects produced by psychiatric drugs. This cific treatments. Psychiatric drugs might need date rather than overcome.
information is typically obscured by short renaming, to avoid the presumption of spe­ People with depression are likely to
clinical trials that focus on narrow complaints cificity built into labels like antidepressants respond differently to an offer of a drug
and outcomes and relegate and antipsychotics. intended to produce an altered state than a
other effects to the status of There has been little systematic The drug centred drug said to act on the underlying biological
side effects.16 There is also exploration of the full range of model may change mechanism of depressive symptoms. Various
a paucity of research on psychoactive and physical effects attitudes to psychiatric p
­ sychoactive drugs, such as antipsychotics
the often unpredictable, produced by psychiatric drugs drugs and empower and possibly SSRIs, may suppress the expe­
long term effects of drugs, patients to be more rience or expression of emotions, including
the consequences of drug withdrawal, and the involved in decisions about treatment. feelings of depression, but it seems unlikely
nature of the large black box presently called Whereas a disease centred model has a built- that many people would desire this kind of
the placebo effect. in assumption that drug treatment is likely to effect. On the other hand, some people with
For example, the nature of the subjec­ be physiologically corrective and therefore depression may find drugs with sedative
tive state induced by taking selective serot­ beneficial, a drug centred model, by stress­ effects, such as benzodiazepines and low dose
onin reuptake inhibitors (SSRIs), and how ing that drugs are extrinsic substances that tricyclic antidepressants, useful temporarily
it interacts with expectancy effects, remains alter how the body works, demands that to bring relief from troubled sleep, anxiety,
unclear. Volunteer studies ­ uggest these drugs
s the advantages and disadvantages of tak­ and agitation.
may have concurrent sedative and activat­ ing a drug be carefully weighed up and dis­ In this way, the drug centred model
ing or stimulant effects,17 and some research tinguished from the effects of treatment in p
­ rovides a rationale for periodic rather­
i
­ndicates they reduce emotional responsive­ general. Highlighting that psychiatric drugs than continuous drug use, to cope with
1536 BMJ | 27 June 2009 | Volume 338

3. ANALYSIS
e
­ xacerbations of symptoms or to palliate Joanna Moncrieff senior lecturer, Department of Psychiatry 8 Abse DW, Dahlstrom WG, Tolley AG. Evaluation of
and Behavioural Sciences, University College London, tranquilizing drugs in the management of acute mental
stressful environmental events and avoid the London W1N 8AA disturbance. Am J Psychiatry 1960;116:973-80.
harm associated with long term use. It ques­ David Cohen professor , School of Social Work, Florida 9 Moncrieff J, Kirsch I. Efficacy of antidepressants in adults.
tions the use of complex drug cocktails, com­ International University, Miami FL 33199, USA BMJ 2005 16;331:155-7.
monly prescribed in the United States, for Correspondence to: J Moncrieff j.moncrieff@ucl.ac.uk 10 Moncrieff J. Lithium: evidence reconsidered. Br J
Accepted: 3 February 2009 Psychiatry 1997;171:113-9.
example, based on the presumed fit between 11 Johnstone EC, Crow TJ, Frith CD, Owens DG. The Northwick
Contributors and sources: JM and DC have both published
different drugs and multiple diagnoses given extensive critical analyses of the research literature on
Park “functional” psychosis study: diagnosis and
treatment response. Lancet 1988 16;ii:119-25.
to a patient. It also allows doctors, patients, psychiatric drugs. This paper arises from discussions with 12 Prien RF, Caffey EM Jr, Klett CJ. Comparison of lithium
and people who know patients to properly several patient groups about how a new drug centred carbonate and chlorpromazine in the treatment of
understanding could benefit patients and foster more mania. Report of the Veterans Administration and
monitor the full consequences of drug treat­ collaborative relations with health professionals. JM had the National Institute of Mental Health Collaborative Study
ment and engage in an ongoing dialogue original idea for the paper and drafted the initial manuscript. Group. Arch Gen Psychiatry 1972;26:146-53.
about how it compares with alternative DC and JM worked on subsequent revisions. JM will act as 13 Kapur S. Psychosis as a state of aberrant salience:
i
­nterventions. guarantor. a framework linking biology, phenomenology, and
Competing interests: JM is co-chairperson of the Critical pharmacology in schizophrenia. Am J Psychiatry
Medicine, as a whole, has started to rec­ Psychiatry Network and a member of the International 2003;160:13-23.
ognise the importance of involving patients Centre for the Study of Psychology and Psychiatry. DC 14 Moncrieff J. A critique of the dopamine hypothesis of
schizophrenia and psychosis. Harv Rev Psychiatry (in
in decisions about their care. By highlighting is funded by the National Institute of Mental Health, the
press).
the nature of psychiatric drugs as psychoac­ State Attorney’s general consumer and prescriber grant
15 Belmaker RH, Agam G. Major depressive disorder. N Engl
programme for the CriticalThinkRx project and is a board J Med 2008;358:55-68.
tive substances that produce altered states, member of the Alliance for Human Research Protection. 16 Cohen D, Jacobs D. Randomized controlled trials of
the drug centred model may enable patients Provenance and peer review: Not commissioned; antidepressants: clinically and scientifically irrelevant.
to participate more equally in the process externally peer reviewed. Debates Neurosci 2007;1:44-54.
1 Moncrieff J. The myth of the chemical cure: a critique 17 Dumont GJ, de Visser SJ, Cohen AF, van Gerven JM.
of evaluating the likely effect of drug treat­ of psychiatric drug treatment. Basingstoke: Palgrave Biomarkers for the effects of selective serotonin reuptake
ment in their particular situation. A drug Macmillan, 2008. inhibitors (SSRIs) in healthy subjects. Br J Clin Pharmacol
centred model also imposes a duty on the 2 Deniker P. Experimental neurological syndromes and 2005;59:495-510.
the new drug therapies in psychiatry. Compr Psychiatry 18 Opbroek A, Delgado PL, Laukes C, McGahuey C, Katsanis
psychiatric research community to produce 1960;1:92-102. J, Moreno FA, et al. Emotional blunting associated with
relevant, unbiased information about the 3 Cohen D. A critique of the use of neuroleptic drugs in SSRI-induced sexual dysfunction. Do SSRIs inhibit
psychiatry. In: Fisher S, Greenberg RP, eds. From placebo emotional responses? Int J Neuropsychopharmacol
range of effects that psychiatric drugs exert to panacea. New York: John Wiley, 1997:173-228. 2002;5:147-51.
on thought, emotion, and all bodily systems, 4 Healy D. Neuroleptics and psychic indifference: a review. J 19 American Psychiatric Association. Mental illness
R Soc Med 1989;82:615-9.
both during short term and long term use. At 5 Mizrahi R, Bagby RM, Zipursky RB, Kapur S. How
stigmas are receding, but misconceptions remain. Press
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Newsroom/NewsReleases/2005NewsReleases/05-
model keeps the full range of effects of many Neuropsychopharmacol Biol Psychiatry 2005;29:859-64.
24apanewsreleaseonpoll-%20final.aspx.
6 Jacobs D, Cohen D. What is really known about the
drugs obscured, and hence neither doctors psychological alterations produced by psychiatric drugs?
20 Moncrieff J, Cohen D, Mason JP. The subjective
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nor patients can make properly informed Int J Risk Safety Med 1999;12:37-47.
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using them. J Psychiatry 1991;148:714-26. Cite this as: BMJ 2009;338:b1963
answers to endgames, p 1571. For long answers use advanced search at bmj.com and enter question details
Picture Quiz
Statistical question
A woman with tuberous sclerosis and acute onset
Number needed to treat
a
right sided abdominal pain
1 Bilateral renal angiomyolipoma is the most likely cause of the masses seen in
the figures. The computed tomography scans show that the renal parenchyma is
Case report abnormal, with enhancing vessels and low attenuation fat representing vascular
and fatty components, respectively, within the angiomyolipoma.
A case of secondary amenorrhoea
2 The patient’s symptoms are caused by acute haemorrhage. Her physical condition
1 This patient has Asherman’s syndrome, a condition
and the imaging findings can be explained by haemorrhage from the vascular
characterised by scarring of the uterine cavity.
component of the angiomyolipoma.
2 Hysteroscopy is recommended in a patient with
3 Selective renal arterial embolisation is the treatment of choice. Embolisation not
these symptoms.
only stops further bleeding but is less invasive than surgery and spares functioning
3 Hysteroscopically directed division of adhesions is renal tissue. After our patient was scanned, she immediately went to angiography
the optimum treatment.
for embolisation.
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