Florida International University FIU Digital Commons All Faculty 5-29-2009 How do psychiatric drugs work? Joanna Moncrieff David Cohen School of Social Work, Florida International University, [email protected] Follow this and additional works at: https://digitalcommons.fiu.edu/all_faculty Recommended Citation BMJ 2009;338:b1963 This work is brought to you for free and open access by FIU Digital Commons. It has been accepted for inclusion in All Faculty by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. 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, extrapyramidal 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. outcome.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 chlorpromazine, but the names of the major drug classes: antide- commentators have comparisons with pressants are believed to reverse biochemi- suggested that the VEM/SPL BSIP 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. Psychoactive effects, including 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 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 generation antipsychotics, how they differ 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 produced by older antipsy- on an underlying disease altered state ing dopamine dysregulation.13 However, little chotics. Obviously, this information is crucial process 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