Tuesday, 29 September 2009

Stop prescribing antipsychotics! - when possible

Charlton BG. Why are doctors still prescribing neuroleptics? QJM 2006; 99: 417-20.

This is a version of my paper "Why are doctors still prescribing neuroleptics? - in which the word 'neuroleptic' has been replaced by the word 'antipsychotic'. Both neuroleptic and antipsychotic refer to the same class of drugs - but neuroleptic was the original and most scientifically-accurate name. Antipsychotic is a dishonest marketing term, since these drugs are not anti-psychotic. However, antipsychotic has now all-but taken over from neuroleptic in mainstream discourse - so I have prepared this version of my paper containing the more common term.

Bruce G Charlton


There are two main pharmacological methods of suppressing undesired behavior: by sedation or with antipsychotics. Traditionally, the invention of antipsychotics has been hailed as one of the major clinical breakthroughs of the twentieth century, since they calmed agitation without (necessarily) causing sedation. The specifically antipsychotic form of behavioral control is achieved by making patients psychologically Parkinsonian – which entails emotional-blunting and consequent demotivation. Furthermore, chronic antipsychotic usage creates dependence so that - in the long term, for most patients - antipsychotics are doing more harm than good. The introduction of ‘atypical’ antipsychotics (ie. antipsychotically-weak but strongly sedative antipsychotics) has made only a difference in degree, and at the cost of a wide range of potentially fatal metabolic and other side effects. It now seems distinctly possible that, for half a century, the creation of many millions of Parkinsonian patients has been misinterpreted as a ‘cure’ for schizophrenia. Such a wholesale re-interpretation of antipsychotic therapy represents an unprecedented disaster for the self-image and public reputation of both psychiatry and the whole medical profession. Nonetheless, except as a last resort, antipsychotics should swiftly be replaced by gentler and safer sedatives.

* * *

It is usually said, and I have said it myself, that the invention of antipsychotics was one of the major therapeutic breakthroughs of the twentieth century [1]. But I now believe that this opinion is due for revision, indeed reversal. Antipsychotics have achieved their powerful therapeutic effects at too great a cost, and a cost which is intrinsic to their effect [2, 3]. The cost has been many millions of formerly-psychotic patients who are socially-docile but emotionally-blunted, de-motivated, chronically antipsychotic-dependent and suffering significantly increased mortality rates. Consequently, as a matter of some urgency, antipsychotic prescriptions should be curtailed to the point that they are used only as a last resort.

Behavioral suppression in medicine

Psychiatrists, especially those working in hospitals, have frequent need for interventions to calm and control behavior – either for the safety of the patient or of society. The same applies – less frequently – for other medical personnel dealing with agitation, for example due to delirium or dementia. Broadly speaking, there are two pharmacological methods of suppressing agitated behavior: with sedatives or with antipsychotics [2, 3].
Sedation was the standard method of calming and controlling psychiatric patients for many decades prior to the discovery of antipsychotics, and sedation remained the only method in situations where antipsychotics were not available (eg in the Eastern Bloc and under-developed countries) [3, 4].

The therapeutic benefits of sedation should not be underestimated. In the first place sedation can usually be achieved safely and without sinister side effects; and an improved quality of sleep makes patients feel and function better. Sedation may also be potentially ‘curative’ where sleep disturbance has been so severe and prolonged as to lead to delirium, which (arguably) may be the case for some psychotic patients such as those with mania [2, 5].

But clearly - except in the short term - sedation is far from an ideal method of suppressing agitation. The discovery of antipsychotics offered something qualitatively new in terms of behavioral control: the possibility of powerfully calming a patient without (necessarily) making them sleepy [4]. In practice, sedative antipsychotics (such as chlorpromazine or thioridazine), or a combination of a sedative (such as lorazepam or promethazine) with a less-sedating antipsychotic such as haloperidol or droperidol, were often used to combine both forms of behavioral suppression.

The Parkinsonian core effect of antipsychotics

The Parkinsonian (emotion-blunting and de-motivating) core effect of antipsychotics has been missed by most observers. This failure relates to a blind-spot concerning the nature of Parkinsonism.

Parkinsonism is not just a motor disorder. Although abnormal movements (and an inability to move) are its most obvious feature, Parkinsonism is also a profoundly ‘psychiatric’ illness in the sense that emotional-blunting and consequent de-motivation are major subjective aspects. All this is exquisitely described in Oliver Sack’s famous book Awakenings [10], as well as being clinically apparent to the empathic observer.

Emotional-blunting is de-motivating because drive comes from the ability subjectively to experience in the here-and-now the anticipated pleasure deriving from cognitively-modeled future accomplishments [2]. An emotionally-blunted individual therefore lacks current emotional rewards for planned future activity, including future social interactions, hence ‘cannot be bothered’.

Demotivation is therefore simply the undesired other side of the coin from the desired therapeutic effect of antipsychotics. Antipsychotic ‘tranquillization’ is precisely this state of indifference [8]. The ‘therapeutic’ effect of antipsychotics derives from indifference towards negative stimuli, such as fear-inducing mental contents (such as delusions or hallucinations); while anhedonia and lack of drive are predictable consequences of exactly this same state of indifference in relation to the positive things of life.

So, Parkinsonism is not a ‘side-effect’ of antipsychotics, neither is it avoidable. Instead, Parkinsonism is the core therapeutic effect of antipsychotics: as reflected in the name, which refers to an agent which ‘seizes’ the nervous system and holds it constant (ie. indifferent, blunted) [4]. Demotivation should be regarded as inextricable from the antipsychotic form of tranquillization [2]. And the so-called ‘negative symptoms’ of schizophrenia are (in most instances) simply an inevitable consequence of antipsychotic treatment [4].

By this account, the so-called ‘atypical’ antipsychotics (risperidone, olanzapine, quetiapine etc.) are merely weaker Parkinsonism-inducing agents. The behavior-controlling effect of ‘atypicals’ derives from inducing a somewhat milder form of Parkinsonism, combined with strong sedation [11]. However, clozapine is an exception, because clozapine is not a antipsychotic, does not induce Parkinsonism, and therefore (presumably) gets its behavior- controlling therapeutic effect from sedation. The supposed benefit from clozapine of ‘treating’ the ‘negative symptoms of schizophrenia’ (such as de-motivation, lack of drive, asocial behavior etc.) is therefore that – not being a antipsychotic – clozapine does not itself cause these negative symptoms.

What next?

Whatever the historical explanation for the wholesale misinterpretation of antipsychotic actions, recent high profile papers in the New England Journal of Medicine [12, 13] and JAMA [14] have highlighted serious problems with antipsychotics as a class (whether traditional or atypical), and the tide of opinion now seems to turning against them.
In particular the so-called ‘atypical antipsychotics’ which now take up 90 percent of the US market [12], and are increasingly being prescribed to children [6] seem to offer few advantages over the traditional agents [12] while being highly toxic and associated with significantly-increased mortality from metabolic and a variety of other causes [13, 14, 15, 16]. This new data has added weight to the idea that usage of antipsychotics should now be severely restricted [3, 7, 17].

Indeed, it looks as if after some 50 years widespread prescribing there is going to be a massive re-evaluation and re-interpretation of these drugs, with a reversal of their evaluation as a great therapeutic breakthrough. It now seems distinctly possible that for half a century the creation of millions of asocial, antipsychotic-dependent but docile Parkinsonian patients has been misinterpreted as a ‘cure’ for schizophrenia. This wholesale re-interpretation represents an unprecedented disaster for the self-image and public reputation – not just of psychiatry – but of the whole medical profession.

Perhaps the main useful lesson from the emergence of the 'atypical' antipsychotics is that psychiatrists did not need to make all of their agitated and psychotic patients Parkinsonian in order to suppress their behavior. ‘Atypicals’ are weakly antipsychotic but highly sedative. This implies that sedation is probably sufficient for behavioral control in most instances [3, 17]. In the immediate term, it therefore seems plausible that already-existing, cheap, sedative drugs (such as benzodiazepines or antihistamines) offer realistic hope of being safer, equally effective and subjectively less-unpleasant substitutes for antipsychotics in many (if not all) patients.

I would argue that this should happen sooner rather than later. If we apply the test of choosing what treatment we would prefer for ourselves or our relatives with acute agitation or psychosis, knowing what we now know about antipsychotics, I think that many people (perhaps especially psychiatric professionals) would now wish to avoid antipsychotics except as a last resort. Few would be happy to wait a decade or so for the accumulations of a mass of randomized trial data (which may never emerge, since such trials would lack a commercial incentive) before making the choice of less dangerous and unpleasant drugs [17].

But there is no hiding the fact that if antipsychotics were indeed to be replaced by sedatives then this would seem like stepping-back half a century. It would entail an acknowledgement that psychiatry has been living in a chronic delusional state – and this may suggest that the same could apply to other branches of medicine. Since such a wholesale cognitive and organizational reappraisal is unlikely, perhaps the most realistic way that the desired change in practice will be accomplished is not by an explicit ‘return’ to old drugs but by the introduction of a novel (and patentable) class of sedatives which are marketed as having some kind of (more-or-less plausible) new therapeutic role.

Such a new class of tacit sedatives would enable the medical profession to continue its narrative of building-upon past progress, and retain its self-respect; albeit at the price of cognitive evasiveness. But, if such developments led to a major cut-back in antipsychotic prescriptions, then this deficiency of intellectual honesty would be a small price to pay.


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2. Charlton B. Psychiatry and the human condition. Radcliffe Medical Press: Oxford, UK, 2000.

3. Moncrieff J, Cohen D. Rethinking models of psychotropic drug action. Psychotherapy and Psychosomatics 2005; 74: 145-153.

4. Healy D. The creation of psychopharmacology. Harvard University Press: Cambridge, MA, USA, 2002.

5. Charlton BG, Kavanau JL. Delirium and psychotic symptoms: an integrative model. Medical Hypotheses. 2002; 58: 24-27.

6. Whitaker R. Mad in America. Perseus Publishing: Cambridge, MA, USA, 2002.

7. Whitaker R. The case against antipsychotic drugs: a 50 year record of doing more harm than good. Medical Hypotheses 2004; 62: 5-13.

8. Healy D. Psychiatric drugs explained. 3rd edition. Churchill Livingstone: Edinburgh, 2002.

9. Healy D, Farquhar G: Immediate effects of droperidol. Human Psychopharmacology 1998; 13: 113-120.

10. Sacks O. Awakenings. London: Picador, 1981.

11. Janssen P. From haloperidol to risperidone. In D Healy (Ed.) The psychopharmacologists. London: Altman, 1998, pp 39-70

12. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 2005; 353: 1209-23.

13. Wang, Philip S.; Schneeweiss, Sebastian; Avorn, Jerry; Fischer, Michael A.; Mogun, Helen; Solomon, Daniel H.; Brookhart, M. Alan. Risk of Death in Elderly Users of Conventional vs. Atypical Antipsychotic Medications. New England Journal of Medicine 2005; 353: 2335-2341.

14. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294: 1934-43.

15. Montout C, Casadebaig F, Lagnaoui R, Verdoux H, Phillipe A, Begaud B, Moore N. Neuroleptics and mortality in schizophrenia: a prospective analysis of deaths in a French cohort of schizophrenic patients. Schizophrenia Research 2002; 147-156.

16. Morgan MG, Scully PJ, Youssef HA, Kinsella A, Owens JM, Waddington JL. Prospective analysis of premature mortality in schizophrenia in relation to health service engagement: a 7.5 year study within an epidemiologically complete, homogenous population in rural Ireland. Psychiatry Research. 2003; 117: 127-135.

17. Charlton BG. If 'atypical' neuroleptics did not exist, it wouldn't be necessary to invent them: Perverse incentives in drug development, research, marketing and clinical practice. Medical Hypotheses 2005; 65 :1005-9