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Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?

  • Robin M. Murray (a1), Diego Quattrone (a1), Sridhar Natesan (a1), Jim van Os (a2), Merete Nordentoft (a3), Oliver Howes (a4), Marta Di Forti (a5) and David Taylor (a5)...

Patients who recover from an acute episode of psychosis are frequently prescribed prophylactic antipsychotics for many years, especially if they are diagnosed as having schizophrenia. However, there is a dearth of evidence concerning the long-term effectiveness of this practice, and growing concern over the cumulative effects of antipsychotics on physical health and brain structure. Although controversy remains concerning some of the data, the wise psychiatrist should regularly review the benefit to each patient of continuing prophylactic antipsychotics against the risk of side-effects and loss of effectiveness through the development of supersensitivity of the dopamine D2 receptor. Psychiatrists should work with their patients to slowly reduce the antipsychotic to the lowest dose that prevents the return of distressing symptoms. Up to 40% of those whose psychosis remits after a first episode should be able to achieve a good outcome in the long term either with no antipsychotic medication or with a very low dose.

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Corresponding author
Robin M. Murray, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK. Email:
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Declaration of interest

R.M.M. and J.v.O. have received honoraria from Bristol-Myers Squibb, Janssen, Lilly, Roche, Servier and Lundbeck for lectures, and M.D.F. has received honoraria from Janssen and Lundbeck. O.H. has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Astra-Zeneca, Autifony, Bristol-Myers Squibb, Eli Lilly, Heptares, Janssen, Lundbeck, Leyden Delta, Otsuka, Servier, Sunovion, Rand and Roche.

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Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?

  • Robin M. Murray (a1), Diego Quattrone (a1), Sridhar Natesan (a1), Jim van Os (a2), Merete Nordentoft (a3), Oliver Howes (a4), Marta Di Forti (a5) and David Taylor (a5)...
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Should psychiatrists prescribe ' long term antipsychotics ' for relapse prevention of schizophrenia ?

K.A.L.A. Kuruppuarachchi, Senior Professor of Psychiatry, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
24 January 2017

The editorial on Should psychiatrists be more cautious about the long- term prophylactic use of antipsychotics? (Murray RM et al. 2016) has been read with much interest as it is thought provoking and has a global relevance.

As correctly highlighted in the article the common practice is to continue the antipsychotics for a considerable period of time after the remission. This is a universal perception and many clinicians adhere to this practice all over the world at present.

The views of schizophrenia have been changed over the last few decades after focusing on organic factors in the aetiology. On the other hand in the first episode of psychosis, even though there is some evidence to suggest that the duration of untreated psychosis may contribute to neurotoxicity it is still not very clear those structural changes are permanent or reversed by antipsychotics(Anderson 2014).

The other important aspect note worthy is many other psycho-social factors influence the prognosis of schizophrenia. The people who continue to take antipsychotics may be more motivated , having other good prognostic factors such as good psycho- social support etc. These compounding variables may add to the course of the illness. On the other hand patients with other poor prognostic factors may not adhere to long term medication. In such situations we may erroneously believe/interpret that the poor outcome is a result of non compliance of antipsychotic medication.

A recent study done in China demonstrated that the outcomes of the never treated patients with schizophrenia were poor compared to the treated group( Ran et al. 2015). It has also been mentioned that the outcome may be better with long term antipsychotics. Also incorporating psychosocial interventions such as family psychoeducation, social skill training, cognitive behavior therapy in addition to pharmacotherapy is beneficial in preventing relapses and recovery process (Schooler NR 2006).

It has also been shown that the new generation antipsychotics help to prevent relapses in schizophrenia (Leucht et al. 2003).

As medical teachers we continue to teach postgraduates as well as undergraduates that patients with schizophrenia particularly relapses need long term medication in addition to psychosocial interventions. Hence the general perception among them is also that those patients need long term antipsychotics to prevent relapses and enhance recovery process.

It is interesting to note that the necessity to maintain the patients on minimal effective dose after careful assessment which was highlighted in the article. However the general assumption/practice is to continue with the same antipsychotic dose after full recovery unless there are other adverse consequences. As clinicians we have an inherent fear of reduction of antipsychotic dosage believing that the patient may end up with having a relapse. On the other hand many believe that the therapeutic response is poor with relapses. An earlier review has shown that the stable patients with schizophrenia who developed relapses when the neuroleptics were withdrawn may come across difficulties in returning to the previous level of functioning (Wyatt 1991). We still tend to prescribe high doses as well as seek polypharmacy when the response is poor even though there is poor scientific evidence. Particularly in developing countries clinicians appear to rely on medication more often, may be due to scarcity of resources and time constraints. On the other hand there is a possibility of delaying clozapine therapy due to problems with monitoring etc as well as reservations among clinicians. It appears that there is a reluctance of initiating clozapine across the globe (Cetin 2014).

Obviously socio-cultural factors as well as genetic factors will interfere with the long term outcome. Therapeutic response , drug metabolism etc. are influenced by the genetic variability.

We need to do more cross-culturally appropriate research work in order to unravel the mysteries of this fascinating area.


Murray RM, et al. Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics? British Journal of Psychiatry 2016; 209: 361-365.

Anderson KK, Voineskos A, Mulsant BH, George TP, McKenzie KJ. The role of untreated psychosis in neurodegeneration: A review of hypothesized mechanisms of neurotoxicity in first-episode psychosis. Can J Psychiatry 2014; 59(10): 513-517.

Ran MS, et al. Different outcomes of never-treated and treated patients with schizophrenia: 14 -year follow- up study in rural China. British Journal of Psychiatry 2015; 207: 495-500.

Schooler NR, Relapse prevention and recovery in the treatment of schizophrenia. J Clin Psychiatry

2006 ; 67 suppl 5: 19-23.

Leucht S, Barnes TRE, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new-generation antipsychotics: A systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 2003; 160: 1209- 1222.

Wyatt RJ, Neuroleptics and the natural course of schizophrenia. Schizophrenia Bulletin 1991; 17(2): 325-351.

Cetin M, Clozaphobia: Fear of prescribers of clozapine for treatment of schizophrenia. Bulletin of Clinical Psychopharmacology 2014; 24: 295-301.

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Conflict of interest: None Declared

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Murray and colleagues could be offering a therapeutic dead-end.

Stanley V. Catts, Professor (honorary) in Psychiatry, School of Medicine, University of Queensland
Brian I. O'Toole, Senior Clinical Lecturer, Brain & Mind Centre University of Sydney
18 January 2017

Murray and colleagues’ confident advice (1) conveyed to psychiatrists, encouraging them to leave fewer patients with schizophrenia on long-term medication, is based on one of several possible interpretations of a selected literature, and little clinical evidence. We consider that at times Murray and colleagues misrepresented the literature in their descriptions of what some papers report: sometimes these descriptions are misleading (e.g., their references 17, 30, and 31) or incorrect (their reference 8). If the evidence so strongly supports the authors’ recommendations, why have they relied so heavily on single case reports and personal communication and on qualifying words such as “doubts”; “possibilities”; “suggest”; “appear”; “raise the possibilities”; “several Japanese groups have suggested” and given prominence to a study (their reference 38) that they admit has a “major confounder” and another study (their reference 42) that Murray and colleagues describe as “a study less open to bias”, which others consider grossly flawed (reviewed in [2]). And why do they consistently use the phrase “low or no dose”, without ever describing the conditions that discriminate these indications? Murray and colleagues assert that continuous antipsychotic medication loses its effectiveness over time but do not present any clinical evidence for this, and that this putative treatment resistance is due to antipsychotic-induced dopamine receptor supersensitivity that has been found in animal studies. Indeed, the authors rely heavily on animal studies generally to make their case for a range of issues without highlighting the fact that the relevant animal studies were all carried out on HEALTHY animals. The authors seem overly confident that the results of these animal studies can be applied directly to the clinical situation where no psychiatrist uses antipsychotic medication in healthy humans. The authors fail to see the complete disconnect between healthy animal research and clinical research on patients with schizophrenia. It seems to us that the reliance on animal studies by Murray and colleagues has resulted in their treatment recommendations being almost the opposite to ones based on clinical literature (2). We suggest that Murray and colleagues are proposing a therapeutic dead-end. With current practice, most patients stop their medication anyway, mainly due to non-adherence to oral medication, within 60 days after hospital discharge in 60% of first-episode patients (3): so how will taking more patients off their antipsychotic medication improve the current overall recovery rates in schizophrenia of 13.5% (4), and the death rates that all agree are unacceptably high? Murray and colleagues’ answer is more psychosocial intervention but they present no evidence for its effectiveness in un-medicated patients. The clinical evidence for antipsychotic medication reducing the mortality rate at all stages of the illness is of high quality and very consistent (summarised in [5]): the simple truth is that taking more patients off maintenance medication will result in more patients dying unnecessarily – the ultimate therapeutic dead-end.


1.Murray RM, Quattrone D, Natesan S, van Os J, Nordentoft M, Howes O, Di Forti M, Taylor D. Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics? Br J Psychiatry 2016, 209, 361-365.

2.Catts SV & O’Toole BI. The treatment of schizophrenia: Can we raise the standard of care? Aust & NZ J Psychiatry 2016 50, 12, 1128-1138.

3.Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel Mx, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011, 168, 6, 603-609.

4.Jaaskelainen E, Juola P, Hirvonen N, McGrath JJ, Saha S, Isohanni M, Veijola J, Miettunen J. A systematic review and meta-analysis of recovery in schizophrenia. Schiz Bull 2013, 39, 6, 1296-1306.

5.Tiihonen J Editorial: real-world effectiveness of antipsychotics. Acta Psychiatrica Scandinavica 2016, 134,371-373.

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Conflict of interest: SVC has received funding for acting in the role of an advisory board member, as a sponsored educational speaker, and for research projects from the following pharmaceutical companies: Janssen-Cilag Pty Ltd, Eli Lilly Australia Pty Ltd, Lundbeck Australia Pty Ltd, Novartis Pharmaceuticals Australia Pty Ltd, Pfizer Australia Pty Ltd, Bristol-Myers Squibb Pty Ltd, Sanofi-Aventis Australia Pty Ltd, Hospira Australia Pty Ltd, and AstraZeneca Pty Ltd. The author is a Trustee for the Psychosis Australia Trust and the Queensland Schizophrenia Research Foundation. He is a board member of Clearthinking Queensland Ltd. BIO has no conflicts of interest to declare.

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