What to do when clozapine is discontinued?J Clin Psychopharmacol:Feb.2013


Clozapine’s superiority in resistant schizophrenia is well established. When clozapine has to be discontinued ( due to side effects or lack of efficacy) clinicians are left with a difficult question. What next?

Feras Ali Mustafa review the evidence for the efficacy of the alternative antipsychotic medication in patients with schizophrenia who discontinued clozapine.

The literature search revealed 15 eligible papers of which  only two were  randomized trials. Tollefson et al (1999 ) reported an RCT on 106 subjects who discontinued clozapine abruptly ( most stopped it electively though). None of the subjects had been treated with olanzapine previously. Subjects were randomized into either receiving olanzapine, or placebo.Patients were  followed up for only 3 to 5 days.  Those who received olanzapine  had 7.5% discontinuation symptoms (defined as an increase in at least one psychotic sign or symptom), compared to 25% in  placebo group. .The very short duration of this study is an important limitation.

Lin et al 2003 reported an RCT in which 56 subjects on clozapine were randomized either to continue with clozapine (n = 24) or to switch to zotepine (n = 35). At 12 weeks 65.7% of the subjects receiving zotepine completed the study without an increase in their Clinical Global Impression24 (CGI) scores compared to 95.8% of the subjects who continued to take clozapine. The poor  quality of reporting of this study limits any further interpretations.

There is no evidence from RCTs on the comparative efficacy of nonclozapine antipsychotics in patients who discontinue clozapine. Most reports involve small number of patients and generalisability is limited. Studies that followed up subjects for 12 months or longer reported that alternative antipsychotics often changed and a considerable proportion of subjects had eventually had to be reinstated on clozapine. Olanzapine was the most tested clozapine alternative (8 of 13 studies of switching clozapine into a single antipsychotic drug). Olanzapine had a generally favourable outcome in most of the 8 studies, especially in subjects with less severe illness and those who discontinued clozapine for reasons other than lack of response. However, studies that reported positive outcome with olanzapine lacked active comparators. 

Conclusion: Evidence remains lacking with regard to treatment of schizophrenic patients who discontinue clozapine. However, there is some evidence to suggest that  a trial of olanzapine would be worthwhile, especially in those who discontinue clozapine for reasons other than poor response.

Summary of the article: 

Schizophrenia past clozapine: what works? Mustafa FA.J Clin Psychopharmacol. 2013 Feb;33(1):63-8

2 thoughts on “What to do when clozapine is discontinued?J Clin Psychopharmacol:Feb.2013

  1. Hello

    Thanks for the super updates on research.

    Can I ask something?

    We talk about reduced life expectancy for patients with mental illness. Have studies been done to see if this actually is the case?

    I am aware of the Nordic study published in BJPsych . Are there any other studies around or data available?



    • Some references for excess mortality. You can see that supportive evidence come from a wide range of countries.
      Laursen et al 2007
      Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a commu- nity cohort with schizophrenia. Br J Psychiatry. 2010;196(2):116-121.
      Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007; 64(10):1123-1131.
      Chang CK, Hayes RD, Perera G, Broadbent MTM, Fernandes AC, Lee WE, Hotopf M, Stewart R. Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental health care case register in London. PLoS One. 2011;6(5):

      Cuijpers P, Smit F. Excess mortality in depression: a meta-analysis of commu- nity studies. J Affect Disord. 2002;72(3):227-236.
      KiselyS,SmithM,LawrenceD,MaatenS.Mortalityinindividualswhohavehad psychiatric treatment: population-based study in Nova Scotia. Br J Psychiatry.

      Wahlbeck K, Westman J, Nordentoft M, Gissler M, Laursen TM. Outcomes of Nordic mental health systems: life expectancy of patients with mental disorders.
      Br J Psychiatry. 2011;199(6):453-458.

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