Antipsychotics for treatment-resistant schizophrenia


Clozapine is often the last resort for treatment-resistant schizophrenia. This is supported by clinical trials, a meta-analysis, a Cochrane review and network meta-analysis (NMA) (Kane et al 1988a, Kane et al 1988b, Wahlbeck et al 1999, Essali et al 2009, Leucht et al 2013).

However, superiority was driven by data from older studies (Kane et al 1988a, Kane et al 1988b). Newer studies show a smaller effect size between clozapine and first generation antipsychotics (Buchanan et al 1998, Rosenheck et al 1997).

Furthermore, a Cochrane Review comparing clozapine to second generation antipsychotics found them to be of similar efficacy and newer second generation antipsychotics could be more effective than clozapine if non-refractory patients are considered (Leucht et al 2013, Asenjo Lobos et al 2010, Leucht et al 2009, Davis et al 2003).

This new paper reviews antipsychotics in treatment resistant schizophrenia using simple pairwise meta-analyses and a network meta-analysis (Samara et al, 2016).

This new network meta-analysis looks at the efficacy, acceptability, and tolerability of antipsychotics for treatment-resistant schizophrenia.

This new network meta-analysis looks at the efficacy, acceptability, and tolerability of antipsychotics for treatment-resistant schizophrenia.

Methods and participants

The analysis considered:

  • All published and unpublished single-blind and double-blind randomised controlled trials (RCTs, >3 weeks)
  • Of adult patients with a treatment-resistant form of schizophrenia, schizophreniform disorder, or schizoaffective disorder
  • With any antipsychotic monotherapy, in any dose or formulation, in any country, that was compared to any other antipsychotic or placebo.


Forty unique blinded RCTs with 5,172 unique participants with an average duration of illness of 16.2 years, were published between 1968 and 2012.

The mean dose of the 12 antipsychotics included in the analysis was 794 mg/d in chlorpromazine equivalents, mostly involving clozapine, haloperidol, olanzapine and risperidone.

Severe inconsistency was identified between direct and indirect evidence because of pre-1990 papers and big changes in antipsychotic trials. Consistency is essential for network meta-analyses, so 5 papers published before 1990 were removed.

Here are the main findings as summarised by the authors:

A certain pattern of superiority was found for olanzapine, clozapine, and risperidone in various efficacy outcomes, such as mean change in overall and positive symptoms, response rates, and dropouts owing to inefficacy, but treatment efficacy differences were not definitive and clozapine was no more efficacious than most other second-generation antipsychotics, and this was not an artefact of using the NMA [network meta-analysis]. Although substantial evidence was available for clozapine, haloperidol, olanzapine, and risperidone, data on the other included antipsychotics were limited.

Meaning: Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia.

Rankings based on primary outcomes:

  1. Olanzapine
  2. Ziprasidone 2 studies (n = 453)
  3. Clozapine
This well conducted study shows that we still don't really know which antipsychotics work best for treatment-resistant schizophrenia.

This well conducted study shows that we still don’t really know which antipsychotics work best for treatment-resistant schizophrenia.


The main criticism of this paper is that it gives no firm findings that can be applied in practice. Before reading this paper, a clinician would go through medicines by trial and error before a patient settles on the right one. After reading this paper the process is the same. Do the results mean clozapine should no longer be used for its “apparently” poor risk to benefit ratio? Or should it be used earlier, i.e. not a last resort?

It feels as though the authors were aiming to (dis)prove clozapine’s superiority to other antipsychotics, however, they established an analysis where major clozapine studies would not be included. Clozapine was generally superior in several unblinded clinical and cost-effectiveness studies (McEvoy et 2006, Essock et al 2000, Lewis et al 2006), whose results have been confirmed in real-world observational studies (Nyakyoma et al 2010, Ciudad et al 2008) with hard endpoints such as hospitalisation and number of inpatient days (Ringbäck et al 2014), none of which were included here.

Even if you could say which drug is best, what would it be best for? Schizophrenia presents on a spectrum. It is unclear which part of the spectrum we would be treating. How we classify/diagnose patients needs to change before we say which drug is best. This may have played a role by averaging out the results of the study.

The criteria of treatment resistance in this analysis varied from partial nonresponse to high levels of treatment resistance, differences the analysis was not sensitive to. Consequently, it is possible that clozapine’s lack of consistent superiority was due to the rare inclusion of patients with the most treatment-resistant disease in blinded RCTs. The same explanation could apply to clozapine’s dramatic superiority found in the study by Kane et al (Kane et al 1988a, Kane et al 1988b), which only included patients who were considered “beyond the reach of conventional therapy” (Kane et al 1988b). In the analysis, most included studies were conducted on less severely ill patients with more onerous consenting procedures and commercialisation of the research conduct.

Network meta-analysis has been criticised because it includes indirect evidence, which adds another level of complexity and assumptions.

Enough studies examined clozapine, olanzapine, risperidone, and haloperidol, but, for others the body of evidence was small and conclusions on them are not robust.

Where does this new evidence leave people living with treatment-resistant schizophrenia?

Where does this new evidence leave people living with treatment-resistant schizophrenia?


Primary paper

Samara MT et al. (2016) Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis. JAMA Psychiatry. 2016;73(3):199-210 [Abstract]

Other references

Asenjo Lobos C et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;(11):CD006633.

Buchanan RW et al. Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry. 1998;155(6):751-760. [PubMed abstract]

Ciudad A et al. The Schizophrenia Outpatient Health Outcomes (SOHO) study: 3-year results of antipsychotic treatment discontinuation and related clinical factors in Spain. Eur Psychiatry. 2008;23(1):1-7. [PubMed abstract]

Davis JM et al. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60(6):553-564. [DARE abstract]

Essali A et al. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009;(1):CD000059.

Essock SM et al. Cost-effectiveness of clozapine compared with conventional antipsychotic medication for patients in state hospitals. Arch Gen Psychiatry. 2000;57(10):987-994. [PubMed abstract]

Kane J et al. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988b;45(9):789-796. [PubMed abstract]

Kane JM et al. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988a;24(1):62-67.

Leucht S et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951-962. [Abstract]

Leucht S et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41. [Abstract]

Lewis SW et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32(4):715-723.

McEvoy JP et al; CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600-610. [PubMed abstract]

Nyakyoma K and Morriss R. Effectiveness of clozapine use in delaying hospitalization in routine clinical practice: a 2 year observational study. Psychopharmacol Bull. 2010;43(2):67-81. [PubMed abstract]

Ringbäck Weitoft G et al. Mortality, attempted suicide, re-hospitalisation and prescription refill for clozapine and other antipsychotics in Sweden: a register-based study. Pharmacoepidemiol Drug Saf. 2014;23(3):290-298. [PubMed abstract]

Rosenheck R et al; Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med. 1997;337(12):809-815.

Wahlbeck K et al. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry. 1999;156(7):990-999. [PubMed abstract]

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