Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia

Cipriani A, Boso M, Barbui C

Published Online:

March 17, 2010

Schizophrenia is a severe mental illness affecting one per cent of the population throughout the world. The symptoms of schizophrenia are perceptions without cause (hallucinations), fixed false beliefs (delusions) and/or apathy, slowing and less movement or thought. In most Western countries people who do not respond to the majority of common antipsychotics (called treatment resistant people) are tried on the atypical antipsychotic clozapine. If they do not respond to clozapine alone, then another antipsychotic is usually added. This review looks at clinical trials which compare the response to a second antipsychotic in people who are treatment resistant, and on clozapine.

Although 24 studies were looked at, only three fulfilled the criteria to be included, the total number of people randomised was 140. The studies were all less than 8 weeks long, and all compared different second antipsychotics (amisulpiride versus quetiapine, risperidone versus sulpiride and risperidone versus ziprasidone).

When people on clozapine plus risperidone were compared to those on clozapine plus sulpiride, more people taking risperidone showed an improvement generally. However, when specific symptoms of schizophrenia were studied, there was change for the better in all groups but no second antipsychotic was significantly better than the one it was compared to. When looking at adverse effects, people taking sulpiride were slightly more likely to suffer from hypersalivation and weight gain than those taking risperidone.

These three trials contained small numbers of people and the data were not well recorded. Although there is a suggestion that adding a second antipsychotic may improve general functioning and decrease the symptoms of schizophrenia, it is still not possible to say which antipsychotic would help the most. A large, longer and independent trial should be done on people who have not responded completely to clozapine to find the most effective treatment.

(Plain language summary prepared for this review by Janey Antoniou of RETHINK, UK www.rethink.org)

Abstract (click to read)

Background:

Although clozapine has been shown to be the treatment of choice in people with schizophrenia that are resistant to treatment, one third to two thirds of people still have persistent positive symptoms despite clozapine monotherapy of adequate dosage and duration. The need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine is the most common reason for simultaneously prescribing a second antipsychotic drug in combination with clozapine.

Objectives:

To determine the efficacy and tolerability of various clozapine combination strategies with antipsychotics in people with treatment resistant schizophrenia.

Search strategy:

We searched the Cochrane Schizophrenia Group Trials Register (March 2008) and MEDLINE (up to November 2008). We checked reference lists of all identified randomised controlled trials and requested pharmaceutical companies marketing investigational products to provide relevant published and unpublished data.

Selection criteria:

We included only randomised controlled trials recruiting people of both sexes, aged 18 years or more, with a diagnosis of treatment-resistant schizophrenia (or related disorders) and comparing clozapine plus another antipsychotic drug with clozapine plus a different antipsychotic drug.

Data collection and analysis:

Two review authors independently extracted data and resolved disagreement by discussion with third member of the team. When insufficient data were provided, we contacted the study authors.

Main results:

Three small (range of number of participants 28 to 60) randomised controlled trials were included in the review. Even though results from individual studies did not find that one combination strategy is better than the others, the methodological quality of included studies was too low to allow authors to use the collected data to answer the research question correctly.

Authors' conclusions:

In this review we considered the risk of bias too high because of the poor quality of the retrieved information (small sample size, heterogeneity of comparisons, flaws in the design, conduct and analysis). Although clinical guidelines recommend a second antipsychotic in addition to clozapine in partially responsive patients with schizophrenia, the present systematic review was not able to show if any particular combination strategy was superior to the others. New, properly conducted, randomised controlled trials independent from the pharmaceutical industry need to recruit many more patients to give a reliable estimate of effect or of no effect of antipsychotics as combination treatment with clozapine in patients who do not have an optimal response to clozapine monotherapy.

This record should be cited as:

Cipriani A, Boso M, Barbui C. Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006324. DOI: 10.1002/14651858.CD006324.pub2

Assessed as up to date:

March 12, 2008

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Primary Review Group:

Schizophrenia Group

Health topics:

Mental health > Schizophrenia & psychosis > Antipsychotic medication: atypical

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Independent high-quality evidence for health care decision making

Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia

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