Valproate for schizophrenia

Schwarz C, Volz A, Li C, Leucht S

Published Online:

May 12, 2010

Most people with schizophrenia or schizophrenia-like conditions who are in contact with medical services will be treated with antipsychotic medication. Despite this, about 30% will continue to experience some signs of illness. Various other drugs have been added to the antipsychotic medication to try and reduce the symptoms these people experience. One such group of drugs are sodium and magnesium valproate, medication usually used to treat epilepsy or to stabilize mood in people who have bipolar disorder and those who have symptoms of schizophrenia and mood disorder together (schizoaffective disorder). This review looks at trials which attempt to compare valproate with placebo and also looks at valproate in combination with an antipsychotic compared to the antipsychotic alone. The studies included 519 people in seven trials, with the largest trial containing 249 people and the smallest, 12 people. All of the trials used an antipsychotic, and compared it to the antipsychotic plus valproate. There were no trials comparing just valproate with placebo. The antipsychotic used in three trials was haloperidol, one study compared risperidone and olanzapine, with and without valproate and in the other three trials the antipsychotic(s) used were not given. For the majority of outcome measures including becoming more well and improvement in mental state there was no significant difference between those on valproate plus antipsychotic compared to antipsychotic alone. However in one trial it was found that taking valproate lead to some people showing an improvement sooner, although by the end of the trial there was no difference between the two groups. Valproate also increased sedation. None of the studies were longer than 12 weeks so it is not known whether there would be a difference between the groups in the longer term. In addition, it was difficult to compare one trial with another because they recruited people with different groups of symptoms, used several different antipsychotics and looked at a diverse range of outcomes. The use of valproate for schizophrenia would benefit from some bigger and longer trials.

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

Abstract (click to read)

Background:

Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used; valproate is one of these.

Objectives:

To review the effects of valproate for the treatment of schizophrenia and schizophrenia-like psychoses.

Search strategy:

We searched the Cochrane Schizophrenia Group's register (last update February 2007). This register is compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. We also contacted a pharmaceutical company and authors of relevant studies in order to identify further trials.

Selection criteria:

We included all randomised controlled trials comparing valproate to antipsychotics or to placebo (or no intervention), whether as the sole agent or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizophrenia-like psychoses.

Data collection and analysis:

We independently inspected citations and, where possible, abstracts, ordered papers and re-inspected and quality assessed these. Data were extracted independently by at least two reviewers. We analysed dichotomous data using relative risks (RR) and the 95% confidence intervals (CI). We analysed continuous data using weighted mean differences. Where possible we calculated the number needed to treat (NNT) or number needed to harm statistics.

Main results:

The update search identified two further relevant studies, thus the review currently includes seven studies with a total of 519 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With one exception the studies were small, short-term and incompletely reported. Adding valproate was as acceptable as adding placebo to antipsychotic drugs (6 RCT, n=270, RR leaving the study early 1.7 CI 0.9 to 3.2). No significant effect of valproate as an adjunct to antipsychotic medication on the participants' global state or the general mental state at the endpoint was evident. However, one study showed a quicker onset of action in the combination group (Casey 2003). A single small study found the participants in the valproate group to be less aggressive than the control group (n=30, WMD -3.8, CI -5.1 to -2.5). Participants receiving valproate more frequently experienced sedation than those in the placebo group. In a single small study valproate significantly reduced tardive dyskinesia (n=30, WMD -3.3, CI -4.9 to -1.7). The effects of valproate on important subgroups such as those with schizophrenia and aggressive behaviour or those with schizoaffective disorder are unknown.

Authors' conclusions:

Based on currently available randomised trial-derived evidence, there are no data to support or to refute valproate as a sole agent for schizophrenia. There is some evidence for positive effects on aggression and tardive dyskinesia, but given that these results were based on only a single small study they cannot be considered robust. Given the paucity of the available database further large, simple well-designed and reported trials are necessary. Ideally these would focus on people with schizophrenia and aggression, on those with treatment resistant forms of the disorder and on those with schizoaffective disorders.

This record should be cited as:

Schwarz C, Volz A, Li C, Leucht S. Valproate for schizophrenia. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD004028. DOI: 10.1002/14651858.CD004028.pub3

Assessed as up to date:

May 5, 2008

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Primary Review Group:

Schizophrenia Group

Health topics:

Mental health > Schizophrenia & psychosis > Other drug treatments

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