This review concluded that L-dopa as an adjunct to antipsychotic drugs can be beneficial in patients already receiving antipsychotic drugs. Considering the methodological limitations of the review and the limited number of high-quality studies, the general conclusions should be treated with some caution. The recommendations for further evaluation seem appropriate.

To determine whether levodopa (L-dopa) administered in addition to antipsychotic drugs (APDs) is beneficial for patients with schizophrenia.

PubMed and the National Library of Medicine were searched from 1965 to July 2003 without language restrictions; the search terms were reported. The reference lists of relevant articles were also screened for additional studies. Only studies published in peer-reviewed journals were included.

Study designs of evaluations included in the review

There were no specific inclusion criteria relating to the study design. Once studies had been retrieved, it was decided to exclude single case reports.

Specific interventions included in the review

Studies of at least 5 days of L-dopa treatment were eligible for inclusion. Studies where L-dopa was administered in conjunction with a monoamine oxidase inhibitor were excluded. The dose of L-dopa ranged from 150 to 7,000 mg/day, with treatment duration ranging from 5 days to 18 months.

Participants included in the review

Studies of adults with schizophrenia were eligible for inclusion. The age of the participants ranged from 15 to 75 years.

Outcomes assessed in the review

Studies that described or measured a psychiatric response were eligible for inclusion. The outcome measures consisted of a range of rating scales and clinical diagnosis.

How were decisions on the relevance of primary studies made?

The authors did not state how the studies were selected for the review, or how many reviewers performed the study selection.

Study quality was assessed in terms of allocation concealment, blinding, use of a placebo, rating scales and diagnostic criteria used, inclusion of asymptomatic patients, and the administration of concomitant APDs. The authors did not state how study quality was assessed, or how many reviewers performed the quality assessment.

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction.

The effect size (Cohen's d) was calculated for each placebo-controlled study. The proportions of patients that were better or worse were extracted from open studies that were not placebo-controlled.

How were the studies combined?

The results of placebo-controlled trials were assigned to one of two groups: poor (no change or worsening) or good (improved) response. The results were pooled by averaging the Cohen's d values, with each study weighted by the reciprocal of its variance. For open studies that were not placebo-controlled, the mean and median proportions of patients that were better and worse were calculated. The number of patients that were better or worse in the open studies was plotted against the number of participants in the study.

How were differences between studies investigated?

Heterogeneity between studies that were pooled was assessed using the Q statistic.

Twenty-seven studies (n=654) were included in the review, of which two were randomised controlled trials (RCTs, n=46).

Of the 27 included studies, 18 were open label (67%), 5 were double-blind (19%), 4 were single-blind (15%), 8 were placebo- controlled (30%), 17 used formalised rating scales (63%), 6 used formal diagnostic criteria (22%), and 6 included asymptomatic patients (22%).

The addition of L-dopa to APD treatment was beneficial when the results of 5 placebo-controlled trials were pooled (mean Cohen's d 0.7116, P<0.00001). However, there was statistically significant heterogeneity between the studies.

From the 16 open trials, when added to APD treatment, the median proportion of people that were better with L-dopa treatment was 45.8% (mean 42.4%). The median proportion of people that were worse with L-dopa treatment was 9.2% (mean 22.2%).

L-Dopa can be beneficial for schizophrenic patients already receiving APDs. It could not be determined whether L-dopa was more likely than placebo to cause worsening in APD-free patients.

The review question was clear in terms of the participants, interventions and outcomes. There were no inclusion criteria relating to the study design. Relevant sources were searched for studies in any language. However, only peer-reviewed studies were included, thereby increasing the potential for publication bias which the authors did not investigate. It was not reported whether the study selection, data extraction and quality assessment processes were conducted in duplicate, therefore the potential for error and bias during the review process cannot be ruled out. The main conclusion was based on the mean Cohen's d value calculated using the results of only 5 of the 27 included studies. Considering the methodological limitations of the review, and the limited number of high-quality studies on which the conclusion and implications for practice were based, the general conclusions of the review should be treated with some caution. The recommendations for further evaluation seem appropriate.

Practice: The authors stated that there is no evidence that administering L-dopa to APD-free patients is therapeutic, and that high-dose L-dopa should not be administered to APD-free patients with schizophrenia in the absence of a highly compelling reason and careful supervision. They also stated that they are not recommending that L-dopa is routinely combined with typical or atypical APDs for patients with schizophrenia who are poor or partial treatment responders.

Research: The authors stated that further evaluation of L-dopa and other dopamine agonists as adjunctive treatments for schizophrenia is warranted.

Louis Stokes Cleveland Department of Veterans Affairs Medical Center.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.