Antipsychotics in Adults With Schizophrenia: Comparative Effectiveness of First-Generation Versus Second-Generation Medications

Background: Debate continues about the comparative benefits and harms of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) in treating schizophrenia. Purpose: To compare the effects of FGAs with those of SGAs in the treatment of adults aged 18 to 64 years with schizophrenia and related psychosis on illness symptoms, diabetes mellitus, mortality, tardive dyskinesia, and a major metabolic syndrome. Data Sources: English-language studies from 10 electronic databases to March 2012, reference lists of relevant articles, and gray literature. Study Selection: Randomized trials for efficacy and cohort studies at least 2 years in duration for adverse events. Data Extraction: Two independent reviewers extracted data from 114 studies involving 22 comparisons and graded the strength of evidence for primary outcomes as insufficient, low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation approach. Data Synthesis: Few differences of clinical importance were found for core illness symptoms; lack of precision in effect estimates precluded firm conclusions for many comparisons. Moderate-strength evidence showed a clinically important benefit of haloperidol over olanzapine for improving positive symptoms, but the benefit was scale-dependent: It was seen when the Scale for the Assessment of Positive Symptoms was used but not when the Positive and Negative Syndrome Scale (PANSS) was used. Moderate-strength evidence showed a clinically important benefit of olanzapine over haloperidol in improving negative symptoms when the PANSS and the Scale for the Assessment of Negative Symptoms were used. Low-strength evidence showed no difference in mortality for chlorpromazine verus clozapine or haloperidol versus aripiprazole, increased incidence of the metabolic syndrome for olanzapine versus haloperidol (risk differences, 2% and 22%), and higher incidence of tardive dyskinesia for chlorpromazine versus clozapine (risk differences, 5% and 9%). Evidence was insufficient to draw conclusions for diabetes mellitus. Limitations: All studies had high or unclear risk of bias. Length of study follow-up was often too brief to adequately measure adverse events. Medication comparisons, dosage, and outcome measurement were heterogenous for head-to-head comparisons. Selective patient populations limit generalizability. Conclusion: Clear benefits of FGAs versus SGAs for treating schizophrenia remain inconclusive because of variation in assessing outcomes and lack of clinically important differences for most comparisons. The strength of evidence on safety for major medical events is low or insufficient. Primary Funding Source: Agency for Healthcare Research and Quality.