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First-Generation Versus Second-Generation Antipsychotics in Adults: Comparative Effectiveness

Systematic Review ARCHIVED Aug 14, 2012
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Archived: This report was last assessed in December 2014 and some conclusions were considered out of date. Findings may be used for research purposes, but should not be considered current.

Notice of Erratum: On August 20, 2012, Appendix O was updated to clarify that the route of administration for INVEGA SUSTENNA is IM injection (dosage 39 mg - 234 mg) and the route of administration for RISPERIDOL CONSTA is IM injection (dosage 25 mg).

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Structured Abstract


To compare individual first-generation antipsychotics (FGAs) with individual second-generation antipsychotics (SGAs) in adults (18 to 64 years) with schizophrenia, schizophrenia-related psychoses, or bipolar disorder, with a focus on core illness symptoms, functional outcomes, health care system utilization, and adverse events.

Data Sources

We conducted comprehensive searches in 10 electronic databases up to July 2011. We hand-searched conference proceedings, clinical trials registers, and reference lists of relevant studies. We contacted content experts and authors of relevant studies.


Two reviewers independently conducted study selection, assessed methodological quality, extracted data, and graded the strength of evidence. We conducted a descriptive analysis and performed meta-analyses when appropriate.


We included 113 studies of schizophrenia (22 comparisons) and 11 studies of bipolar disorder (6 comparisons), and 1 study included both. Trials (n = 123) had an unclear (63 percent) or high (37 percent) risk of bias. Cohort studies (n = 2) had good methodological quality.

Core illness symptoms (global ratings and total scores)

For schizophrenia, clozapine was more efficacious than chlorpromazine based on the one reported scale. Results for haloperidol versus olanzapine were discordant, with olanzapine favored for one scale but no differences based on two other scales. Haloperidol was favored over quetiapine based on one of four scales reported. No differences were found for haloperidol versus aripiprazole, clozapine, risperidone, and ziprasidone.

For bipolar disorder, haloperidol was favored over ziprasidone on the one scale reported. No differences were observed for haloperidol versus aripiprazole, olanzapine, or risperidone.

Functional outcomes and health care system utilization

Evidence came primarily from single studies and showed no differences between groups.

Adverse events

No differences were found in mortality for chlorpromazine versus clozapine and haloperidol versus aripiprazole, or in metabolic syndrome for haloperidol versus olanzapine. The most frequently reported adverse events with significant differences were extrapyramidal symptoms; in most cases, the SGA had fewer extrapyramidal symptoms than haloperidol.

Other outcomes

For schizophrenia, few differences were found across comparisons and outcomes. No differences were observed in health-related quality of life. For bipolar disorder, there were few comparisons or differences.


The most common subgroups were race and treatment resistance. No notable differences were found compared with overall results.


Few differences of clinical importance for outcomes of effectiveness were found. Patient-important outcomes were rarely assessed. Data were sparse for the four key adverse events deemed a priori to be most clinically important.

Journal Publications

Hartling L, Abou-Setta AM, Dursun S, et al. Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis. Ann Intern Med 2012 Aug 14. [Epub ahead of print.]

Project Timeline

First-Generation Versus Second-Generation Antipsychotics in Adults: Comparative Effectiveness

Dec 16, 2009
Topic Initiated
Dec 1, 2010
Aug 14, 2012
Systematic Review Archived
Page last reviewed December 2019
Page originally created November 2017

Internet Citation: Systematic Review: First-Generation Versus Second-Generation Antipsychotics in Adults: Comparative Effectiveness. Content last reviewed December 2019. Effective Health Care Program, Agency for Healthcare Research and Quality, Rockville, MD.

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