Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected

To understand the mechanism of action of antipsychotic drugs, it is critical to recognize the time course over which these medications take effect. Current models of antipsychotic action presume a "delayed onset" of action.

To test the delayed-onset hypothesis of antipsychotic action via a meta-analytic study.

Double-masked studies that reported results from active or placebo-controlled trials of antipsychotic response during the first 4 weeks of treatment were selected. These studies were identified by searching MEDLINE, 1996 to 2001; the Cumulative Index to Nursing and Allied Health, 1982 to 2001; EMBASE, 1980 to 2001; the ACP Journal Club; the Cochrane Database of Systematic Reviews; and the Database of Abstracts of Reviews of Effectiveness. Leads from these sources were followed up by manual searches.

Forty-two published studies, including 7450 patients and 119 independent response vs time curves, were identified. Reductions in total scores on the Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale were 13.8% during week 1, 8.1% during week 2, 4.2% during week 3, and 4.7% during week 4. This pattern of "early-onset" improvement was present even after the estimated effect of placebo treatment was removed and when results were restricted to the psychotic subscales of the scales.

This analysis rejects the commonly held hypothesis that antipsychotic response is delayed. Rather, these findings suggest that the antipsychotic response starts in the first week of treatment and accumulates over time. Furthermore, greater improvement occurs in the first 2 treatment weeks than in the subsequent 2 treatment weeks. Proposed mechanisms of action of antipsychotic drugs need to account for this early-onset antipsychotic effect.