Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia

Abstract

Our objective was to prospectively assess whether early (ie, 2 weeks) response to an antipsychotic predicts later (12-week) response and whether 'switching' early non-responders to another antipsychotic is a better strategy than 'staying'. This randomized, double-blind, flexible-dosed, 12-week study enrolled 628 patients diagnosed with schizophrenia or schizoaffective disorder. All initiated treatment with risperidone. Early response was defined as > or =20% improvement on the Positive and Negative Syndrome Scale (PANSS) total score following 2 weeks of treatment. Early responders (ERs) continued on risperidone, whereas early non-responders (ENRs) were randomized (1 : 1) to continue on risperidone 2-6 mg/day or switch to olanzapine 10-20 mg/day for 10 additional weeks. Compared with ENRs, risperidone ERs showed significantly greater reduction in PANSS total score (end point; p<001). Early response/non-response was highly predictive of subsequent clinical outcomes. Switching risperidone ENRs to olanzapine at week 2 resulted in a small but significantly greater reduction in PANSS total score (end point; p=0.020) and in depressive symptoms (end point; p=0.004); the reduction in PANSS was greater among those who were still moderately ill at 2 weeks. Switching risperidone ENRs to olanzapine also resulted in significantly greater increases in triglycerides, a significantly greater decrease in prolactin, and significantly less treatment-emergent dyskinesia. This is the first study to prospectively show that early response/non-response to an antipsychotic (risperidone) is a reliable clinical marker of subsequent clinical outcomes and that a 'switching' strategy based on this information may lead to greater clinical improvement than staying on a drug for a longer period in some patients.

Trial registration: ClinicalTrials.gov NCT00337662.

Figures

Figure 1

(a) Study design. (b) Patient flow diagram. ER, early responder; ENR, early non-responder; ENR–OLZ, early non-responder switched to olanzapine; ENR–RIS, early non-responder maintained on risperidone; mg, milligram; SPI, Study Period I; SPII, Study Period II; SPIII, Study Period III; V, Visit; wk, week.

Figure 2

Comparison of change in PANSS total score from baseline between early responders and early non-responders treated with risperidone and between early non-responders maintained on risperidone (ENR–RIS) and those switched to olanzapine (ENR–OLZ). PANSS, Positive and Negative Syndrome Scale; RIS, risperidone.

Figure 3

A comparison of the proportion of patients who met response criteria at end point between the two ENR groups. Responses are defined with varied cutoffs on percent change of PANSS total score from baseline. ENR–OLZ, early non-responder switched to olanzapine; ENR–RIS, early non-responder maintained on risperidone.