Dose escalation of antipsychotic drugs in schizophrenia: a meta-analysis of randomized controlled trials

Non-response to an initial antipsychotic trial emerges frequently in the pharmacological management of schizophrenia. Increasing the dose (high-dose treatment, dose escalation) is an often applied strategy in this regard, but there are currently no meta-analytic data available to ascertain the evidence of this treatment option.

We systematically searched for all randomized controlled trials (RCTs) that compared a dose increase directly to the continuation of standard-dose medication in patients with initial non-response to a prospective standard-dose pharmacotherapy with the same antipsychotic compound. Primary outcome was mean change in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) total score. Secondary outcomes were positive and negative symptoms, response rates, and attrition rates. Hedges's g and risks ratios were calculated as effect sizes and the influence of the amount of the dose increase was examined by meta-regressions.

Altogether, five trials with 348 patients investigating dose escalation with quetiapine, ziprasidone, haloperidol, and fluphenazine could be included. We did not find any significant difference for the mean PANSS/BPRS score change between the dose-increase and control group, neither for the pooled antipsychotic group nor for the individual antipsychotic drugs. Moreover, there were no between-group differences in positive and negative symptoms, response rates, and drop-out rates. The meta-regressions indicate no significant influence of the different amounts of dose increments on effect sizes.

This meta-analysis suggests no evidence for a dose-escalation of the investigated antipsychotic drugs fluphenazine, haloperidol, quetiapine, and ziprasidone in case of initial non-response to standard-dose pharmacotherapy.