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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Introduction

Although precise estimates are missing, a considerable number of patients with schizophrenia do not respond satisfactorily to an antipsychotic trial in a standard dose within the officially approved dose range (Bondolfi et al., 1996, Conley and Buchanan, 1997, Hasan et al., 2012). In this case, the question of the next therapeutic measures within an algorithm to achieve sufficient treatment response arises. Strategies that are often employed in clinical routine care contain, among various polypharmaceutical medications, increasing the dose of the current administered antipsychotic agent (dose escalation, high-dose pharmacotherapy, “off-label”-medication) and switching to another new antipsychotic drug (Dold and Leucht, 2014). However, in terms of the latter two strategies, there are currently no meta-analyses available that systematically investigated these frequently applied pharmacological approaches. Therefore, we aimed to close this empirical gap for the efficacy of dose-increase strategies.

At present, treatment guidelines for the pharmacotherapy of schizophrenia do not recommend dose escalation of antipsychotic drugs above the officially approved dose range as general treatment option in case of non-response to a standard dose (Lehman et al., 2004, Buchanan et al., 2010, Hasan et al., 2012). However, these judgments are primarily based on reviews comparing high-dose with standard-dose treatment in general by the evaluation of mainly comparative dose studies and therapeutic drug monitoring (TDM) studies (Baldessarini et al., 1988, Davis and Chen, 2004). Therefore, this literature cannot directly be transferred without reservation to the clinically meaningful question of whether increasing the dose is beneficial for subjects with insufficient initial symptom improvement to standard-dose treatment with the same antipsychotic compound.

To elucidate this, we sought to cover and meta-analyze all randomized controlled trials (RCTs) comparing a dose increase directly to the continuation of standard-dose medication in patients with initial non-response to this standard-dose pharmacotherapy. We applied this methodological approach with very strict inclusion criteria to reflect the common clinical practice where a dose increase is often employed as next treatment measure after a standard-dose trial of the same drug had failed.