More Is Not Always Better

September 3, 2015

Dose escalation is often applied in the management of psychosis when patients do not initially respond to therapy, but a recent study brings this strategy under question.


Dose escalation is often applied in the management of psychosis when patients do not initially respond to therapy, but the effectiveness of this strategy has not yet been assessed via meta-analysis. Results from a systematic review of randomized controlled trials suggest that dose escalation of an antipsychotic agent does not improve response in patients who inadequately response to standard-dose therapy of that agent.1

Dold and colleagues1 identified trials in which nonresponders to an initial course of an antipsychotic agent were randomly selected to continue on the standard dose or receive high-dose treatment with that drug. Studies that were not double-blinded and those that used dose increases below targets recommended by the International Consensus Study of Antipsychotic Dosing2 were excluded.

Of 1396 dose-escalation studies, 5 trials that assessed dose escalation with quetiapine, ziprasidone, haloperidol, or fluphenazine met the inclusion criteria. Increments in the dose-escalation phase of the studies ranged from 1.5-fold to 4-fold above the standard dose administered.

The total study population was 348 patients with schizophrenia and/or schizoaffective or schizophreniform disorder, with the large majority (77%) having schizophrenia. The primary outcome was mean change in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) score. Positive and negative symptoms and response and attrition rates also were assessed.

The bottom line
More is not better when standard-dose antipsychotic therapy fails. No meaningful evidence for dose-escalation of quetiapine, ziprasidone, haloperidol, or fluphenazine was found. No change in PANSS/BPRS scores was seen either in the trials of individual antipsychotic agents or in pooled data. Neither were between-group differences in positive and negative symptoms, response rates, and drop-out rates detected. Whereas 39% of patients in the pooled dose-escalation group achieved clinical response, 35% in the pooled standard-dose continuation group did so as well. In fact, no parameter met statistical significance, defined as P < 05.

The researchers concluded that upping the dose of an antipsychotic drug in a nonresponder does not benefit the patient. No high-dose regimen outperformed the continued standard-dose regimen in the studies evaluated. The researchers conjectured that a ceiling effect, as has been demonstrated with haloperidol,3 occurs.

These findings are consistent with international psychiatric society guidelines regarding pharmacotherapy of schizophrenia as well as findings from therapeutic drug monitoring studies. Nevertheless, a concerning discrepancy exists between these guidelines and the degree of high-dose pharmacotherapy used in clinical practice. Pointing out that only 5 randomized clinical trials have addressed the issue via well-designed methods, the researchers called for additional studies in hopes that continued scrutiny will better influence clinical practice.


1. Dold M, Fugger G, Aigner M, et al. Dose escalation of antipsychotic drugs in schizophrenia: A metaanalysis of randomized controlled trials. Schizophr Res. 2015;166:187-193.
2. Gardner DM, Murphy AL, O'Donnell H, et al. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010;167:686-693.
3. Dold M, Samara MT, Li C, et al. Haloperidol versus first-generation antipsychotics for the treatment of schizophrenia and other psychotic disorders. Cochrane Database Syst. Rev. 2015:CD009831.