Prescribing antipsychotics at higher than 95% effective dose may not offer additional efficacy

Patients with chronic schizophrenia who have acute exacerbations may not experience increased benefit from receiving antipsychotic doses higher than the identified 95% effective doses, according to results of a meta-analysis published in American Journal of Psychiatry.

“The dose-response relationships of antipsychotic drugs for the acute treatment of schizophrenia are not well understood, but further defining them would be important for many reasons,” Stefan Leucht, MD, of the department of psychiatry and psychotherapy at the Technical University of Munich’s School of Medicine, and colleagues wrote. “Clinicians need to know the minimum effective doses and the maximum effective doses when they prescribe antipsychotics, and guidelines attempt to provide such information.”

To help define the dose-response relationships of antipsychotic drugs for schizophrenia, Leucht and colleagues searched electronic databases through November 2018 for all placebo-controlled dose-finding studies of 20 second-generation antipsychotic drugs and haloperidol in individuals with acute schizophrenia symptoms. They constructed dose-response curves with a spline model and random-effects dose-response meta-analyses. They used the total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating scale as the outcome measure.

Leucht and colleagues included 68 studies that met the inclusion criteria. They reported the 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, as follows:

• amisulpride for patients with positive symptoms = 537 mg/day and 85.8 mg;

• aripiprazole = 11.5 mg/day and 1.8 mg;

• apripiprazole long-acting injectable = 463 mg every 4 weeks and 264 mg;

• asenapine = 15 mg/day and 2.4 mg;

• brexpiprazole (Rexulti, Otsuka) = 3.36 mg/day and 0.54 mg;

• haloperidol = 6.3 mg/day and 1.01 mg;

• iloperidone = 20.13 mg/day and 3.2 mg;

• lurasidone = 147 mg/day and 23.5 mg;

• olanzapine = 15.2 mg/day and 2.4 mg;

• olanzapine long-acting injectable = 277 mg every 2 weeks and 3.2 mg;

• paliperidone = 13.4 mg/day and 2.1 mg;

• paliperidone long-acting injectable = 120 mg every 4 weeks and 1.53 mg;

• quetiapine = 482 mg/day and 77 mg;

• risperidone = 6.3 mg/day and 1 mg;

• risperidone long-acting injectable = 36.6 mg every 2 weeks and 0.42 mg;

• sertindole = 22.5 mg/day and 3.6 mg; and

• ziprasidone = 186 mg/day and 30 mg.

“We stress that our results provide some guidance based on ‘average’ patients with chronic illness,” the researchers wrote. “Individual dosing decisions should be guided by the properties of each drug (eg, pharmacodynamic and pharmacokinetic properties, side effects), patient characteristics (eg, age, illness stage, severity, physical comorbidities and previously unknown individual effective doses) and concomitant treatments that could, by interaction, influence drug plasma levels.” – by Joe Gramigna

Disclosures: Leucht reports receiving honoraria for service as a consultant or adviser and/or for lectures from numerous pharmaceutical companies. Please see the study for all other authors’ relevant financial disclosures.