Comparison of polypharmacy using low-dose second-generation antipsychotics plus low-dose first-generation antipsychotics with monotherapy using therapeutic-dose second-generation antipsychotics in schizophrenia - a pooled analysis.

Abstract

To the editor: Antipsychotics were classified according to the risk of extrapyramidal side effects (EPS) as first-generation antipsychotics (FGA) (e.g. haloperidol, sulpiride, and trifluoperazine), or second-generation antipsychotics (SGA) (e.g. olanzapine, risperidone, and amisulpride) if the risk for the development of EPS is low. Treatment guidelines for schizophrenia favor antipsychotic monotherapy. However, antipsychotic polypharmacy is a common clinical practice. The rate of polypharmacy has increased over the past decade.1 To date, evidence supporting this practice is still mixed or inconclusive. Polypharmacy may maintain efficacy by additively blocking D2 receptors. An FGA at dosages lower than 600 mg/day of chlorpromazine equivalents may have no more EPS than SGAs.2 We conducted a pooled analysis from three published 6-week, fixed dose, randomized, double-blind trials to explore whether polypharmacy using low-dose SGAs plus low-dose FGAs had efficacy and safety comparable with monotherapy using therapeutic-dose SGA in the acute treatment of 270 schizophrenia patients. For Trial 1 (NCT00998608), patients were randomly assigned to a 1:1 ratio of 2 mg/day of risperidone plus 2 mg/day of haloperidol or 4mg/day of risperidone alone for 6 weeks. For Trial 2 (NCT01615185), patients were randomly assigned to a 1:1 ratio of 400 mg/day of amisulpride plus 800 mg/day of sulpiride or 800 mg/day of amisulpride alone for 6 weeks. For Trial 3 (NCT02704962), patients were randomly assigned to a 1:1 ratio of 5 mg/day of olanzapine plus 5 mg/day of trifluoperazine or 10 mg/day of olanzapine alone for 6 weeks. Benzodiazepine p.r.n. and biperiden, up to 6 mg/day, were also allowed for clinical requirement. Three trials were similar in design and were therefore pooled together. Efficacy measures, including the Positive and Negative Syndrome Scale (PANSS) and other scales, safety measures, side effect measures, and quality of life, were rated at baseline, and again at weeks 1, 2, 3, 4, and 6 (or upon early termination) or at baseline and again at endpoint. The responsewas defined as at least a 30% reduction in the PANSS total score. Remission was defined according to “Andreasen criteria.” Patients were included in the analyses only if they had both a baseline and at least one post-baseline rating. Missing data were imputed according to the principle of last observation carried forward. Analyses of group differences were performed by analysis of covariance, with treatment as a fixed factor and sex, age, age at onset, and baseline values as covariates. Kaplan–-Meier analysis was used to determine time to discontinuation, time to response, and time to remission between the two groups. Significance was defined as an alpha < 0.05. Polypharmacy (n= 138) and monotherapy groups (n= 132) were similar in (1) sex (male: 55.8% [n= 77)] *Address correspondence to: Ching-Hua Lin, Department of Adult Psychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, 130, Kai-Syuan 2nd Rd., Ling-Ya District, Kaohsiung 802, Taiwan. (Email: [email protected]) CNS Spectrums (2019), 1–2. © Cambridge University Press 2019 doi:10.1017/S1092852919000877