title: Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: a systematic review and meta-analysis of randomized-controlled trials.
abstract: Limited options are available for clozapine-resistant schizophrenia and intolerable side effects of clozapine. We conducted a systematic review of randomized-controlled trials (RCTs) to determine the efficacy and safety of aripiprazole augmentation of clozapine for schizophrenia. Electronic databases searched included PubMed, Scopus, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. This review synthesized the data of four short-term (8-24 weeks), placebo-controlled trials (N = 347). The overall relative risk (RR, 95% confidence interval) of discontinuation rates was not significantly different between groups (RR = 1.41, 95% CI = 0.78 to 2.56). The pooled standardized mean differences (SMDs, 95% CIs) (Z-test; number of study; I(2)-index) suggested trends of aripiprazole augmentation benefits on overall psychotic [-0.40 (-0.87 to 0.07) (n = 3; Z = 1.68, p = 0.09; I(2) = 68%)], positive [-1.05 (-2.39 to 0.29) (n = 3; Z = 1.54, p = 0.12; I(2) = 94%)], and negative [-0.36 (-0.77 to 0.05) (n = 3; Z = 1.74, p = 0.08; I(2) = 54%)] symptoms. Despite of no benefit on three cardiometabolic indices (i.e., fasting plasma glucose, triglyceride, and high-density lipoprotein), aripiprazole augmentation was superior for weight change with a mean difference (95% CI) of -1.36 kg (-2.35 to -0.36) (n = 3; Z = 2.67, p = 0.008; I(2) = 39%) and LDL-cholesterol with a mean difference of -11.06 mg/dL (-18.25 to -3.87) (n = 3; Z = 3.02, p = 0.003; I(2) = 31%). Aripiprazole augmentation was not correlated with headache and insomnia but significantly associated with agitation/akathesia (RR = 7.59, 95% CI = 1.43 to 40.18) (n = 3; Z = 2.38, p = 0.02; I(2) = 0%) and anxiety (RR = 2.70, 95% CI = 1.02 to 7.15) (n = 1; Z = 2.00, p = 0.05). The limited short-term data suggested that aripiprazole augmentation of clozapine can minimize the cardiometabolic risk, causes agitation/akathesia, and may be effective in attenuating psychotic symptoms.
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Electronic address: manit.s@cmu.ac.th.
authors.forename: Manit
authors.initials: M
authors.lastname: Srisurapanont
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Sirijit
authors.initials: S
authors.lastname: Suttajit
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Narong
authors.initials: N
authors.lastname: Maneeton
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Benchalak
authors.initials: B
authors.lastname: Maneeton
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D000068180:Aripiprazole / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use*; D004357:Drug Synergism; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003024:Clozapine
keywords: Adverse effects; Aripiprazole; Clozapine; Drug augmentation; Metabolic syndrome; Schizophrenia