title: Clozapine Augmentation With Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials.
abstract: OBJECTIVE
  To meta-analyze randomized controlled trials (RCTs) for the efficacy and safety of adjunctive antiepileptic drugs (AEDs) to augment clozapine therapy for treatment-resistant schizophrenia.
  
  
  METHODS
  The search included databases in English (PubMed, PsycINFO, Embase, and Cochrane Library databases and the Cochrane Controlled Trials Register) and in Chinese (China Journal Net [CJN], WanFang, and China Biology Medicine [CBM]) and references from retrieved articles. The databases were searched using dates inclusive from their onset until January 1, 2016, for terms reflecting (a) schizophrenia, (b) clozapine, and (c) adjunctive drugs.
  
  
  METHODS
  From 1,969 potentially relevant articles, 21 articles describing 22 RCTs were selected.
  
  
  METHODS
  Two independent investigators extracted data for a random-effects meta-analysis and assessed the quality of the studies using risk of bias and the Jadad scale. Standard mean difference, risk ratio (RR) ± 95% confidence intervals (CIs), and the number needed to harm (NNH) were used.
  
  
  RESULTS
  A total of 22 RCTs (N = 1,227) with 4 AEDs (topiramate [5 RCTs, n = 270], lamotrigine [8 RCTs, n = 299], sodium valproate [6 RCTs, n = 430], and magnesium valproate [3 RCTs, n = 228]) were analyzed. The means weighted by sample size were 12.1 weeks for treatment duration, 36.2 years for age, and 61% for male frequency. Significant superiority in total psychopathology was observed for topiramate (P < .0001), lamotrigine (P = .05), and sodium valproate (P = .002), compared to clozapine monotherapy. After removing outliers, the positive effect of sodium valproate remained, but the positive effect of lamotrigine disappeared (P = .40). Significantly improved efficacy in positive and general symptom severity was observed for topiramate (P = .04 and P = .02, respectively) and sodium valproate (P = .009 and P = .003, respectively). There were no significant differences regarding adverse drug reactions and all-cause discontinuations except for topiramate, which was associated with more all-cause discontinuations (RR = 1.99; 95% CI, 1.16 to 3.39; P = .01; I² = 0%; NNH = 7).
  
  
  CONCLUSIONS
  Sodium valproate augmentation was efficacious and safe. Topiramate augmentation had a too-high discontinuation rate. High-quality RCTs are needed to inform clinical recommendations.
authors.affiliation: Guangzhou Huiai Hospital, Guangzhou, China. zhengwei0702@163.com.|Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, China.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Xiang
authors.affiliation: Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.
authors.forename: Xin-Hu
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Beijing Anding Hospital, Capital Medical University, Beijing, China.
authors.forename: Ying-Qiang
authors.initials: YQ
authors.lastname: Xiang
authors.affiliation: Mental Health Research Center at Eastern State Hospital, Lexington, Kentucky, USA.|Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain.|Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: de Leon
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D003024:Clozapine / Q000009:adverse effects / Q000627:therapeutic use*; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology
chemical_list: D000927:Anticonvulsants; D003024:Clozapine