title: Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review.
abstract: Approximately 40-70% of treatment-resistant schizophrenic patients fail to benefit from clozapine monotherapy or are partial responders. During the last years several clozapine adjunctive agents have come into clinical practice. This study aims to critically review all published randomized, double-blind, placebo-controlled clinical trials (RCTs) regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. A MEDLINE search for RCTs on clozapine adjunctive agents published from January 1980 to February 2004 was conducted. All identified papers were critically reviewed and examined against several methodological features as well as clinical and pharmacological parameters. Eleven trials including 270 patients, partial or non-responders to clozapine, assessed the efficacy of sulpiride, lithium, lamotrigine, fluoxetine, glycine, d-serine, d-cycloserine and ethyl-eicosapentanoate (E-EPA) as clozapine adjuncts. There were eight parallel-group and three crossover trials. The inclusion criteria varied widely. The duration as well as the dosage of clozapine monotherapy were reported adequate in only one trial. Plasma clozapine levels were assessed in only three trials. Main side-effects reported were hypersalivation, sedation, diarrhea, nausea, hyperprolactinaemia. The outcome favored clozapine augmentation with sulpiride, lamotrigine and E-EPA. Lithium was shown to benefit only schizoaffective patients. However, the methodological shortcomings of trials analyzed limit the impact of evidence provided.
authors.affiliation: Department of Psychiatry, Eginition Hospital, University of Athens, 74 Vas. Sophias Avenue, 11528 Athens, Greece. bkont@cc.uoa.gr
authors.forename: Vassilis P
authors.initials: VP
authors.lastname: Kontaxakis
authors.forename: Panayotis P
authors.initials: PP
authors.lastname: Ferentinos
authors.forename: Beata J
authors.initials: BJ
authors.lastname: Havaki-Kontaxaki
authors.forename: Dimitris K
authors.initials: DK
authors.lastname: Roukas
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use*; D004351:Drug Resistance / Q000502:physiology*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine