title: The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review.
abstract: BACKGROUND
  New clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC).
  
  
  OBJECTIVE
  This study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine.
  
  
  METHODS
  MEDLINE, Embase, and the Cochrane Library were searched with the search terms "clozapine" and "fluvoxamine" without any time limit. Language was restricted to English, Scandinavian, Polish, and German. Studies were sorted for relevance based on title and abstract. Clinical recommendations of potential indications/effects were graded as level A, B, C, or D depending on studies of high, moderate, low, or very low quality, respectively.
  
  
  RESULTS
  Based on data from 24 case reports/series, seven cohort studies, and two randomized controlled trials, 241 patients were studied. Evidence (A) supported that adjunctive fluvoxamine increased clozapine plasma levels. This may increase the probability of response in patients, where sufficient clozapine plasma levels cannot be achieved. Adjunctive fluvoxamine reduced metabolic adverse effects of clozapine (B) but not agranulocytosis risk (B). Although depressive or obsessive-compulsive symptoms may improve, a SSRI with no CYP1A2 inhibition should rather be used (C). No studies investigated the effect of adjunctive fluvoxamine to minimize clozapine rebound psychosis (D) or to reduce the effects of smoking on clozapine plasma levels (D).
  
  
  CONCLUSIONS
  Adjunctive fluvoxamine may have clinical potentials for optimizing clozapine treatment but further clinical studies are warranted to explore the clinical implications.
authors.affiliation: Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Polcwiartek
authors.affiliation: Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark. jin@rn.dk.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. jin@rn.dk.
authors.forename: Jimmi
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003024:Clozapine / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D016666:Fluvoxamine / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy* / Q000523:psychology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D003024:Clozapine; D016666:Fluvoxamine
keywords: Adjunctive treatment; Adverse effects; Clozapine; Drug-drug interaction; Fluvoxamine