The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review

RATIONALE: 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).

OBJECTIVES: 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.