Low-Dose Fluvoxamine as an Adjunct to Reduce Olanzapine Therapeutic Dose Requirements

Abstract

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.

Olanzapine-Induced Suppression of Cocaine Self-Administration in Rhesus Monkeys

“…Pretreatment with olanzapine completely eliminated cocaine self-administration in three of four subjects, and markedly suppressed responding to less than 10% of control rates in the fourth subject. Effective doses of olanzapine were within the therapeutic dose range for treatment of psychosis in humans (Brown et al, 1999;Albers et al, 2005). In separate experiments, substitution of olanzapine for cocaine failed to maintain self-administration behavior above saline extinction levels in any subject.…”

Simultaneous determination of fluvoxamine isomers and quetiapine in human plasma by means of high-performance liquid chromatography

“…On the other hand, this property can willingly be exploited to reduce the administered doses of some CYP1A2 metabolised substrates. In fact, fluvoxamine at sub-therapeutic doses has recently been used in studies of pharmacoeconomy to reduce the doses of olanzapine administered to psychotic patients and consequently the costs of therapy [6]. Chemical-clinical correlations are always useful to increase the efficacy of therapy and decrease the incidence of side effects: comorbidity, uncertain compliance, evaluation and management of pharmacological interactions are good reasons to carry out the therapeutic drug monitoring (TDM) of psychiatric patients.…”

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

“…Carbamazepine and indinavir also increased the clearance of olanzapine, which is consistent with induction of CYP1A2 and/or UDP-glucuronosyl transferase conjugation enzymes (Lucas et al 1998;Penzak et al 2002). In contrast, a recent study indicated that administration of fluvoxamine (25 mg/day) enabled the dose of olanzapine to be decreased by $25% (Albers et al 2005). Monitoring of serum olanzapine concentrations is recommended during such combination therapy to avoid drug toxicity (Hiemke et al 2002).…”

“…Like clozapine, olanzapine is oxidized by hypochlorous acid -the oxidant utilized by myeloperoxidase -to the corresponding nitrenium ion, but this has a lower toxic potential than the clozapine nitrenium ion. Moreover, the concentrations of olanzapine that are required for reactive metabolite formation are unlikely to be achieved during therapy with the drug (Albers et al 2005); these factors contribute to the relative safety of olanzapine over clozapine.…”