Fluvoxamine Augmentation of Olanzapine in Chronic Schizophrenia: Pharmacokinetic Interactions and Clinical Effects

Abstract

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

“…While fluvoxamine appears to affect minimally and in a dosedependent manner the elimination of risperidone, it should be pointed out that this agent, already at the dose of 100 mg/day, may cause a significant elevation of plasma concentration of various antipsychotics, such as haloperidol (1.8-4.2-fold increase), clozapine (up to 5-10-fold) and olanzapine (up to 2-fold), due to its potent inhibitory effect on CYP1A2, CYP2C19 and, to a lesser extent, CYP3A4, the major CYP isoforms involved in the biotransformation of these compounds [32][33][34][35].…”

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

“…Improvement was noted in controlled studies in patients treated with SSRI added to typical antipsychotics 9 -12 and in open studies and case reports on SSRI augmentation of atypical drugs (clozapine and olanzapine). [13][14][15][16]18 The response is in negative symptoms primary to the illness, 19 requires a serotonergic mechanism, 12 and can be detected within 2 weeks of starting augmentation. 20 The mechanism of SSRI augmentation is unknown.…”

Chronic treatment with serotonin reuptake inhibitor antidepressant (SSRI) combined with an antipsychotic regulates GABA-A receptor in rat prefrontal cortex

“…SSRIs can increase blood levels of typical antipsychotics (Daniel et al 1994), and there is evidence that fluvoxamine, fluoxetine, and paroxetine can increase levels of clozapine (Wetzel et al 1998;Chang et al 1999;Lammers et al 1999;Lu et al 2000;Spina et al 1998Spina et al , 2000Diaz et al 2008). Fluvoxamine can increase olanzapine levels (Callaghan et al 1999;Hiemke et al 2002), and in this combination, fluvoxamine levels are also increased (Hiemke et al 2002).…”

“…Indeed, successful SSRI augmentation of atypical antipsychotics, which have antiserotonergic activity, is contrary to predictions. Pharmacokinetic interactions with SSRIs can alter levels of antipsychotic drugs (Hiemke et al 2002), but there is no evidence that they can explain the synergistic clinical effectiveness against negative symptoms (see Discussion in (Silver 2001;Silver et al 2003a). However, changes in blood concentrations can influence side effects, so appropriate caution and monitoring in clinical setting is needed when using drug combinations.…”