Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

Abstract

Augmentation with low-dose fluvoxamine (50-100 mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6 mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150 mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150 mg/day were 120% (95%CI; 114-127%), 139% (95%CI; 130-149%), and 160% (95%CI; 142-178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

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

“…However, improvement in negative symptoms of schizophrenic patients treated with SSRI and haloperidol did not correlate with the increase of antipsychotic levels in plasma. 26,27 Increasing antipsychotic drug levels does not increase the overall efficacy or the range of responsive symptoms, and may have adverse effects. 28 -30 Antidepressant doses used in antidepressant-antipsychotic combinations are usually lower than those used in monotherapy.…”

The effect of chronic co-administration of fluvoxamine and haloperidol compared to clozapine on the GABA system in the rat frontal cortex

“…Recent studies reported that adding a selective serotonin reuptake inhibitor (SSRI) such as fluvoxamine Silver and Nassar, 1992 ;Silver and Shmugliakov, 1998 ;Yasui-Furukori et al, 2004) or fluoxetine (Goff and Evins, 1998) to typical antipsychotics can improve negative symptoms in patients who did not respond to antipsychotics alone. The improvement included key negative symptoms primary to the illness (Silver et al, 2003a) and could be detected as early as 2 wk after treatment onset (Silver et al, 2003c).…”

In the Balance

“…Dose-dependent inhibition of haloperidol metabolism has been described with 150 mg of fluvoxamine resulting in 160% increase in haloperidol levels. 6 It is unlikely that the NMS reaction was precipitated by the increased serum haloperidol level since the oral haloperidol had been discontinued 2 weeks prior to the reaction (elimination halflife 18 hours) and the haloperidol level had likely declined significantly after its discontinuation despite the interaction with fluvoxamine, although a subsequent level was not obtained. In addition, both haloperidol decanoate and fluvoxamine had been prescribed for several months at the same dose prior to the NMS reaction.…”