In a patient taking risperidone, does adding fluvoxamine 100 mg increase risperidone plasma concentrations?

Fluvoxamine 100mg Does Not Significantly Affect Risperidone Levels

Fluvoxamine at 100 mg/day does not cause clinically significant changes in risperidone plasma concentrations and can be safely co-administered without dose adjustment of risperidone. 1

Evidence for No Interaction at 100mg Daily

The most direct evidence comes from a prospective pharmacokinetic study in 11 schizophrenic patients stabilized on risperidone 3-6 mg/day. When fluvoxamine 100 mg/day was added for 4 weeks:

• Mean plasma concentrations of risperidone, 9-hydroxyrisperidone, and the active moiety (combined risperidone + 9-hydroxyrisperidone) showed no significant changes 1
• The combination was well tolerated with no extrapyramidal side effects developing 1
• No dose adjustment of risperidone was required 1

Dose-Dependent Effect: Higher Fluvoxamine Doses May Increase Risperidone Levels

When fluvoxamine was increased to 200 mg/day in a subset of patients, risperidone active moiety concentrations increased by a mean of 26% (P < 0.05), suggesting a dose-dependent inhibitory effect on CYP2D6 and/or CYP3A4-mediated metabolism of risperidone 1. This indicates that:

• At 100 mg/day: No clinically significant interaction 1
• At 200 mg/day: Modest but statistically significant increase in risperidone levels 1

Mechanism and Clinical Context

Fluvoxamine is a potent inhibitor of CYP1A2 and moderately inhibits CYP2C19, CYP2C9, CYP3A4, and CYP2D6 2, 3. Risperidone is metabolized primarily by CYP2D6 to its active metabolite 9-hydroxyrisperidone 1. However, at the 100 mg dose, fluvoxamine's inhibitory effect on these enzymes is insufficient to produce clinically meaningful changes in risperidone pharmacokinetics 1.

Important Safety Caveat: Neurotoxic Syndrome Risk

While the pharmacokinetic interaction is minimal at 100mg, there is a documented case report of a severe neurotoxic syndrome (overlapping features of neuroleptic malignant syndrome and serotonin syndrome) when risperidone and fluvoxamine were combined 4. The patient developed:

• Confusion, diaphoresis, diarrhea, hyperreflexia, and myoclonus progressing to rigidity, fever, and unresponsiveness requiring intubation 4
• Symptoms resolved over 10 days with medication discontinuation, hydration, and bromocriptine 4

Monitor closely for signs of serotonin syndrome—confusion, agitation, tremor, clonus, hyperreflexia, muscle rigidity, and autonomic instability—especially within 24-48 hours after initiating the combination 3. This pharmacodynamic risk exists independent of the pharmacokinetic interaction.

Practical Algorithm

For patients on stable risperidone therapy:

1. Fluvoxamine 100 mg/day can be added without risperidone dose adjustment 1
2. Monitor for neurotoxic symptoms (not drug levels) in the first 24-48 hours 3, 4
3. If fluvoxamine dose exceeds 100 mg/day, consider monitoring for increased risperidone effects and potential dose reduction of risperidone 1
4. If increasing to 200 mg/day fluvoxamine, anticipate approximately 26% increase in risperidone levels 1