From the Guidelines
Fluoxetine can significantly increase serum levels of haloperidol, and therefore, caution should be exercised when co-administering these medications, with consideration of reducing the haloperidol dose and close monitoring for adverse effects. The interaction between fluoxetine and haloperidol is attributed to fluoxetine's inhibitory effect on the CYP2D6 enzyme, which is responsible for metabolizing haloperidol 1. When initiating fluoxetine in a patient already taking haloperidol, consider reducing the haloperidol dose by approximately 25-30% and monitor closely for signs of increased side effects such as sedation, extrapyramidal symptoms, QTc prolongation, or other adverse reactions. Some key points to consider when co-administering fluoxetine and haloperidol include:
- The full inhibitory effect of fluoxetine on haloperidol metabolism may take several weeks to develop due to fluoxetine's long half-life and active metabolite (norfluoxetine) 1.
- This interaction is particularly important in patients who are CYP2D6 poor metabolizers or elderly patients who may be more sensitive to elevated haloperidol levels.
- Regular monitoring of haloperidol serum levels, if available, can help guide dosage adjustments.
- The interaction may persist for weeks after fluoxetine discontinuation due to the long elimination half-life of fluoxetine and its metabolite, so continued monitoring is necessary even after stopping fluoxetine. Key considerations for managing this interaction include:
- Close monitoring for adverse effects
- Potential dose reduction of haloperidol
- Awareness of the prolonged duration of the interaction after fluoxetine discontinuation
- Consideration of alternative medications or therapies if necessary.
From the FDA Drug Label
Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine.
Fluoxetine may increase serum levels of haloperidol due to a possible pharmacodynamic and/or pharmacokinetic interaction.
- Key points:
- Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine.
- Caution is advised when coadministering fluoxetine with antipsychotics, including haloperidol.
- Consideration should be given to using lower initial doses of haloperidol and monitoring of clinical status when coadministered with fluoxetine 2
From the Research
Fluoxetine's Effect on Serum Levels of Haloperidol
- The effect of fluoxetine on serum levels of haloperidol has been studied in several research papers 3, 4, 5.
- A study published in 1996 found that the addition of fluoxetine to haloperidol decanoate treatment resulted in a significant increase in haloperidol concentrations (more than 100%) two weeks after the addition of fluoxetine 4.
- Another study published in 1997 found that mean plasma concentrations of haloperidol increased significantly from 6.5 +/- 2.4 nmol l-1 at baseline to 8.8 +/- 3.6 nmol l-1 at week 12 of fluoxetine treatment 5.
- However, this increase in haloperidol levels was not associated with an increase in mean extrapyramidal side effects score on the Simpson and Angus Scale 5.
- A study published in 2022 found that there are no long-term studies on fluoxetine to provide a dose correction factor for its effect on haloperidol levels 3.
- The mechanism of the interaction between fluoxetine and haloperidol is thought to be due to fluoxetine's inhibition of cytochrome P450 (CYP) 2D6, which is involved in the metabolism of haloperidol 5.
Clinical Implications
- The interaction between fluoxetine and haloperidol may have clinical implications, particularly in terms of the risk of QT prolongation and torsades de pointes 6, 7.
- However, the evidence suggests that the risk of QT prolongation associated with fluoxetine is relatively low, and that fluoxetine is not typically associated with an increased risk of sudden cardiac death 6, 7.
- Nevertheless, patients receiving fluoxetine and haloperidol should be monitored for signs of QT prolongation and cardiac arrhythmias, particularly if they have underlying cardiovascular disease or are taking other medications that may increase the risk of QT prolongation 7.