Association of propranolol with treatment-emergent akathisia during aripiprazole treatment

Menus, Ádám and Kiss, Ádám and Csukly, Gábor and Bitter, István and Monostory, Katalin and Réthely, János M. (2025) Association of propranolol with treatment-emergent akathisia during aripiprazole treatment. IDEGGYOGYASZATI SZEMLE / CLINICAL NEUROSCIENCE, 78 (11-12). pp. 395-404. ISSN 0019-1442

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Abstract

Background and purpose – Akathisia is acommon side effect of aripiprazole treatment, which is associated with subjective distress for patients, and represents a frequentcause of treatment discontinuation. Propranolol and other beta-receptor blockers arecommonly used for treatment of akathisia.Cytochrome P450 2D6 (CYP2D6) enzymeplays a major role in the metabolism of aripiprazole. Our previous study has shown thatCYP2D6 inhibitory activity of beta-blockers(metoprolol and propranolol) may result inelevated aripiprazole plasma concentrations.The objective of the present retrospective study was to assess the prevalence ofakathisia in patients receiving propranolol ormetoprolol comedication, as well as in thosenot receiving any CYP2D6 inhibitors such aspropranolol, metoprolol, risperidone.Methods – Using the data of our previouspharmacogenetic study involving 67 patientsdiagnosed with schizophrenia or schizoaffective disorder and receiving aripiprazoletreatment, we retrospectively investigated theemergence of akathisia within 6 months following aripiprazole initiation. Information onthe onset of akathisia was obtained from patients’ medical records. The effects of CYP2D6genotype, aripiprazole plasma concentration,propranolol and metoprolol comedication onthe development of akathisia were analysed.The included patients had already been takingpropranolol and metoprolol comedicationprior to the initiation of aripiprazole and notfor the treatment of akathisia.Results – Schizophrenia and schizoaffectivedisorder patients treated with propranolol had a significantly higher incidence ofdocumented akathisia (38,5%) compared tothe group not receiving CYP2D6 inhibitors(5.9%), and the group treated with metoprolol comedication (7.1%). Among the CYP2D6inhibitors, only the administration of propranolol increased the risk of akathisia (WaldChi2=5.5, p=0.02, OR=7.6 [95% CI=1.4-41.4]).The polymorphic CYP2D6 alleles resultingin low CYP2D6 function showed a statisticaltrend-level association with the occurrenceof akathisia (Wald Chi2=2.6, p=0.11, OR=4.7[95% CI=0.7-30.8]). In a subsequent analysis,we investigated the possible interaction ofpropranolol and CYP2D6 genotypes on thedevelopment of akathisia. The interactionmodel showed that the effect of propranololwas not dependent on CYP2D6 genotype(Wald Chi2=0.1, p=0.92), however, its independent effect remained significant (WaldChi2=4.4, p=0.04).Conclusion – Our findings suggest thatpropranolol comedication increases therisk of the development of akathisia duringaripiprazole treatment. It is of paramountimportance to avoid propranolol comedication during aripiprazole treatment. However,two major limitations should be considered:akathisia was not assessed using a standardized clinical rating scale, and the majority ofpatients (80.6%) received antipsychotic combination therapy, which may have influencedthe findings. Further prospective studiesare needed to confirm these findings basedon retrospective, naturalistic analysis aboutthe development of aripiprazole-inducedakathisia.

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