Association of propranolol with treatment-emergent akathisia during aripiprazole treatment.

Abstract

Background and purpose: Akathisia is a common side effect of aripiprazole treatment, which is associated with subjective distress for patients, and represents a frequent cause of treatment discontinuation. Propranolol and other beta-receptor blockers are commonly used for treatment of akathisia. Cytochrome P450 2D6 (CYP2D6) enzyme plays a major role in the metabolism of aripiprazole. Our previous study has shown that CYP2D6 inhibitory activity of beta-blockers (metoprolol and propranolol) may result in elevated aripiprazole plasma concentrations. The objective of the present retrospective study was to assess the prevalence of akathisia in patients receiving propranolol or metoprolol comedication, as well as in those not receiving any CYP2D6 inhibitors such as propranolol, metoprolol, risperidone.

Methods: Using the data of our previous pharmacogenetic study involving 67 patients diagnosed with schizophrenia or schizoaffective disorder and receiving aripiprazole treat- ment, we retrospectively investigated the emergence of akathisia within 6 months following aripiprazole initiation. Information on the onset of akathisia was obtained from patients' medical records. The effects of CYP2D6 genotype, aripiprazole plasma concentration, propranolol and metoprolol comedication on the development of akathisia were analysed. The included patients had already been taking propranolol and metoprolol comedication prior to the initiation of aripiprazole and not for the treatment of akathisia.

Results: Schizophrenia and schizoaffective disorder patients treated with propranolol had a significantly higher incidence of documented akathisia (38,5%) compared to the group not receiving CYP2D6 inhibitors (5.9%), and the group treated with metoprolol comedication (7.1%). Among the CYP2D6 inhibitors, only the administration of propranolol increased the risk of akathisia (Wald Chi2=5.5, p=0.02, OR=7.6 [95% CI=1.4-41.4]). The polymorphic CYP2D6 alleles resulting in low CYP2D6 function showed a statistical trend-level association with the occurrence of 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 of propranolol and CYP2D6 genotypes on the development of akathisia. The interaction model showed that the effect of propranolol was not dependent on CYP2D6 genotype (Wald Chi2=0.1, p=0.92), however, its independent effect remained significant (Wald Chi2=4.4, p=0.04).

Conclusion: Our findings suggest that propranolol comedication increases the risk of the development of akathisia during aripiprazole treatment. It is of paramount importance 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 of patients (80.6%) received antipsychotic combination therapy, which may have influenced the findings. Further prospective studies are needed to confirm these findings based on retrospective, naturalistic analysis about the development of aripiprazole-induced akathisia.