Increased Anticholinergic Agent Use With Co-prescription of CYP2D6-Inhibiting SSRIs and Risperidone, but not...

Co-prescription of selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics is common in the management of schizophrenia. However, the real-world clinical impact of cytochrome P450 (CYP)-mediated drug-drug interactions (DDIs) remains unclear. We investigated whether the co-prescription of risperidone or aripiprazole with SSRIs that differ in their CYP2D6 inhibition potential is associated with an increased burden of extrapyramidal symptoms (EPS).

Using the Korean National Health Insurance Service database (2002-2022), we identified 4100 patients with schizophrenia who were treated with one of four medication combinations: risperidone plus escitalopram (Risp+Esc; n = 1611), risperidone plus fluoxetine/paroxetine (Risp+CYP2D6i; n = 1051), aripiprazole plus escitalopram (Arip+Esc; n = 1025), or aripiprazole plus fluoxetine/paroxetine (Arip+CYP2D6i; n = 413). The primary outcome was the mean proportion of days covered (PDC) by anticholinergic agents, used as a proxy for EPS burden. Groups were compared using multivariate analysis of covariance, adjusting for confounders.

The Risp+CYP2D6i group had a significantly higher mean PDC for anticholinergics compared with the Risp+Esc group (56.4% vs. 47.3%; F = 23.98, P < .0001). Conversely, no significant difference was observed between the Arip+CYP2D6i and Arip+Esc groups (26.1% vs. 28.6%; F = 1.47, P = .225). The use of zolpidem and mood stabilizers was also significantly higher in both CYP2D6i groups.

Co-prescription of strong CYP2D6-inhibiting SSRIs with risperidone, but not aripiprazole, is associated with a significant increase in anticholinergic use, providing large-scale, real-world evidence of a clinically meaningful DDI. These findings underscore the importance of considering SSRI metabolic profiles to mitigate EPS risk in patients treated with risperidone.