Drug-Drug Interaction Signals for Sexual Dysfunction with Antidepressants and Antipsychotics: A Pharmacovigilance-Pharmacodynamic Study

Objective: Sexual dysfunction is a common adverse event associated with antidepressants and antipsychotics, yet its risk during combination therapy remains unclear.This study evaluated sexual dysfunction signals associated with antidepressant-antipsychotic combinations using the FDA Adverse Event Reporting System (FAERS) and explored potential pharmacodynamic mechanisms.Methods: A pharmacovigilance-pharmacodynamic analysis of the FAERS database covering the fourth quarter of 1997 through the first quarter of 2022 was conducted.Combinations of antidepressants (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors) with seven antipsychotics (aripiprazole, brexpiprazole, cariprazine, olanzapine, quetiapine, risperidone, and ziprasidone) were evaluated.Drug-drug interaction signals were assessed using five frequency statistical models ( shrinkage, additive, multiplicative, combination risk ratio, and chi-square).The association between antipsychotic receptor occupancy and sexual dysfunction was analyzed using a linear regression model.Results: In total, 15,808,026 reports were analyzed.Drug-drug interaction signals for desire-related sexual dysfunction were detected for the SSRI-brexpiprazole combination in four algorithms ( shrinkage, additive, multiplicative, and chi-square).Linear regression analysis showed that the desire-related sexual dysfunction signal values were positively associated with 5-HT1A receptor occupancy ( = 0.082, p = 0.008, R 2 = 0.782).Conclusion: Brexpiprazole augmentation of SSRIs may be associated with desire-related sexual dysfunction.The findings also suggest a potential association between 5-HT1A receptor occupancy and desire-related sexual dysfunction.As this study used a hypothesis-generating design based on spontaneous reporting data, further epidemiological studies are warranted.