Sex differences in response to intranasal oxytocin as an adjunctive therapy for patients with severe mental illness

•Oxytocin as add-on therapy may reduce depression and anxiety in severe mental illness.•INOT shows sex-specific benefits, improving outcomes mainly in females.•Females on INOT had greater reductions in depressive symptoms and distress than males.•More research needed on INOT's varied effects in clinical populations. Studies investigating the potential benefits of intranasal oxytocin (INOT) as an add-on treatment for patients with severe mental illness (SMI) have yielded inconsistent results, potentially due to sex differences in response to INOT. This study explored the differential effects of INOT among male and female patients with SMI. A secondary analysis was conducted on a previously studied group of patients who participated in a double-blind, placebo-controlled trial evaluating the impact of INOT as an add-on treatment for patients with SMI. Patients treated in inpatient settings (N = 87) received twice-daily INOT (32IU) or placebo (PLC) for a period of four weeks. Sex moderated the effect of OT/PLC on the Hamilton Rating Scale for Depression (HRDS) (p < 0.001). A significant effect for sex was found in the Hopkins Symptom Checklist–short form (HSCL-11) (p = 0.04) and HRDS (p < 0.001), with females showing greater reductions in anxiety and depression symptoms and severity. This effect was not found for males. We conclude that the addition of INOT to the treatment of patients with SMI in an inpatient setting was beneficial for female patients, particularly reducing depressive symptoms, but not for male patients. Future studies should aim to identify patients who are more likely to benefit from INOT administration.