Repeated intranasal esketamine augmentation in treatment-resistant obsessive-compulsive disorder with comorbid major depressive disorder: a prospective case series

Patients with obsessive–compulsive disorder (OCD) and comorbid major depressive disorder (MDD) represent a severe subgroup with increased treatment resistance, greater functional impairment, and limited therapeutic options. Intranasal esketamine is a rapidly acting treatment for resistant depression, with emerging interest in potential anti-obsessional effects. However, prospective data in this comorbid population remain lacking. We present eight adult cases (mean age 47.3 ± 8.8 years) with treatment-resistant OCD (TR-OCD) and comorbid MDD treated at Bellvitge University Hospital. All patients had failed at least two adequate SSRI trials, clomipramine, cognitive-behavioral therapy with exposure and response prevention, and at least one pharmacological augmentation strategy. Intranasal esketamine (56–84 mg/session) was administered according to the standard antidepressant protocol over 12 weeks. Response was defined as ≥ 35% reduction in Y-BOCS and ≥ 50% reduction in MADRS. Depressive symptoms improved substantially, with MADRS scores decreasing by 48.8% at Week 12 (p = 0.0026). Obsessive-compulsive symptoms showed a more modest and heterogeneous reduction, with a 30.3% decrease in Y-BOCS scores (p = 0.0037). Four of the eight participants (50.0%) achieved depression response, including two (25.0%) remissions, and four of the eight participants (50.0%) met OCD response criteria. Depressive symptoms improved earlier, whereas OCD symptoms followed a slower and more variable trajectory. Repeated intranasal esketamine may offer a therapeutic window for patients with severe TR-OCD and comorbid MDD. These preliminary findings support further controlled studies to clarify its role, optimal administration, and integration with psychotherapy.