Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression with Comorbid Autism Spectrum Disorder: Three Case Reports.

Abstract

<h4>Introduction</h4>Major depressive disorder (MDD) is a leading cause of disability worldwide and contributes significantly to the global burden of disease. Recent data show an increasing prevalence of treatment-resistant depression (TRD). Patients with autism spectrum disorder (ASD) often exhibit MDD as a comorbidity and it is often resistant to conventional treatments. ASD determines emotional dysregulation and a reduced ability to understand mental states (mentalization). These features can lead to suicidal ideation and/or behavior. Intranasal esketamine may offer a novel therapeutic option for this population.<h4>Methods</h4>This case series focuses on the clinical response to intranasal esketamine in patients with autism and TRD; esketamine is approved in Italy as an add-on therapy in TRD, so our case study is based on an in-label treatment. Three young patients (<i>n</i> = 3, F/M 2:1, age range 20-25 y) with light to moderate autism (Level 1 or 2) were treated. Esketamine was administered in augmentation with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in accordance with EMA/AIFA guidelines. A structured follow-up protocol was set to monitor depressive symptoms, social cognition, and mentalization. Follow-up during treatment was maintained for six months, and psychometric evaluations were performed at six time points: baseline (T0), 1 week (T1), 1 month (T2), 2 months (T3), 3 months (T4), and 6 months (T5). Also, subjective quality of life was investigated before and after the observation period.<h4>Results</h4>Despite differences in clinical profile, all patients showed good efficacy of esketamine in reducing depressive symptoms: two patients experienced clinical remission at T5 (MADRS < 10), one patient showed partial response (dMADRS = 43.24%). No major side effects were reported. Significant improvements were observed after the first week of treatment (P1: MADRS_T0 = 37, MADRS_T1 = 12; P2: MADRS_T0 = 32, MADRS_T1 = 21; P3: MADRS_T0 = 25, MADRS_T1 = 12). Depressive relapses occurred (e.g., P1, T3-T4), but they were not associated with hospitalizations and/or suicidal attempts. Suicidal ideation, when present, decreased by the end of the follow-up period. Lack of mentalization and in social cognition was noted, with just mild improvements during therapy. Subjective quality of life improved significantly for all patients (P1: 28% at T0, 73% at T5. P2: 25% at T0, 71% at T5. P3: 35% at T0, 80% at T5).<h4>Conclusions</h4>Intranasal esketamine showed a favorable efficacy and safety in these three cases of TRD in comorbidity with ASD (at six months: total remission = 66.66%, partial remission = 33.33%, inefficacy = 0%, drop-out = 0, severe adverse events = 0). Besides improvements in depressive symptoms, esketamine was associated with a constant decrease in suicidal thoughts. A case series is unfit to form statistical conclusions; preliminary data warrant further investigation in randomized controlled studies to validate the therapeutic potential of esketamine in this population.

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