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

INTRODUCTION 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 behaviour. Intranasal Esketamine, approved for TRD, may offer a novel therapeutic option for this population. METHODS Our study evaluates the clinical response to intranasal Esketamine in patients with autism and TRD. The sample was composed of three young patients (n=3, F/M 2:1, age range 20-25 y) with light to moderate autism (Level 1 or 2). Esketamine was administered in augmentation with Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). 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. RESULTS Despite differences in clinical profile, all patients showed good efficacy of Esketamine in reducing depressive symptoms: two patients experienced clinical remission (MADRS decrease > 50% from T0 to T5), while one patient showed partial remission (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 in mentalization and in social cognition were 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). CONCLUSIONS Intranasal Esketamine showed a favourable efficacy and safety profile 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. The small sample size doesn’t allow us to formalize statistical conclusions; preliminary data warrant further investigation in larger and randomized control studies to validate the therapeutic potential of Esketamine in this population.