{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T15:21:12Z","timestamp":1773415272674,"version":"3.50.1"},"reference-count":24,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinics and Practice"],"abstract":"<jats:p>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 behavior. Intranasal esketamine may offer a novel therapeutic option for this population. Methods: 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 (n = 3, F\/M 2:1, age range 20\u201325 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. Results: Despite differences in clinical profile, all patients showed good efficacy of esketamine in reducing depressive symptoms: two patients experienced clinical remission at T5 (MADRS &lt; 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\u2013T4), 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). Conclusions: 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.<\/jats:p>","DOI":"10.3390\/clinpract16030061","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T11:12:25Z","timestamp":1773400345000},"page":"61","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression with Comorbid Autism Spectrum Disorder: Three Case Reports"],"prefix":"10.3390","volume":"16","author":[{"given":"Alessandro","family":"Guffanti","sequence":"first","affiliation":[{"name":"Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Department of Mental Health and Addiction Services, Azienda Socio-Sanitaria Territoriale di Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3930-5923","authenticated-orcid":false,"given":"Matteo","family":"Leonardi","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, 20157 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3128-1592","authenticated-orcid":false,"given":"Natascia","family":"Brondino","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Department of Mental Health and Addiction Services, Azienda Socio-Sanitaria Territoriale di Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernardo","family":"Dell\u2019Osso","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, 20157 Milan, Italy"},{"name":"\u201cAldo Ravelli\u201d Centre for Neurotechnology and Brain Therapeutic, University of Milan, 20143 Milan, Italy"},{"name":"Department of Psychiatry and Behavioural Sciences, Bipolar Disorders Clinic, Stanford University, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3344-1000","authenticated-orcid":false,"given":"Vassilis","family":"Martiadis","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Azienda Sanitaria Locale Napoli 1 Centro, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0914-0539","authenticated-orcid":false,"given":"Miriam","family":"Olivola","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, 20157 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"ref_2","unstructured":"World Health Organization (2025, August 29). 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