Glutamatergic Resonance and Dopaminergic Stability: Intranasal Esketamine in Treatment-Resistant Depression with Comorbid ADHD and Autism Spectrum Disorder – A Case Report
M. C. Angeletti, K. La Monica, V. Casati, G. Versaci, T. Prodi, F. Mazzoni, A. Guffanti, N. Brondino, V. Martiadis, R. Anniverno, B. M. Dell’Osso, M. OlivolaIntroduction
Treatment-resistant depression (TRD) represents a major clinical challenge, particularly in the presence of neurodevelopmental comorbidities such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Both conditions complicate illness trajectories and may limit the efficacy of conventional pharmacological strategies. Recent evidence suggests that intranasal esketamine, through modulation of glutamatergic neurotransmission and indirect stabilization of dopaminergic circuits, may constitute a novel therapeutic approach.
Objectives
To describe the clinical effects, safety profile, and potential neurobiological implications of intranasal esketamine in a patient with TRD and comorbid ADHD and ASD.
Methods
We report the case of a 24-year-old female with major depressive disorder unresponsive to multiple antidepressants and augmentation strategies, who presented with persistent depressive symptoms, severe functional impairment, and marked suicidality. She also met diagnostic criteria for ADHD and ASD. The patient was treated at the Esketamine Outpatient Clinic of Macedonio Melloni Hospital (ASST Fatebenefratelli Sacco, Milan) , where intranasal esketamine was administered according to approved TRD protocols, with close clinical monitoring. Outcome measures included standardized rating scales for depression, suicidality, and global functioning. Particular attention was devoted to the evolution of ADHD- and ASD-related symptomatology, with a focus on emotional regulation, attentional control, and social reciprocity.
Results
A rapid reduction in depressive symptoms and suicidality was observed within the first weeks, with progressive functional recovery over subsequent sessions. Symptomatic improvement extended beyond mood, encompassing emotional regulation, attentional control, and social interaction, suggesting a broader modulatory effect on glutamatergic–dopaminergic networks. The treatment was well tolerated; transient dissociative symptoms occurred early but resolved spontaneously without discontinuation. No major adverse events were reported.
Image 1: Long description.