Depression in Autism Spectrum Disorder: Neurobiological Convergence and Emerging Therapeutic Strategies

The high comorbidity between autism spectrum disorder (ASD) and major depressive disorder (MDD) represents a complex and heterogeneous clinical challenge. Although elevated rates of depression in autistic individuals are well documented, the neurobiological and psychosocial mechanisms underlying this overlap remain debated, particularly in adulthood. This review synthesizes convergent evidence from genetics, monoaminergic and glutamatergic neurotransmission, neuroinflammatory signaling, hypothalamic–pituitary–adrenal axis dysregulation, large-scale brain network alterations, and gut–brain axis modulation to clarify the biological and psychosocial pathways contributing to ASD–depression comorbidity. In addition to shared neurobiological vulnerability, cumulative environmental stressors such as chronic social masking, stigma, and structural barriers may amplify depressive risk across the lifespan. We propose a hypothesis-generating framework that integrates these findings into a mechanistic stratification model, linking dominant biological profiles to targeted therapeutic hypotheses. Within this preliminary model, plant-derived compounds and microbiota-targeted interventions are hypothesized to serve as promising adjunctive strategies, particularly in neuroinflammatory and stress-related subtypes, complementing established pharmacological and neuromodulatory treatments. By moving beyond descriptive overlap toward biologically informed stratification, this review aims to support precision-guided and neurodiversity-affirming approaches for the assessment and treatment of depression in autistic individuals, especially adults who bear a disproportionate burden of mood disorders. This narrative review is based on a structured literature search conducted in PubMed, Scopus, and Web of Science using combinations of keywords such as “autism spectrum disorder,” “major depressive disorder,” “neuroinflammation,” and “gut–brain axis.