Insulin resistance (IR) plays a significant role in the pathophysiology of comorbid type 2 diabetes mellitus (T2DM) and depression (CDD) through multifaceted mechanisms, including dysregulation of insulin signaling (both central and peripheral), neuroendocrine disturbances (hypothalamic-pituitary-adrenal axis dysfunction and monoaminergic neurotransmission impairment), chronic inflammation, oxidative stress, disruption of the microbiota-gut-brain axis, reduced brain-derived neurotrophic factor levels, and altered synaptic plasticity. These IR-related pathways may predispose individuals to depressive symptoms or exacerbate existing mood disorders. A comprehensive understanding of these mechanisms is critical for developing integrated therapeutic strategies that concurrently target metabolic and psychiatric dysfunction. Antidepressant medications exhibit divergent effects on glucose metabolism. Tricyclic antidepressants, particularly amitriptyline and nortriptyline, worsen metabolic profiles by exacerbating IR, promoting weight gain, and inducing hyperglycemia, thereby increasing diabetes risk with prolonged use. Consequently, tricyclic antidepressants should be avoided in metabolically vulnerable populations unless alternatives are unavailable. Mirtazapine presents a paradoxical profile-while its appetite-stimulating effects often lead to weight gain (a known IR risk factor), some evidence suggests potential β-cell function preservation, necessitating cautious use of mirtazapine in individuals with metabolic syndrome. Among selective serotonin reuptake inhibitors, fluoxetine and escitalopram demonstrate favorable metabolic effects, including improved insulin sensitivity and glycemic control, though hypoglycemia risk (particularly with concomitant sulfonylureas) warrants monitoring. Bupropion, a norepinephrine-dopamine reuptake inhibitor, uniquely promotes weight loss and enhances glycemic control, making it a preferred option for depression comorbid with obesity or T2DM. Agomelatine, with its neutral metabolic profile and circadian rhythm-modulating properties, represents a safer alternative for patients with metabolic concerns. Concurrently, certain antidiabetic agents show promise in managing depression. Metformin and sodium-glucose cotransporter-2 inhibitors may be prioritized for diabetic patients at risk for depression, while glucagon-like peptide-1 receptor agonists appear particularly beneficial for obesity-related mood disturbances. Thiazolidinediones offer value in treatment-resistant cases, whereas insulin secretagogues should be used cautiously in psychiatrically vulnerable individuals. Future research should prioritize three key directions: (1) Mechanistic investigations using advanced neuroimaging to elucidate the contribution of IR to depressive phenotypes and evaluate novel interventions (such as intranasal insulin); (2) Precision medicine approaches incorporating biomarkers, including genetic polymorphisms, inflammatory markers, and gut microbiome signatures, to optimize antidepressant selection and develop personalized treatment algorithms; and (3) Therapeutic innovation, including dual GLP-1/GIP agonists and anti-inflammatory-antidepressant combinations, as well as integrating digital health technologies (e.g., continuous glucose monitoring coupled with mood tracking), will enable real-time, data-driven management. These advances will be instrumental in establishing integrated care paradigms for this comorbidity, which intertwines metabolic and psychiatric conditions.
