Antidepressants and cognitive function in major depressive disorder: Mechanisms, clinical evidence, and implications for precision treatment.

Cognitive impairment is a core feature of major depressive disorder (MDD) and significantly impairs functional recovery. This review summarizes current evidence on the effects of antidepressants on cognitive function and discusses the underlying mechanisms. Antidepressants may exert their effects through multiple mechanisms, including modulation of monoaminergic neurotransmission, enhancement of neuroplasticity, and regulation of stress and inflammatory pathways. Available studies indicate that antidepressants differ in their cognitive benefits, with vortioxetine showing the most consistent procognitive evidence. Duloxetine, bupropion, and some augmentation strategies may also improve specific cognitive domains, though the evidence is limited. Importantly, cognitive improvement may result from direct drug effects on cognition or indirectly via alleviation of depressive symptoms, highlighting the need for mediation analyses in future research. In patients with late-life depression, vortioxetine and duloxetine have shown relatively clear benefits, and augmentation with cognitive enhancers has demonstrated some potential. The long-term cognitive protective effects of antidepressants remain unconfirmed. Immuno-metabolic depression subtypes, high-dose-related adverse effects, and comorbidity with anxiety and sleep disorders may constitute important sources of residual cognitive deficits. Emerging treatments such as ketamine, psychedelic compounds, and interventions targeting the gut-brain axis may offer new opportunities for addressing cognitive dysfunction in MDD. Current evidence is limited by small sample sizes and heterogeneous cognitive assessments. Future research should prioritize large, randomized controlled trials with cognition as the primary endpoint, using standardized assessment tools. A better understanding of the cognitive profiles and mechanisms of antidepressants may support precision medicine strategies and promote functional recovery in patients with MDD.