Abstract
Treatment-resistant depression (TRD), defined as the failure to achieve adequate response to at least two antidepressant trials, affects 20-30% of patients with major depressive disorder and poses substantial personal and socioeconomic burdens. This review aimed to synthesize current knowledge on the genetic, epigenetic, and neurobiological underpinnings of TRD to understand its pathophysiology better and inform future treatment strategies. A systematic search identified relevant studies focusing on genetic predispositions, epigenetic modifications, structural and functional brain alterations, the role of chronic inflammation, and deficits in neuroplasticity and neurogenesis associated with TRD. Findings highlight the involvement of polymorphisms in genes regulating neurotransmission, neuroplasticity, and stress response, though replication across studies remains inconsistent. Genome-wide association studies suggest polygenic contributions but are limited by small sample sizes and heterogeneous definitions of TRD. Emerging evidence points to aberrant DNA methylation, histone modifications, and dysregulated non-coding RNAs as potential mediators of treatment resistance. Neuroimaging studies reveal TRD-specific patterns, particularly altered default mode network connectivity and white matter disruptions, supporting its distinction as a subtype of depression. Collectively, the evidence underscores TRD as a multifactorial condition shaped by genetic and neurobiological factors, while emphasizing the need for standardized definitions, larger cohorts, and longitudinal designs to advance the field.