Mechanisms of Selective Serotonin Reuptake Inhibitors in Treatment-Resistant Obsessive-Compulsive Disorder: Cortico-Striatal Circuitry, Glutamatergic Dysregulation, and Neuroplastic Constraints.

Obsessive-compulsive disorder (OCD) is a chronic and disabling neuropsychiatric condition for which selective serotonin reuptake inhibitors (SSRIs) remain the first-line pharmacological treatment. Despite their widespread use, a substantial proportion of patients fail to achieve adequate symptom remission following appropriately dosed and prolonged SSRI therapy, highlighting the clinical challenge of treatment-resistant OCD. Traditional serotonin-centric models do not fully account for delayed therapeutic onset, incomplete response, or the frequent need for pharmacological augmentation. This review synthesizes current evidence examining the neurobiological mechanisms underlying SSRI response and resistance in OCD, with a particular focus on cortico-striato-thalamo-cortical (CSTC) circuit dysfunction, glutamatergic imbalance, and impaired neuroplasticity. The review discusses how SSRIs exert indirect effects on excitatory-inhibitory balance, synaptic remodeling, and intracellular signaling pathways, and why these downstream processes may fail in treatment-resistant individuals. Emerging roles of glutamatergic dysregulation, intracellular plasticity signaling deficits, and neuroinflammatory constraints are integrated into a unified mechanistic framework. The present review advances a conceptual framework in which treatment-resistant OCD may involve constraints on neuroplastic adaptation, such that serotonergic modulation alone is insufficient to induce durable circuit-level recalibration in a subset of patients. This model offers a potential biological rationale for augmentation strategies targeting dopaminergic, glutamatergic, and plasticity-related pathways, and underscores the need for mechanism-based, personalized therapeutic approaches. By reframing SSRI efficacy and failure at the circuit and systems level, this review aims to inform future translational research and guide more effective treatment strategies for refractory OCD.