Do selective serotonin reuptake inhibitors enhance post-stroke recovery beyond mood? An updated, narrative mini-review

Stroke remains a leading cause of long-term disability worldwide, and selective serotonin reuptake inhibitors (SSRIs), beyond their established role in treating post-stroke depression, have been investigated for potential neurorestorative effects through modulation of neuroplasticity, cortical excitability, and synaptic remodeling. This narrative mini-review summarizes the current clinical evidence on the use of SSRIs for motor recovery, cognitive recovery, and global functional outcomes after stroke. Early small-scale studies, particularly with fluoxetine, suggested improvements in motor performance and neurophysiological markers of plasticity, generating interest in a possible disease-modifying role. However, subsequent large multicenter randomized controlled trials failed to demonstrate benefits on global functional outcomes and instead reported an increased risk of adverse events, including fractures, falls, seizures, and hyponatremia. Evidence for other SSRIs remains limited, heterogeneous, and largely inconclusive. The observed discrepancy between mechanistic plausibility and neutral clinical outcomes may reflect limitations in outcome sensitivity, patient heterogeneity, differences in stroke subtypes, and suboptimal alignment between biological targets and clinical endpoints. Overall, current data do not support the routine use of SSRIs as neurorestorative agents in non-depressed stroke patients. Future research should focus on biomarker-guided patient selection, optimized timing of intervention, and the use of domain-specific outcome measures more closely aligned with neuroplasticity mechanisms, in order to clarify whether serotonergic modulation may have a selective, context-dependent role in post-stroke recovery.