BACKGROUND: Desvenlafaxine, a serotonin-norepinephrine reuptake inhibitor, has demonstrated efficacy in improving affective symptoms of Major Depressive Disorder (MDD)
however, its effects on associated cognitive and functional difficulties remain underexplored. This study seeks to assess the antidepressant effects of desvenlafaxine in patients with SSRI-resistant MDD, its impact on both objective and subjective cognitive performance, where cognitive improvements occur independently of clinical recovery or not, and its influence on psychosocial functioning. METHODS: An observational case-control prospective study with 66 participants was conducted, including 26 patients with a current MDD episode, with an inadequate SSRI response, and with the prescription of desvenlafaxine as the next antidepressant therapeutic option, and 40 healthy controls. Sociodemographic, clinical, cognitive, and functional assessments were conducted both before and after a 12-week treatment period. Changes were analyzed using two tailed paired-samples t-tests, with Cohen's d for effect sizes. Cognitive improvements were compared between the patients who achieved remission and those who did not. RESULTS: Patients showed significant improvements in depressive and anxiety symptoms, attention/working memory and processing speed, self-perceived cognitive difficulties and psychosocial functioning. Highlighting the fact these cognitive enhancements occurred independently of patients' clinical improvement. CONCLUSIONS: The findings of this study focus on the therapeutic potential of desvenlafaxine, demonstrating its efficacy not only in ameliorating clinical and functional symptoms but also in addressing specific cognitive impairments in patients with depression. Further research is needed to elucidate the mechanisms underlying desvenlafaxine's effects and optimize treatment strategies for individuals with MDD. TRIAL REGISTRATION NUMBER: NCT03432221 (clinical. TRIALS: gov). Registration date: 08-01-2018.