Cognitive Flexibility Deficits as Predictors of Treatment Resistance in Major Depressive Disorder
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Background: Major depressive disorder (MDD) is frequently accompanied by cognitive dysfunction, and impaired cognitive flexibility may be associated with poorer treatment response. Evidence regarding this relationship in Pakistani clinical populations remains limited. Objective: To determine whether baseline cognitive-flexibility impairment was associated with treatment-resistant depression (TRD) among adults with MDD. Methods: A retrospective observational study analyzed 186 psychiatric records from tertiary-care settings in Lahore, Pakistan. Adults aged 18–60 years with MDD, baseline cognitive or executive-function assessment, antidepressant treatment records, and at least 12 weeks of follow-up were included. Cognitive flexibility was categorized as preserved, mildly impaired, or significantly impaired using available neuropsychological and clinical documentation. TRD was defined as inadequate response to at least two adequate antidepressant trials. Associations were examined using chi-square testing and binary logistic regression adjusted for age, gender, and illness duration. Results: Overall, 88/186 patients (47.3%) met criteria for TRD. TRD occurred in 23.5% of patients with preserved flexibility, 35.9% with mild impairment, and 74.6% with significant impairment (χ²(2)=36.18, p<0.001). Significant impairment was associated with greater adjusted odds of TRD (OR=3.80, 95% CI: 2.10–6.70; p<0.001). Conclusion: Greater baseline cognitive-flexibility impairment was associated with treatment resistance in MDD, although prospective studies using standardized cognitive assessment are required before clinical predictive use
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