Background: Tricyclic antidepressants (TCAs) have historically played a central role in treating depression but are often overshadowed by newer antidepressants due to their side effect profiles. However, TCAs remain a valuable option, particularly for patients with treatment-resistant depression (TRD), where other medications fail to achieve symptom remission. Objective: This study aims to evaluate the efficacy of TCAs in resolving treatment-resistant depression by analyzing clinical outcomes in patients unresponsive to multiple antidepressants. Methods: This case report includes 100 participants diagnosed with major depressive disorder (MDD) who failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Participants were divided into two groups: Group A received Amitriptyline (75 mg/day), and Group B received Nortriptyline (50 mg/day), added to their existing treatment regimens. Clinical outcomes were measured using the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI) over a 6-month period. Machine learning models were used to analyze treatment success and predict key outcome factors. Results: Both groups demonstrated significant improvement in depressive symptoms. HDRS scores decreased from a mean baseline of 24.28 to 12.44, and BDI scores from 29.36 to 12.93 across all participants. Machine learning analysis identified 6-month HDRS and BDI scores as the most significant predictors of treatment success, with age and baseline scores contributing less significantly. Conclusion: TCAs, specifically Amitriptyline and Nortriptyline, show substantial efficacy in treating treatment-resistant depression, particularly in patients who do not respond to newer antidepressants. These findings suggest that TCAs remain a viable treatment option in modern psychiatric practice, though their side effects require careful management. Future studies should explore personalized treatment strategies to optimize TCA use in TRD cases.
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