MODERN STRATEGIES FOR THE TREATMENT OF TREATMENT-RESISTANT DEPRESSION – A LITERATURE REVIEW

Treatment-resistant depression affects many people with major depressive disorder who do not achieve remission with standard antidepressants. This review examines current and emerging strategies, including medication combinations, neuromodulation, and psychedelic-assisted therapies. Ketamine, esketamine, and psilocybin show promise for non-responders. Future approaches may repurpose drugs like lurasidone, pioglitazone, and minocycline for new mechanisms and better tolerability. A personalized, evidence-based, multidimensional treatment plan is emphasized to improve short-term response and long-term recovery.

Study at a glance

Abstract

Treatment-resistant depression (TRD) remains a major therapeutic challenge in psychiatry, affecting a substantial proportion of individuals diagnosed with major depressive disorder and contributing significantly to the overall burden of mental illness. Despite decades of research and the availability of numerous antidepressant agents, many patients fail to achieve full remission, which underscores the urgent need for more effective interventions. This review provides a comprehensive and up-to-date analysis of both established and novel strategies for the management of TRD, encompassing pharmacological augmentation approaches, a variety of neuromodulation techniques, the clinical application of psychedelic- assisted therapies, and the development of innovative compounds currently under investigation. Particular emphasis is placed on the therapeutic potential and clinical outcomes associated with ketamine, esketamine, and psilocybin, which have emerged as promising options for patients who do not respond to conventional treatments. In addition, the review explores future directions in TRD management, including the repurposing of agents such as lurasidone, pioglitazone, and minocycline, which may offer new mechanisms of action and improved tolerability. Finally, the discussion highlights the importance of adopting a personalized, evidence-based, and multidimensional treatment approach, with the goal of improving both short-term response rates and long-term functional recovery in individuals suffering from TRD.