Treatment-resistant depression: Current therapeutic strategies
Samuel Cândido Freres, Marco Antonio Franco Cançado, Aline Ferreira Catrolio, Vanderli Barbosa Amaecing, Rodolfo Nunes Mendes Da Cunha, Sharie Lohanna de Moraes Nascimento
International Health Sciences Review August 18, 2026 DOI: 10.70164/ihsr.v2i4.208 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Topics | Depression |
| Key findings | The review reports that treatment-resistant depression involves monoaminergic and glutamatergic alterations, reduced neuroplasticity, inflammation, neuroendocrine dysfunction, and genetic factors, which may explain limited response to conventional antidepressants. It describes ketamine and esketamine as producing rapid antidepressant response in selected cases, and argues that management should be individualized, evidence-based, and multidisciplinary, aiming at remission, functional recovery, and improved quality of life. |
Abstract
Treatment-resistant depression (TRD) represents one of the most complex forms of major depressive disorder, characterized by the persistence of clinically significant symptoms despite the performance of appropriate therapeutic interventions. This condition is associated with a worse prognosis, higher risk of recurrence, functional impairment, increased morbidity and mortality, and high socioeconomic impact. The objective of this article was to review the main aspects related to ESRD, addressing its definition, diagnostic criteria, epidemiology, pathophysiological mechanisms, and currently available therapeutic strategies. A narrative review of the literature was carried out, including national and international studies that discuss advances in the management of resistant depression. It is observed that the pathophysiology of ESRD involves alterations in mon oaminergic and glutamatergic neurotransmission, reduced neuroplasticity, inflammatory processes, neuroendocrine dysfunctions, and genetic factors, justifying the limited efficacy of conventional antidepressants in some patients. Current therapeutic strategies include optimization and combination of antidepressants, pharmacological potentiation, use of atypical antipsychotics, lithium, and thyroid hormones, as well as innovative therapies such as ketamine and esketamine, which demonstrate rapid antidepressant response in selected cases. It is concluded that the management of ESRD should be individualized, based on up-to-date scientific evidence, and integrated with multidisciplinary approaches, aiming at symptom remission, functional recovery, and improvement of patients' quality of life.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |