Rethinking Treatment-Resistant Depression: A Systematic Review of Novel Therapeutic Strategies and Precision Medicine Approaches.
Safiye Zeynep Tatlı, Murat İlhan Atagün
Actas espanolas de psiquiatria December 1, 2025 Peer reviewed DOI: 10.62641/aep.v53i6.1946 via PubMed
Summary
Novel interventions such as ketamine, esketamine, psychedelics, and neuromodulation therapies show promise for treating treatment-resistant depression (TRD), which affects patients unresponsive to standard antidepressants. The review emphasizes the importance of personalized treatment strategies, including biomarker-driven and pharmacogenetic approaches, especially for those with TRD who may also fall within the bipolar spectrum. A multidisciplinary approach is essential for optimizing management of this complex condition.
Study at a glance
| Design | systematic review |
|---|---|
| Population | patients with treatment-resistant depression |
| Key finding | Emerging interventions like ketamine and neuromodulation therapies are promising for treating treatment-resistant depression. |
Abstract
Treatment-resistant depression (TRD) is a complex and heterogeneous condition affecting a considerable subset of patients who do not respond to conventional antidepressants. Given the limitations of traditional treatment strategies, there is a growing need for alternative and personalized approaches. This review explores the neurobiological underpinnings of TRD and examines the efficacy of emerging pharmacological and neuromodulatory interventions. We also highlight the potential role of the bipolar spectrum in TRD and the need for tailored treatment strategies. A systematic review of literature from 2015 to 2025 was conducted using PubMed and Scopus. Studies on TRD treatment modalities, including augmentation strategies, mood stabilizers, atypical antipsychotics, and neuromodulation techniques, were analyzed. Our findings indicate that novel interventions, such as ketamine, esketamine, psychedelics, and neuromodulation therapies (e.g., repetitive transcranial magnetic stimulation, magnetic seizure therapy) show promise in addressing TRD. Additionally, biomarker-driven and pharmacogenetic approaches may enhance treatment selection and improve outcomes. Evidence suggests that a subset of patients with TRD could fall within the bipolar spectrum, requiring mood stabilizers and antipsychotics rather than standard antidepressant regimens. A multidisciplinary and precision-based approach is essential for optimizing TRD management. Future research should focus on biomarker-driven treatment selection, artificial intelligence-assisted decision making, and large-scale trials to refine personalized therapeutic strategies.