Rethinking Treatment-Resistant Depression: A Systematic Review of Novel Therapeutic Strategies and Precision Medicine Approaches.

Treatment-resistant depression (TRD) affects many people who do not get better with standard antidepressants. This review of studies from 2015 to 2025 finds that newer treatments such as ketamine, esketamine, psychedelics, and neuromodulation therapies like repetitive transcranial magnetic stimulation and magnetic seizure therapy show promise. Some patients with TRD may actually have a bipolar spectrum condition and respond better to mood stabilizers and antipsychotics. Using biomarkers and pharmacogenetics could help choose the right treatment for each person. A multidisciplinary, personalized approach is needed to improve outcomes for TRD.

Study at a glance

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.