KETAMINE IN THE TREATMENT OF DEPRESSION - A REVIEW ARTICLE

Depression involves neurotransmitter dysregulation, HPA axis hyperactivity, neuroinflammation, and impaired neuroplasticity. While first-line treatment combines psychotherapy and pharmacotherapy, about 30% of patients develop treatment-resistant depression (TRD). Subanesthetic intravenous or intranasal ketamine produces rapid antidepressant effects within hours, reduces suicidal ideation, and enhances synaptic connectivity through AMPA receptor, BDNF, and mTOR signaling. Ketamine-assisted psychotherapy (KAP) leverages this neuroplastic window to consolidate cognitive and emotional restructuring. Intranasal esketamine has received FDA and EMA approval as adjunctive therapy for TRD. Ketamine is generally well-tolerated, though patient selection, monitoring, and safety protocols are essential. Further large-scale, randomized studies are needed to optimize protocols and understand long-term efficacy.

Study at a glance

Abstract

Background: Depression is a multifactorial disorder involving neurotransmitter dysregulation, HPA axis hyperactivity, neuroinflammation, and impaired neuroplasticity. While combination psychotherapy and pharmacotherapy remains first-line, ~30% of patients develop TRD. In the last few years ketamine has emerged as a rapid-acting therapeutic option for treatment-resistant cases. Aim: To review the etiology, treatment options, and emerging interventions for major depressive disorder (MDD), with a particular focus on treatment-resistant depression (TRD) and the therapeutic potential of ketamine and ketamine-assisted psychotherapy (KAP). Methods: A comprehensive literature review was conducted, analyzing 29 studies from the PubMed database (English-language, up to October 2025) that assess the etiology, treatment options of depression with emphasis on the therapeutic role of ketamine, especially in treatment-resistant depression (TRD). Results: Subanesthetic intravenous or intranasal ketamine produces rapid antidepressant effects within hours, reduces suicidal ideation, and enhances synaptic connectivity through AMPA receptor, BDNF, and mTOR signaling. KAP leverages this neuroplastic window to consolidate cognitive and emotional restructuring. Intranasal esketamine has received FDA and EMA approval as adjunctive therapy for TRD. Ketamine is generally well-tolerated, though patient selection, monitoring, and adherence to safety protocols are essential. Conclusions: Ketamine and KAP represent transformative interventions for TRD, offering rapid symptom relief and potential enhancement of psychotherapeutic outcomes. Further large-scale, randomized studies are required to optimize treatment protocols, understand long-term efficacy, and determine the additive benefits of psychotherapy.