COMPARATIVE EFFICACY OF ELECTROCONVULSIVE THERAPY, KETAMINE, AND OTHER PHARMACOLOGICAL APPROACHES REGARDING NEUROBIOLOGICAL ADAPTATIONS IN TREATMENT RESISTANCE

Abstract

Introduction:Treatment-resistant depression (TRD) is defined by the persistence of depressive symptoms despite at least two adequate trials with different classes of antidepressants. Limitations of traditional monoaminergic drugs have driven the search for rapid-acting, innovative interventions such as ketamine and electroconvulsive therapy (ECT), which target neuroplasticity and the glutamatergic system. Objective: To evaluate the comparative efficacy of ketamine and ECT in TRD, analyzing their effects on rapid clinical response, suicidal ideation reduction, neuroplasticity, and neurobiological adaptations. Methodology: This is an integrative literature review based on systematic searches in PubMed and SciELO databases using strategic keywords. Original articles and reviews published between 2020 and 2025 addressing the efficacy, safety, and neurobiological mechanisms of ketamine and ECT were selected and critically analyzed. Results: Evidence highlights major limitations of monoaminergic monotherapies, showing reduced remission rates in STAR*D. The ELEKT-D trial demonstrated non-inferiority of ketamine compared to ECT in non-psychotic depression, with a response rate of 55.4% versus 41.2% and faster initial symptom relief. Both modalities significantly reduced acute suicidal ideation. However, ECT maintained superiority in severe and psychotic presentations. Safety profiles differed: ketamine was linked to transient dissociative effects, whereas ECT caused higher rates of headache, myalgia, and temporary cognitive impairment. Both treatments converge on BDNF upregulation, mTORC1 activation, and adenosine-mediated purinergic signaling. Discussion: Findings confirm that TRD encompasses distinct endophenotypes. Psychotic symptoms favor ECT indication, whereas non-psychotic TRD responds preferentially to glutamatergic modulation. Increasing relapse rates over six months underscore the necessity of structured maintenance protocols. Conclusion: Ketamine and ECT are non-competitive, complementary therapeutic tools. Treatment decisions must be individualized based on clinical phenotypes, taking into account severity, tolerability, psychotic features, and long-term maintenance strategies.