Abstract

NOVEL AND EMERGING THERAPIES FOR DEPRESSION: FROM SSRIs TO PSYCHEDELIC – ASSISTED INTERVENTIONS

*Kalangi Kujitha, B.Venkata Lakshmi, L. Sahana, Dr. M. Tabithasharon, Dr. K. Padmalatha

ABSTRACT

Major depressive disorder (MDD) is one of the most prevalent and disabling psychiatric illnesses worldwide and represents a substantial public health challenge across all age groups. Epidemiological evidence indicates that hundreds of millions of individuals are affected globally, contributing significantly to years lived with disability and loss of productivity.[1,2] Beyond the emotional burden experienced by patients, depression is associated with impaired social functioning, reduced quality of life, increased healthcare utilization, and heightened risk of comorbid medical disorders including cardiovascular disease, diabetes, and chronic pain syndromes.[3] Importantly, depression remains a major risk factor for suicide and premature mortality, further emphasizing the urgency of effective therapeutic strategies.[4] For several decades, pharmacological management has centered primarily on monoaminergic antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin– norepinephrinereuptake inhibitors (SNRIs). Although these medications demonstrate acceptable safety and moderate efficacy, their clinical limitations are well recognized. Delayed onset of action, incomplete remission, and treatment resistance affect a substantial proportion of patients, with nearly one-third failing to achieve adequate response after first-line therapy.[5,7] These shortcomings have prompted reconsideration of the traditional monoamine hypothesis and encouraged exploration of broader neurobiological mechanisms. Recent advances in neuroscience have reframed depression as a disorder involving impaired synaptic plasticity, disrupted neural circuitry within prefrontal–limbic networks, neuroinflammatory activation, hypothalamic–pituitary–adrenal axis dysregulation, and epigenetic influences.[8,10] This expanded understanding has catalyzed the development of innovative interventions that act beyond conventional neurotransmitter modulation. Rapid-acting glutamatergic agents such as ketamine and esketamine, neuromodulation approaches including electroconvulsive therapy and repetitive transcranial magnetic stimulation, and psychedelic-assisted therapies such as psilocybin and MDMA are now being investigated as alternatives or adjuncts, particularly for treatment-resistant depression.[20,36] This review provides a comprehensive and critical synthesis of conventional antidepressant treatments and emerging therapeutic modalities, discussing their mechanisms of action, clinical evidence, safety considerations, and broader public health implications. Collectively, these strategies represent a paradigm shift from slow monoaminergic pharmacotherapy toward rapid, circuit-based, and neuroplasticity-focused approaches that may improve outcomes for individuals with refractory depression.

Keywords: Major depressive disorder, global burden, monoaminergic antidepressants, treatment-resistant depression, synaptic plasticity, neuroinflammation, ketamine/esketamine, neuromodulation/ECT/rTMS, psychedelic-assisted therapy.