Abstract

CURRENT AND EMERGING DRUG TARGETS FOR THE TREATMENT OF DEPRESSION: FROM MONOAMINERGIC SIGNALING TO NEUROPLASTICITY

Burlapalle Subhashini*, M. Sudeep, Sneha N., Brunda M. A., Bindu M. A., E. Gopinath

ABSTRACT

Major depressive disorder (MDD) is a prevalent and disabling psychiatric disorder characterized by persistent depressed mood, anhedonia, cognitive impairment, sleep disturbance, altered appetite and impaired psychosocial functioning. Although conventional antidepressants that primarily modulate serotonin, norepinephrine and dopamine remain important therapeutic options, their clinical utility is limited by delayed onset of action, incomplete response, adverse effects and treatment resistance. These limitations have stimulated the development of pharmacological strategies directed toward novel molecular and cellular targets. Recent advances in neurobiology have expanded the therapeutic landscape beyond the classical monoamine hypothesis toward glutamatergic neurotransmission, γ-aminobutyric acid (GABA) signaling, neurotrophic pathways, inflammatory signaling, the hypothalamic-pituitary-adrenal (HPA) axis, opioid receptors, orexin receptors, melatonin receptors, sigma-1 receptors, cholinergic receptors and intracellular pathways associated with synaptic plasticity. The clinical success of ketamine and esketamine has provided strong evidence that modulation of glutamatergic neurotransmission can produce rapid antidepressant effects. Similarly, neuroactive steroid modulation of GABA_A receptors has introduced another mechanistically distinct approach, with brexanolone and zuranolone demonstrating the therapeutic potential of neurosteroid-based interventions. Emerging targets such as kappa-opioid receptors, orexin receptors, sigma-1 receptors, α7 nicotinic acetylcholine receptors, BDNF–TrkB signaling and inflammatory pathways are currently being investigated for their potential to improve efficacy and overcome treatment resistance. This review summarizes established and emerging pharmacological targets for depression, their mechanisms of action, representative drugs, clinical development status and major challenges associated with translation from preclinical research to clinical practice.

Keywords: Major depressive disorder; antidepressants; drug targets; serotonin; glutamate; NMDA receptor; GABA_A receptor; BDNF; TrkB; inflammation; orexin; kappa opioid receptor; neuroplasticity.