Neurobiological mechanisms and recent advances in drug-based therapeutics in depression

Depression is a multifaceted mental disorder with significant global prevalence, with diverse pathophysiological mechanisms and pathways. Neurobiological foundations of depression, including serotonergic, noradrenergic, dopaminergic, cholinergic, glutamatergic, and GABAergic neurotransmitter systems, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and inflammatory pathways are explored in this review. We aim to explore drug-based therapeutics, outlining the shortcomings of current treatments, such as delayed efficacy and treatment-resistant depression (TRD). Additionally, the existing medication often has side effects, and the unclear guidelines on which drugs to prioritize for particular cases hinder the effective use of antidepressants. Groundbreaking drug delivery systems, such as nanoparticles, intranasal administration, and non-invasive procedures including focused ultrasound (FUS) and transcranial magnetic stimulation (TMS), are outlined as promising strategies to enhance drug bioavailability and target-specific brain regions, often by overcoming the blood-brain barrier (BBB), thereby achieving improved therapeutic outcomes. By emphasizing nanotechnology and biomarker diagnostics, the review presents these tools as transformative technologies in depression treatment, paving the way for personalized treatments, provided that challenges, including nanoparticle biocompatibility and scalable manufacturing, are addressed. Additionally, this review offers an integrative perspective by connecting neurobiological mechanisms with innovative drug delivery and diagnostic technologies, providing a conceptual framework for future personalized antidepressant strategies.