Molecular Mechanisms of Emerging Antidepressant Strategies: From Ketamine to Neuromodulation

Depression is a common, debilitating, and potentially life-threatening mental disorder affecting individuals across all age groups and populations. It represents one of the major challenges of contemporary medicine. It is estimated that more than 300 million people worldwide are affected, and patients with major depressive disorder (MDD) exhibit a significantly increased risk of suicide, underscoring the urgent need for effective and long-lasting therapeutic strategies. Growing evidence indicates that the pathophysiology of depression involves a complex interplay of genetic vulnerability, chronic stress, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity, collectively contributing to symptom heterogeneity and treatment resistance. In this review, we synthesize data derived from PubMed, Google Scholar, and ClinicalTrials.gov databases concerning pharmacological and non-pharmacological treatment strategies, with particular emphasis on their cellular and molecular mechanisms of action. We present currently used classes of antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), discussing their limitations in the context of contemporary pathophysiological models of depression. We then focus on emerging therapies targeting the glutamatergic, GABAergic, and dopaminergic systems, including ketamine, esketamine, (R)-ketamine, the dextromethorphan–bupropion combination (DMX–BUP), neurosteroids (zuranolone, brexanolone), as well as selective serotonin receptor modulators (gepirone ER) and dopaminergic modulators (cariprazine). The review is complemented by a discussion of non-pharmacological neuromodulatory approaches, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and photobiomodulation. Rather than providing another summary of clinical response indicators, this article integrates the molecular underpinnings of novel antidepressant agents and neuromodulation techniques with current concepts of depression pathophysiology, highlighting their relevance for the development of precise, mechanistically targeted, and multimodal treatment strategies.