Therapeutic Potential of Ketamine in Major Depressive Disorder: Pharmacological Insights and Clinical Evidence

Major depressive disorder (MDD) is one of the leading causes of disability globally, and conventional monoaminergic antidepressants often have a slow onset and limited efficacy. About onethird of patients suffer from treatment-resistant depression (TRD), which emphasizes the urgent need for alternative therapies. This review aims to systematically evaluate the available data about ketamine's involvement in depression, with particular attention to its pharmacological properties, modes of action, clinical effectiveness, safety profile, and potential as a next-generation antidepressant treatment.

The databases ScienceDirect and PubMed/MEDLINE were searched extensively for relevant literature. Ketamine's pharmacodynamics, clinical results, safety, and mechanistic insights in Major depressive disorder (MDD) and treatment-resistant depression (TRD) were all investigated in eligible studies. Particular focus was given to its reported side effects and molecular mechanisms.

The FDA's 2019 clearance of intranasal esketamine further cemented the paradigm shift in treatment for treatment-resistant depression (TRD), which has been revolutionized by ketamine's ability to provide quick and long-lasting symptom relief. A strong neurobiological cascade underlies its therapeutic impact: NMDA receptor antagonistic action causes glutamate-AMPA activation to spike, which in turn activates the BDNF-mTORC1 signalling pathway, promoting fast synaptogenesis and reversing neuronal atrophy in the prefrontal cortex. Although dissociative side effects and cardiovascular risks now limit clinical use, the field is moving toward next-generation drugs like (2R,6R)-hydroxynorketamine. In order to create safer and more easily accessible rapid-acting antidepressants, these metabolites seek to eliminate the negative psychoactive character of ketamine while using its transformative neuroplasticity.

When conventional treatments are ineffective for treating treatment-resistant depression, ketamine offers quick and strong results, marking a paradigm change in psychiatric care. To optimise longitudinal dosage regimens, assess long-term safety profiles, and develop next-generation analogues that maintain neuroplastic benefits while reducing side effects, further investigation is necessary.