This thesis explores the pharmacological management of Major Depressive Disorder (MDD), with a special focus on novel treatment agents beyond traditional monoaminergic approaches. While SSRIs, SNRIs, and other first-line antidepressants remain standard, their delayed onset and limited effectiveness in treatment-resistant depression (TRD) underscore the need for alternative therapies. The central focus is on ketamine, a fast-acting NMDA receptor antagonist, and psilocybin, a serotonergic psychedelic, both of which show promise in modulating neuroplasticity and alleviating depressive symptoms. Their mechanisms, efficacy, safety profiles, and regulatory challenges are discussed in detail. The thesis also critically examines how the dominance of the antidepressant pharmaceutical market may inhibit innovation. Finally, the work emphasizes a shift toward mechanism-based, personalized treatment strategies to address the complexity of MDD.