Major Depressive Disorder (MDD) is a common and serious mental disorder characterized by symptoms such as depressed mood, loss of interest, sleep and appetite disturbances, fatigue, guilt, concentration difficulties, and thoughts of death or suicide. Accor ding to the World Health Organization, depression is the leading cause of disability worldwide, affecting more than 300 million people. The existence of various mechanisms underlying depression, including the interplay of genetic, environmental, and neurobiological factors, results in the heterogeneous nature of depressive behavior with potentially unpredictable responses to available pharmacological, neuromodulatory, and psychotherapeutic treatment methods. Despite multiple and properly administered antide pressant therapies, on average, one third of patients fail to achieve sustainable remission. Treatment resistant depression (TRD) is most commonly described as a subtype of depression where a satisfactory therapeutic response is absent after two consecutive appropriate treatments with antidepressants of different classes. Among traditional pharmacological methods that include optimization, replacement, and augmentation of antidepressants with monoaminergic mechanisms of action, augmentation with lithium, tr iiodothyronine (T3), or atypical antipsychotics has shown the greatest effectiveness. Electroconvulsive therapy (ECT) is the gold standard in the treatment of severe cases of refractory depression that do not respond to antidepressant therapy. Depletion of traditional therapeutic approaches has prompted research into new neuromodulatory and pharmacological treatment methods aimed at achieving rapid and sustainable relief of symptoms. Neuromodulatory methods, through the stimulation of specific brain regions involved in depression, induce changes in their activity and function. The most promising new pharmacological approaches include reducing glutamatergic transmission activity through NMDA and mGlu 5 receptor antagonists, influencing the opioid system through κ receptor antagonists, and the use of hallucinogenic tryptamine derivatives. The only registered treatment for TRD is the NMDA receptor antagonist, S ketamine, but additional therapies such as second generation antipsychotics, specific nutritional, anti inflammatory, and neuroprotective agents also show promising results. The aim of this review is to describe and explore the mechanisms, modes of action, effects, and safety levels of n ovel therapeutic options for treatment resistant depression, with a fo cus on deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and ketamine therapy.