Augmentation strategies in depression are employed when a patient has an inadequate response to an adequate trial of first-line antidepressant monotherapy (typically an SSRI or SNRI at therapeutic dose for at least 6-8 weeks). Treatment-resistant depression (TRD) is defined as failure to achieve remission after two or more adequate antidepressant trials. The neurobiological rationale for augmentation rests on the understanding that depression involves dysregulation of multiple neurotransmitter systems beyond serotonin alone. The monoamine hypothesis (deficiency of serotonin, norepinephrine, and/or dopamine) explains only partial treatment response. Augmentation targets additional pathways: lithium augmentation enhances serotonergic neurotransmission by increasing presynaptic tryptophan uptake and serotonin synthesis, while also inhibiting glycogen synthase kinase-3 (GSK-3) and modulating BDNF (brain-derived neurotrophic factor) signaling, which promotes neuroplasticity. Atypical antipsychotic augmentation (aripiprazole, quetiapine, brexpiprazole) works through partial dopamine D2 agonism (aripiprazole) or 5-HT2A antagonism combined with serotonin reuptake inhibition (quetiapine via its active metabolite norquetiapine). Thyroid hormone (T3) augmentation potentiates noradrenergic and serotonergic transmission, as T3 receptors are co-expressed with monoamine neurons in the limbic system. Glutamatergic agents (esketamine/ketamine) represent a paradigm shift, acting as NMDA receptor antagonists that...