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First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are less than 50%. The authors examine the putative biological substrates underlying Treatment Refractory Depression (TRD) with the goal of elucidating novel rationales to treat TRD.We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin (5-HT) system becomes impervious to the desired enhancement of 5-HT neurotransmission by SSRI’s. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe.We propose, based on a body of translational studies, TRD may not represent a simple 5-HT deficit state but rather an excess of midbrain peri-raphe 5-HT and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in 5-HT-mediated neuroplasticity. Glutamate, 5-HT, noradrenaline and histamine are activated by stress and exert an inhibitory effect on 5-HT outflow, in part by flooding 5-HT1A autoreceptors by 5-HT itself. Certain factors putatively exacerbate this scenario- presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder- each of which has been associated with SSRI-treatment resistance.By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing 5-HT neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for stacked interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on 5-HT neurons. Future studies are recommended to test this biologically based approach for TRD.