esketamine + selective serotonin reuptake inhibitor + serotonin-norepinephrine reuptake inhibitor

Esketamine + selective serotonin reuptake inhibitor (SSRI) + serotonin-norepinephrine reuptake inhibitor (SNRI) describes a **combination therapy** used for the treatment of **treatment-resistant depression (TRD)** in adults. Esketamine is the S-enantiomer of ketamine and acts primarily as an antagonist at the N-methyl-D-aspartate (NMDA) receptor, which leads to rapid antidepressant effects. SSRIs increase serotonin concentrations in the synaptic cleft by inhibiting its reuptake, while SNRIs inhibit reuptake of both serotonin and norepinephrine, modulating neurotransmitter levels involved in mood regulation. Clinical studies have shown that esketamine, administered as a nasal spray (most commonly as the brand Spravato), in combination with either an SSRI or SNRI, provides significant clinical benefit in TRD patients who have not responded to at least two previous antidepressants. The combination may reduce the risk of depressive relapse and hospitalization, with each pairing having distinct clinical advantages (e.g., reduced suicide attempts with SSRI, lower mortality and relapse with SNRI) [1][2][3][5]. The combination is approved in the US, UK, and other countries as a prescription therapy for TRD when standard antidepressants have failed.