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This is a combination therapy involving mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), with a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine or duloxetine. Mirtazapine acts primarily as an antagonist at central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors, increasing noradrenergic and serotonergic neurotransmission. It also antagonizes 5-HT2 and 5-HT3 receptors, which may reduce certain side effects of SSRIs/SNRIs. SNRIs inhibit the reuptake of both serotonin and norepinephrine by blocking their respective transporters, thereby increasing synaptic concentrations of these neurotransmitters. The rationale for combining these agents is to achieve additive or synergistic effects on monoaminergic transmission in treatment-resistant depression; however, large randomized controlled trials have not demonstrated significant clinical benefit over monotherapy but have shown increased adverse effects[1][2][3][6].
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