Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the reuptake of both serotonin (5-HT) and norepinephrine (NE) by blocking their respective presynaptic transporters (SERT and NET). The dual monoamine mechanism provides broader therapeutic effects than SSRIs alone. At lower doses, most SNRIs primarily inhibit serotonin reuptake; norepinephrine reuptake inhibition increases at higher doses (dose-dependent NE effect). The norepinephrine component adds efficacy for pain conditions, energy/motivation, and concentration. Available SNRIs have distinct pharmacological profiles guiding selection: Venlafaxine — primarily serotonergic at <150 mg/day; NE reuptake inhibition becomes significant at ≥150 mg/day; metabolized by CYP2D6 to active metabolite desvenlafaxine (O-desmethylvenlafaxine). Desvenlafaxine — the active metabolite; flat dose-response (50 mg effective); minimal CYP450 interactions (advantage in polypharmacy). Duloxetine — balanced SERT/NET inhibition; FDA-approved for MDD, GAD, diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain, and stress urinary incontinence (Europe); inhibits CYP2D6 (drug interaction concern). Milnacipran/levomilnacipran — most norepinephrine-selective SNRI; milnacipran FDA-approved only for fibromyalgia (not depression in US); levomilnacipran approved for MDD.