SNRIs

When an SSRI isn't enough for a patient's depression and chronic pain, SNRIs add norepinephrine reuptake inhibition — but that second mechanism brings a unique risk profile you need to know.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) block reuptake of both serotonin and norepinephrine, increasing their availability in the synapse. Venlafaxine is dose-dependent: at lower doses (75 mg/day) it acts primarily on serotonin; at higher doses (≥150 mg/day) norepinephrine blockade kicks in. Duloxetine inhibits both transporters across its dosing range. The dual mechanism makes SNRIs first-line for depression with comorbid chronic pain conditions — duloxetine carries FDA indications for diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain. Venlafaxine is also indicated for generalized anxiety disorder, social anxiety disorder, and panic disorder. The norepinephrine component elevates blood pressure, so monitor BP at baseline and regularly throughout therapy — venlafaxine causes sustained hypertension in roughly 3–13% of patients at higher doses. Both drugs require gradual tapering; abrupt discontinuation triggers a withdrawal syndrome (dizziness, nausea, paresthesias, irritability, "brain zaps") that is especially severe with venlafaxine due to its short half-life. Duloxetine is hepatically metabolized and contraindicated in patients with substantial alcohol use or pre-existing hepatic impairment. Full therapeutic effects take 4–6 weeks.

Key Distinctions

Don't confuse SNRIs with SSRIs — SSRIs lack norepinephrine activity and don't raise blood pressure or treat neuropathic pain. Students forget that venlafaxine's norepinephrine effect is dose-dependent, so low-dose venlafaxine essentially functions like an SSRI. Duloxetine's hepatotoxicity risk is unique among antidepressants — always screen for liver disease and alcohol use before initiating.

Clinical Pearl

BP check before every refill conversation — the 'N' in SNRI stands for norepinephrine, and norepinephrine raises blood pressure. No taper, no stopping: brain zaps are the penalty.