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Venlafaxine (Effexor XR)

SNRI • Last reviewed 2025-09-26

General information

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) indicated for major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder. It is widely used as a step-up option when SSRIs are ineffective or poorly tolerated.

Immediate-release tablets (37.5, 75, 100 mg) require thrice-daily dosing, whereas the extended-release capsules/tablets (37.5–225 mg) enable once-daily administration and are the preferred form in psychiatry.

Dose-response relationships are pronounced; higher doses (≥150 mg/day) engage norepinephrine transporters and may improve energy or pain symptoms. However, blood pressure elevations become more common above 225 mg/day.

Patients should be counselled about discontinuation syndrome, especially with missed doses or rapid tapers, and the potential for sweating, nausea, or paresthesias during withdrawal.

Dosing & administration

Start XR 37.5–75 mg once daily; increase by 37.5–75 mg every 4–7 days to a usual target of 150–225 mg/day.

Adjust dose in hepatic impairment (reduce by 50%) and renal impairment (reduce by 25–50% depending on creatinine clearance).

Taper slowly (over ≥2–4 weeks) after sustained remission to minimize discontinuation symptoms.

Mechanism of action

Venlafaxine inhibits serotonin and norepinephrine transporters in a dose-dependent fashion and has minimal affinity for muscarinic, histamine, or adrenergic receptors. Its active metabolite O-desmethylvenlafaxine (desvenlafaxine) contributes substantially to clinical response.

Metabolism & pharmacokinetics

Oral bioavailability is ~45% for immediate-release but approaches 80% for extended-release formulations. Peak concentrations occur 2–8 hours post-dose (XR). Venlafaxine undergoes hepatic metabolism via CYP2D6 (major) and CYP3A4 (minor) to desvenlafaxine, which is renally cleared. Elimination half-life is ~5 hours for venlafaxine and 11 hours for desvenlafaxine; steady state occurs in 3 days.

Drug interactions

Avoid MAOIs, linezolid, or IV methylene blue (risk of serotonin syndrome).

CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) may elevate venlafaxine levels and hypertension risk.

Additive blood pressure or QT effects with sympathomimetics, SNRIs, or antipsychotics warrant monitoring.

Monitoring & safety checks

  • Blood pressure and pulse at baseline, after dose increases, and periodically

  • Assess suicidality, irritability, or manic switch risk

  • Monitor renal/hepatic function for dose adjustments

Discontinuation guidance

Due to short half-life, taper over several weeks. If discontinuation symptoms emerge, reinstate the previous dose and taper more gradually or switch to a longer half-life agent such as fluoxetine for cross-taper support.

References

  1. Venlafaxine Extended-Release Prescribing Information — DailyMed
  2. Venlafaxine in major depressive disorder: Evidence review — Journal of Clinical Psychiatry (2023)
  3. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)

Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.