venlafaxine

General Information

Venlafaxine (Effexor XR) is an SNRI with dose-dependent norepinephrine activity, commonly selected for comorbid anxiety or pain syndromes in serious mental illness.

Extended-release formulations dominate due to once-daily dosing and improved tolerability compared with immediate-release tablets.

The contrast view and the venlafaxine evidence feed can help compare activation, blood pressure, and sexual side effects alongside condition hubs (e.g., bipolar disorder) when planning augmentation or cross-taper strategies.

The highest-yield practical issues are blood pressure monitoring and discontinuation planning; missed doses and rapid tapers can trigger significant withdrawal symptoms.

Care transitions are a common source of withdrawal risk; verifying formulation, dose, and refill continuity can prevent abrupt interruption.

Monitor blood pressure and withdrawal risk; counsel on adherence and gradual tapering to avoid discontinuation syndrome.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Serotonin reuptake inhibition across clinical doses; norepinephrine reuptake inhibition emerges ≥150 mg/day; very weak dopamine reuptake inhibition at high doses.

• SERT and NET inhibitor with minimal muscarinic/histamine/α1 affinity.

Metabolism and Pharmacokinetics

• XR Tmax 5.5–9 h; protein binding ~27%.
• Metabolized via CYP2D6 (major) and CYP3A4 to active O-desmethylvenlafaxine.
• Half-life ~11 h (XR); active metabolite ~10–13 h; eliminated renally (87% as parent/metabolites).
• Renal and hepatic impairment both increase exposure; dose reductions and slower titration are common when tolerability limits continuation.

Dosing and Administration

• Initiate XR 37.5 mg once daily with food for 4–7 days, then 75 mg/day; increase by 75 mg increments at ≥7-day intervals up to 225 mg/day (300 mg off-label).
• Reduce total daily dose 25–50% in renal or hepatic impairment.
• Taper gradually over several weeks to prevent discontinuation symptoms.
• If discontinuation symptoms emerge during tapering, slower dose reductions over longer intervals are often better tolerated than larger step-downs.

Monitoring & Labs

• Blood pressure and heart rate at baseline and after titration, with extra attention at higher doses.
• Discontinuation symptoms during missed doses or tapering; plan refill timing and taper steps proactively.
• Sodium in older adults or diuretic users if symptoms suggest hyponatremia (confusion, fatigue, falls).
• Mood elevation or agitation in bipolar-spectrum illness; coordinate prevention plans via the bipolar disorder hub.
• Medication reconciliation to avoid serotonergic combinations and to plan MAOI washouts when regimens change.

Venlafaxine has a short half-life; adherence and taper planning often matter more than the exact starting dose for day-to-day tolerability. Blood pressure checks and predictable tapers prevent avoidable problems during dose changes and missed doses in many patients overall too.

Adverse Effects

Interactions

• CYP2D6/3A4 substrates—strong inhibitors (fluoxetine, paroxetine, ritonavir) can raise concentrations; monitor for hypertension or adverse effects.
• Contraindicated with MAOIs; observe 7-day washout before starting an MAOI.
• Additive bleeding risk with NSAIDs, antiplatelets, anticoagulants.
• Use caution with other serotonergic agents (SSRIs, triptans, tramadol, linezolid, St. John’s wort) that can raise serotonin-syndrome risk.

Other Useful Information

• Encourage once-daily dosing with food to reduce GI upset.
• Consider desvenlafaxine if CYP2D6 interactions limit dosing.
• Set expectations that benefit builds over weeks; early side effects are often earlier than mood improvement and may improve with supportive care.

References

1. Venlafaxine Hydrochloride Extended Release Capsules Prescribing Information — DailyMed (2024)
2. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)
3. Comparative efficacy and acceptability of 21 antidepressant drugs for major depressive disorder — The Lancet (2018)Meta-analysisdepressionefficacy