Venlafaxine

Indications

• FDA-approved as the extended-release capsule for major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder.
• The immediate-release tablet is approved for major depressive disorder only, dosed two or three times daily at 75-225 mg/day.
• Off-label for post-traumatic stress disorder, where it has positive randomized trial data and appears in VA/DoD guidance as an option.
• Off-label for neuropathic pain, fibromyalgia, and diabetic peripheral neuropathy, though duloxetine carries the actual pain indications.
• Off-label for vasomotor symptoms of menopause at 37.5-150 mg/day, a common choice for breast cancer survivors on tamoxifen.
• Off-label for ADHD and for migraine prophylaxis, both supported only by small trials and generally used after first-line options fail.

Mechanism of action

• Inhibits the serotonin transporter potently at all doses and the norepinephrine transporter progressively as the dose rises above 150 mg/day.
• Below 75 mg/day it behaves essentially as an SSRI, which is why partial responders often improve when the dose is pushed higher.
• Noradrenergic engagement at higher doses adds energy, focus, and analgesia but also drives sweating, tachycardia, and rising blood pressure.
• Very weak dopamine transporter inhibition emerges only near the top of the dose range and contributes little to clinical effect.
• Free of muscarinic, histaminic, and alpha-1 blockade, so its adverse effects are almost entirely monoaminergic rather than receptor-blocking.

Pharmacokinetics

• Well absorbed with extensive first-pass metabolism; food slightly delays but does not reduce absorption of either formulation.
• Venlafaxine has a short 5 hour half-life and its equipotent active metabolite O-desmethylvenlafaxine about 11 hours.
• That short half-life is why the extended-release form is preferred and why missed doses so reliably provoke withdrawal symptoms.
• CYP2D6 converts venlafaxine to O-desmethylvenlafaxine, so poor metabolizers carry a higher parent-to-metabolite ratio and more side effects.
• Protein binding is low at about 27 percent and roughly 87 percent of a dose is recovered in urine, so renal impairment raises exposure.

Dosing

• Start the extended-release capsule at 37.5 mg PO daily with food for four to seven days, then increase to 75 mg/day.
• Titrate by up to 75 mg at intervals of no less than four days; the usual outpatient maximum is 225 mg/day of the extended-release form.
• Immediate-release tablets are divided two or three times daily, with up to 375 mg/day used only in severely depressed inpatients.
• Reduce the total daily dose by 25 to 50 percent in renal impairment and by about 50 percent in hepatic impairment.
• Available as 37.5, 75, and 150 mg ER capsules, 37.5 to 225 mg ER tablets, and 25 to 100 mg immediate-release tablets.
• Taper over at least four weeks, and often much longer from higher doses, because abrupt withdrawal is severe and sometimes intolerable.

Adverse effects

• Nausea affects roughly 30 percent early on, along with headache, insomnia, dry mouth, dizziness, and dose-related sweating.
• Sustained diastolic hypertension is dose-dependent, uncommon below 150 mg/day and reported in about 13 percent above 300 mg/day.
• Sexual dysfunction is at least as frequent as with SSRIs and includes reduced libido, delayed ejaculation, and anorgasmia.
• Discontinuation syndrome with dizziness, electric-shock sensations, nausea, and irritability begins within a day of a missed dose.
• Overdose is more dangerous than with SSRIs, with seizures, QRS widening, and cardiotoxicity reported at high ingested doses.
• Hyponatremia, mydriasis with angle-closure glaucoma, increased bleeding, and treatment-emergent mania are the other serious concerns.

Monitoring

• Check blood pressure at baseline, two weeks after each dose increase, and at least quarterly once the dose exceeds 150 mg/day.
• Treat or reduce the dose if sustained diastolic elevation develops, since the hypertension is dose-related and largely reversible.
• Assess suicidality, activation, and agitation weekly for four weeks and after every dose change, most closely in patients under 25.
• Check serum sodium at baseline and within two to four weeks in older adults or diuretic users, and whenever confusion develops.
• Track response with the PHQ-9, GAD-7, or PCL-5 every two to four weeks and use partial response as the trigger for dose escalation.

Interactions

• Contraindicated with MAOIs and within 14 days of stopping one, and with linezolid or intravenous methylene blue.
• Strong CYP2D6 inhibitors such as bupropion, fluoxetine, and paroxetine raise the parent-to-metabolite ratio and worsen tolerability.
• Additive serotonin syndrome risk with triptans, tramadol, fentanyl, lithium, and St. John's wort; watch for clonus and hyperthermia.
• Additive hypertensive and tachycardic effects with stimulants, and additive bleeding risk with aspirin, NSAIDs, and anticoagulants.
• Not a meaningful CYP inhibitor itself, so venlafaxine rarely raises levels of other drugs the way paroxetine or fluoxetine do.

Special populations

• Cohort data in pregnancy show no clear teratogenic signal, but third-trimester exposure carries neonatal adaptation and pulmonary hypertension risk.
• Relative infant dose in breast milk is about 6 to 9 percent, higher than sertraline, so monitor the infant if breastfeeding continues.
• Not approved in pediatrics, and pediatric depression trials showed increased hostility and suicidality without clear efficacy.
• In older adults start at 37.5 mg/day and monitor blood pressure and sodium closely, since both risks increase with age.
• Reduce the dose by 25 to 50 percent when creatinine clearance is under 30 mL/min and by half in moderate to severe hepatic impairment.

Clinical pearls

• Below 75 mg/day it is effectively an SSRI; noradrenergic effects need doses above 150 mg/day.
• Check blood pressure at every dose step above 150 mg/day, since hypertension is dose-related.
• Never stop abruptly. Cross-taper to fluoxetine if withdrawal makes a direct taper impossible.