Introduction
Venlafaxine Extended-Release (ER) is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant medication approved by the FDA in 1997. It is structurally unrelated to other antidepressants and represents an important therapeutic option for multiple psychiatric and neurological conditions. The extended-release formulation allows for once-daily dosing, improving patient adherence while maintaining therapeutic efficacy.
Mechanism of Action
Venlafaxine exerts its pharmacological effects by potently inhibiting the reuptake of both serotonin (5-HT) and norepinephrine (NE) in the central nervous system. It is considered a dual reuptake inhibitor with approximately 30-fold greater potency for serotonin reuptake inhibition compared to norepinephrine at lower doses, with more balanced inhibition occurring at higher doses (>150 mg/day). The drug has negligible affinity for muscarinic, histaminergic, or adrenergic receptors, which contributes to its side effect profile.
Indications
FDA-approved indications:
- Major depressive disorder (MDD)
- Generalized anxiety disorder (GAD)
- Social anxiety disorder (SAD)
- Panic disorder
Off-label uses (with supporting evidence):
- Neuropathic pain
- Migraine prophylaxis
- Vasomotor symptoms of menopause
- Post-traumatic stress disorder (PTSD)
Dosage and Administration
Initial dosing:- MDD: 37.5-75 mg once daily
- GAD: 37.5-75 mg once daily
- Panic disorder: 37.5 mg once daily
- May increase by 75 mg/day at intervals of no less than 4 days
- Maximum recommended dose: 225 mg/day
- Hepatic impairment: Reduce dose by 50%
- Renal impairment (GFR <30 mL/min): Reduce dose by 50%
- Elderly: Consider lower starting doses
- Pediatrics: Not recommended under age 18 due to increased suicide risk
- Take with food to minimize gastrointestinal effects
- Swallow capsule whole; do not crush, chew, or dissolve
- Consistent timing daily maintains steady-state concentrations
Pharmacokinetics
Absorption: Well absorbed with 92-100% bioavailability. Food does not significantly affect absorption but may delay Tmax by approximately 1 hour. Distribution: Volume of distribution: 7.5±3.7 L/kg. Plasma protein binding: 27±2%, primarily to albumin. Metabolism: Extensive hepatic metabolism via CYP2D6 to active metabolite O-desmethylvenlafaxine (ODV) and via CYP3A4 to minor metabolites. Exhibits genetic polymorphism in CYP2D6 metabolizers. Elimination: Terminal elimination half-life: 5±2 hours (venlafaxine), 11±2 hours (ODV). Renal excretion accounts for 87% of eliminated drug.Contraindications
- Hypersensitivity to venlafaxine or any component of formulation
- Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation
- Uncontrolled narrow-angle glaucoma
Warnings and Precautions
Boxed Warning:- Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults
- Serotonin syndrome: Risk increased with concomitant serotonergic drugs
- Elevated blood pressure: Dose-dependent increases requiring regular monitoring
- Discontinuation syndrome: Abrupt cessation may cause dizziness, anxiety, and sensory disturbances
- Bleeding risk: Increased risk of abnormal bleeding, especially with concomitant NSAIDs or anticoagulants
- Mania/hypomania: May precipitate episodes in bipolar disorder
- SIADH: May cause syndrome of inappropriate antidiuretic hormone secretion
- QT prolongation: Observed at higher doses (>300 mg/day)
Drug Interactions
Major interactions:- MAOIs: Risk of serotonin syndrome (contraindicated)
- Other serotonergic drugs: Increased serotonin syndrome risk (triptans, tramadol, linezolid)
- Drugs that inhibit CYP2D6: Increased venlafaxine levels (paroxetine, fluoxetine, quinidine)
- Drugs that prolong QT interval: Additive effects (antiarrhythmics, antipsychotics)
- Warfarin: May increase anticoagulant effect
- NSAIDs/aspirin: Increased bleeding risk
- CNS depressants: Additive sedation
Adverse Effects
Common (≥10%):- Nausea (37%)
- Headache (25%)
- Dry mouth (22%)
- Sweating (12%)
- Constipation (12%)
- Dizziness (11%)
- Insomnia
- Fatigue
- Anorexia
- Nervousness
- Blurred vision
- Sexual dysfunction
- Serotonin syndrome
- Suicidal ideation
- Seizures
- Hyponatremia
- Stevens-Johnson syndrome
- Hepatitis
Monitoring Parameters
Baseline:- Blood pressure and heart rate
- Liver function tests
- Renal function
- Screening for bipolar disorder
- Suicide risk assessment
- Blood pressure monitoring (especially at doses >150 mg/day)
- Mood assessment and suicide risk evaluation
- Signs of serotonin syndrome
- Weight changes
- Serum sodium in at-risk patients
- Therapeutic response assessment
- Taper gradually over at least 2 weeks (reduce by 75 mg/week)
- Monitor for discontinuation symptoms
Patient Education
- Take medication at same time each day with food
- Do not crush, chew, or break capsules
- Report any new or worsening depression symptoms, especially suicidal thoughts
- Avoid abrupt discontinuation
- Be aware of potential side effects including nausea, sweating, and sexual dysfunction
- Inform all healthcare providers about venlafaxine use
- Avoid alcohol during treatment
- Use caution when driving or operating machinery until effects are known
- Report any unusual bleeding or bruising
- Notify provider if pregnancy is planned or occurs
References
1. FDA Prescribing Information: Effexor XR (venlafaxine ER) 2. Stahl SM. Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013. 3. Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci. 2014;11(3-4):37-42. 4. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998;59(10):502-508. 5. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry. 2000;57(5):503-509. 6. Montgomery SA. Tolerability of serotonin norepinephrine reuptake inhibitor antidepressants. CNS Spectr. 2008;13(7 Suppl 11):27-33. 7. Clinical Pharmacokinetics of Venlafaxine and Its Major Metabolites. Clin Pharmacokinet. 2017;56(10):1143-1157.