Introduction
Venlafaxine, marketed under the brand name Effexor, is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant approved by the FDA in 1993. It represents a distinct class of antidepressants that differs from selective serotonin reuptake inhibitors (SSRIs) through its dual mechanism of action. Effexor is widely prescribed for major depressive disorder, anxiety disorders, and other psychiatric conditions, offering an important therapeutic option for patients who may not respond adequately to SSRIs.
Mechanism of Action
Venlafaxine exerts its therapeutic effects primarily through potent inhibition of serotonin and norepinephrine reuptake transporters. Unlike SSRIs that selectively target serotonin, venlafaxine inhibits both serotonin (5-HT) and norepinephrine (NE) reuptake with approximately 30-fold greater potency for serotonin transporters. At higher doses (>150 mg/day), the drug demonstrates significant norepinephrine reuptake inhibition. The drug has minimal affinity for muscarinic, histaminergic, or adrenergic receptors, which contributes to its favorable side effect profile compared to older antidepressants.
Indications
- Major depressive disorder (MDD)
- Generalized anxiety disorder (GAD)
- Social anxiety disorder (social phobia)
- Panic disorder with or without agoraphobia
- Vasomotor symptoms associated with menopause
- Neuropathic pain
- Migraine prophylaxis
- Attention-deficit/hyperactivity disorder (ADHD)
Dosage and Administration
Initial dosing:- Immediate-release: 37.5-75 mg daily in divided doses
- Extended-release: 37.5-75 mg once daily
- May increase by 75 mg/day at intervals of no less than 4 days
- Maximum recommended dose: 225 mg/day for immediate-release, 375 mg/day for extended-release
- Hepatic impairment: Reduce dose by 50%
- Renal impairment (GFR <30 mL/min): Reduce dose by 50%
- Elderly: Use lower starting doses and more gradual titration
- Pediatrics: Not recommended for children under 18 due to increased risk of suicidal ideation
Pharmacokinetics
Absorption: Well absorbed orally (≥92%), food has minimal effect on absorption Distribution: Volume of distribution 7.5 L/kg, 27% protein bound Metabolism: Extensive hepatic metabolism via CYP2D6 to active metabolite O-desmethylvenlafaxine (ODV) Elimination: Half-life 5±2 hours (venlafaxine), 11±2 hours (ODV); renal elimination (87% in urine) Time to peak concentration: Immediate-release: 2 hours; Extended-release: 6-8 hoursContraindications
- Hypersensitivity to venlafaxine or any component of the formulation
- Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation
- Narrow-angle glaucoma
- Severe hepatic impairment
Warnings and Precautions
Boxed Warning:- Increased risk of suicidal thinking and behavior in children, adolescents, and young adults
- Serotonin syndrome risk, particularly with other serotonergic drugs
- Increased bleeding risk
- Activation of mania/hypomania
- Blood pressure elevation (dose-dependent)
- Discontinuation syndrome upon abrupt cessation
- QT interval prolongation at high doses
- Angle-closure glaucoma
- Hyponatremia/SIADH
Drug Interactions
Major interactions:- MAOIs: Risk of serotonin syndrome (contraindicated)
- Other serotonergic agents: Increased serotonin syndrome risk
- Drugs that prolong QT interval: Additive effects
- Warfarin: Increased anticoagulant effect
- CYP2D6 inhibitors: Increased venlafaxine levels
- Drugs affecting hepatic metabolism: Altered venlafaxine concentrations
Adverse Effects
Common (≥10%):- Nausea (37%)
- Headache (25%)
- Somnolence (23%)
- Dry mouth (22%)
- Dizziness (19%)
- Insomnia (18%)
- Constipation (15%)
- Sweating (12%)
- Nervousness (13%)
- Suicidal ideation
- Serotonin syndrome
- Seizures
- Hyponatremia
- Mania/hypomania
- Increased blood pressure
- Abnormal bleeding
- Angle-closure glaucoma
Monitoring Parameters
- Blood pressure at baseline and regularly during treatment (especially doses >200 mg/day)
- Mental status for emerging suicidal ideation, especially during initiation
- Serum sodium in elderly patients and those on diuretics
- Signs and symptoms of serotonin syndrome
- Mood changes indicating emerging mania/hypomania
- Weight changes
- Cholesterol levels (may increase)
- Liver function tests in patients with hepatic impairment
Patient Education
- Take medication exactly as prescribed; do not abruptly discontinue
- Report any emerging suicidal thoughts, especially during initial treatment
- Avoid alcohol during treatment
- Rise slowly from sitting/lying position to prevent dizziness
- Report any unusual bleeding or bruising
- Inform all healthcare providers about venlafaxine use
- Use effective contraception; notify provider if pregnancy is planned or suspected
- Be aware of potential discontinuation symptoms if missing doses
- Allow 4-6 weeks for full therapeutic effect
- Report any vision changes immediately
References
1. FDA Prescribing Information: Effexor (venlafaxine HCl) 2. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 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. Montgomery SA, et al. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs. 1995;49(2):280-294. 6. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. 7. Fava M, et al. Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. Am J Psychiatry. 1997;154(12):1760-1762.