- Last edited on October 26, 2022
Venlafaxine (Effexor)
Primer
Venlafaxine (Trade name: Effexor) is an antidepressant in the serotonin norepinephrine reuptake inhibitor (SNRI) class used in the treatment of major depressive disorder and anxiety disorders.
Pharmacokinetics
See also article: Introduction to Pharmacology
Pharmacokinetics of Venlafaxine
Absorption | Well absorbed by GI tract |
---|---|
Distribution | Volume of distribution is 7.5±3.7 |
Metabolism | Extensively metabolized in the liver, and desvenlafaxine (O-desmethylvenlafaxine, ODV) is the only major active metabolite. |
Elimination | Renal (primary) |
Half-life | Venlafaxine: 5 hours ODV: 11 hours |
Cytochrome P450 Metabolism
See also article: Cytochrome (CYP) P450 Metabolism
Venlafaxine: Cytochrome P450 Metabolism
Substrate of (Metabolized by) | CYP 2D6 and 3A4 to desvenlafaxine (o-desmethylvenlafaxine) an active metabolite |
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Induces | |
Inhibits | Weak inhibitor of 2D6 |
Pharmacodynamics
Mechanism of Action
- Venlafaxine acts on the following receptors:
- Serotonin: at lower doses (<150 mg/day) it acts like an SSRI, and serotonergic reuptake is more prominent
- Norepinephrine: at higher doses (≥150 mg/day) it begins to act more like an SNRI, and norepinephrine reuptake is more prominent
- Dopamine: to a lesser degree has some mild dopaminergic activity
- Venlafaxine has no significant affinity for cholinergic, histaminergic, or α1-adrenergic receptors.
Toxicity
Indications
Formulations (Intermediate vs. Extended Release)
- Venlafaxine comes in two oral formulations. Venlafaxine Extended Release (Effexor XR) is typically prescribed over Effexor Regular/Immediate because it is less activating and has a better side effect profile (improves tolerability, reduces nausea, and requires only once-daily dosing).
Venlafaxine Intermediate vs. Extended Release
Generic name | Venlafaxine Regular/Immediate Release | Venlafaxine Extended Release |
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Tradename | Effexor IR | Effexor XR |
Half-life | 5 hours | 13-14 hours |
Dosage Strengths | 25 mg, 37.5 mg, 75 mg, and 100 mg tablets | 37.5 mg, 75 mg, 150 mg capsules |
Starting Dose | 25 mg PO TID | 37.5 to 75 mg PO daily for 1 week (increase by no more than 75mg q4 days) |
Therapeutic Dose | 150-225 mg per day divided BID/TID | 150mg |
Maximum Dose | Maximum dose is 375 mg per day (doses of up to 600mg has been reported[3]) | 225 mg PO daily |
Advantages | Can be dosed once daily since metabolites offer similar duration to Effexor XR | Once daily dosing and lower side effect profile |
Disadvantages | More adverse effects than Effexor XR | - |
Monitoring
- Blood pressure (especially diastolic)
- ECG monitoring: because of venlafaxine’s association with increased diastolic blood pressure and its prominent noradrenergic activity at higher doses
Withdrawal
See main article: Antidepressant Withdrawal (Discontinuation) Syndrome
Some patients may have severe problems with discontinuation of venlafaxine, compared with other antidepressants. Do not mistake withdrawal symptoms for relapse! Since venlafaxine is noradrenergic, when it is stopped abruptly, it can cause noradrenergic rebound symptoms including brain fog, dizziness, and sensations of “electric shocks.”
California Rocket Fuel
- Combining venlafaxine with mirtazapine has been dubbed “California Rocket Fuel” by psychopharmacologist Stephen Stahl because of the multiple mechanisms of action on neurotransmitter systems.[4] The hypothesis is that mirtazapine increases both serotonin and norepinephrine via a different mechanism than SSRIs/SNRIs. This combination therapy was found to outperform parnate (tranylcypromine) in the landmark STAR*D trial.[5]
- The maximum dosage for this combination therapy is the same as the standard dose for each respective drug (i.e. - venlafaxine ER's maximum dose is 225mg daily (IR = 375mg daily), and mirtazapine's maximum dose is 45mg daily).
Contraindications
Absolute
- If a patient has uncontrolled narrow angle-closure glaucoma (due to its hypertensive effects)
- If a patient is taking an MAO inhibitor
- Hypersensitivity of venlafaxine
Relative
Drug-Drug Interactions
- MAOIs (serotonin syndrome)
- Inhibitors/inducers of 2D6 and 3A4
- Venlafaxine will modestly increase levels of 2D6 substrates (e.g. - aripiprazole, haloperidol)
Side Effects
- Due to its noradrenergic action, notable side effects include headaches, anxiety, and insomnia.
- Other common side effects include: nausea, abdominal pain, anorexia, weight loss, increased appetite, behavioural activation, sedation, irritability, hostility, asthenia, dizziness, dry mouth, nasal congestion, skin problems.
- There is also a dose-dependent increase in diastolic blood pressure (~5mmHg).
Adverse Events
- QTc prolongation (moderate effect)
Clinical Pearls
- Treatment for OCD may require higher doses
- Patients on long-term venlafaxine therapy should have regular blood pressure monitoring for hypertension
- There are few studies involving venlafaxine and polysomnography, it can be activating or sedating depending on the patient, and the objective EEG findings are most similar to SSRIs.
Special Populations
Geriatric
See main article: Geriatric Pharmacology
Pediatric
See main article: Pediatric Pharmacology
Obstetric and Fetal
See main article: Obstetric and Fetal Pharmacology
Medically Ill
See main article: Psychotropic Dosing in the Medically Ill
Resources
References
1)
Howell, C., Wilson, A. D., & Waring, W. S. (2007). Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. British journal of clinical pharmacology, 64(2), 192-197.
2)
Webb, J. (2007). Venlafaxine: troubling toxicity in overdose. BRITISH COLUMBIA MEDICAL JOURNAL, 49(1), 10.
3)
Harrison, C. L., Ferrier, N., & Young, A. H. (2004). Tolerability of high-dose venlafaxine in depressed patients. Journal of Psychopharmacology, 18(2), 200-204.
4)
Stahl's Essential Psychopharmacology, 2nd Edition, pg. 290
5)
McGrath, P. J., Stewart, J. W., Fava, M., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., ... & Luther, J. F. (2006). Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR* D report. American Journal of Psychiatry, 163(9), 1531-1541.
6)
Gándara, J., Agüera, L., Rojo, J. E., Ros, S., & Pedro, J. M. (2005). Use of antidepressant combinations: which, when and why? Results of a Spanish survey. Acta Psychiatrica Scandinavica, 112(s428), 32-35.
7)
Hannan, N., Hamzah, Z., Akinpeloye, H. O., & Meagher, D. (2007). Venlafaxine—mirtazapine combination in the treatment of persistent depressive illness. Journal of Psychopharmacology, 21(2), 161-164.
9)
Malhi, G. S., Ng, F., & Berk, M. (2008). Dual–dual action? Combining venlafaxine and mirtazapine in the treatment of depression. Australian & New Zealand Journal of Psychiatry, 42(4), 346-349.
10)
Silva, J., Mota, J., & Azevedo, P. (2016). California rocket fuel: And what about being a first line treatment?. European Psychiatry, 33, S684.
11)
Pandarakalam, J. P. (2010). SNRI‐NaSSA combination therapy for treatment‐resistant depression. Progress in Neurology and Psychiatry, 14(1), 26-29.