May 2019 By PsychDB.com

Venlafaxine (Effexor)

Venlafaxine (Tradename: Effexor) is an antidepressant in the Serotonin Norepinephrine Reuptake Inhibitor (SNRI) class. It is used to treat both depressive and anxiety disorders.

Venlafaxine acts on the following receptors:

  • Serotonin - At lower doses (<150 mg/day), serotonergic reuptake is more prominent, and venlafaxine acts like an SSRI
  • Norepinephrine - At higher doses (≥150 mg/day) norepinephrine reuptake is more prominent and it begins to act more like an SNRI
  • Dopamine (to a lesser degree)
  • Venlafaxine has no significant affinity for cholinergic, histaminergic, or α1-adrenergic receptors.

Pharmacokinetics

  • Venlafaxine XR (extended release):
    • Parent drug has 6 hour half-life
    • The active metabolite, O-desmethylvenlafaxine (ODV) has 9 hour half-life
  • Venlafaxine is metabolized by 2D6 and3A4 to ODV (active metabolite)
  • Weak inhibitor of 2D6
  • Protein-binding of venlafaxine and ODV is about 30%
  • Taking with food has negligible effects on absorption or metabolism

Venlafaxine comes in two 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
Tradename Effexor IR Effexor XR
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 Therapeutic dose is 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[1]) 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 -
  • Treatment for OCD may require higher doses
  • Patients on long-term venlafaxine therapy should have regular blood pressure monitoring for hypertension

Combining venlafaxine with mirtazapine has been dubbed “California Rocket Fuel” by psychopharmacologist Stephen Stahl because of the multiple mechanisms of action on neurotransmitter systems.[2] 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.[3] No formal randomized trials have been performed, so its evidence is largely based on expert opinion.[4] Smaller open-label trials have been done supporting its efficacy.[5][6][7][8][9]

  • MAOIs (serotonin syndrome)
  • Inhibitors/inducers of 2D6 and 3A4
  • Venlafaxine will modestly increase levels of 2D6substrates
  • Combination of venlafaxine 150 mg/day (steady-state) and haloperidol 2 mg (single dose)resulted in a 70% increase in haloperidol AUCand an 88% increase in venlafaxine Cmax (T1/2unchanged)
  • If patient has uncontrolled narrow angle-closure glaucoma (due to its hypertensive effects)
  • If patient is taking an MAO inhibitor
  • Hypersensitivity

Common

Due to its noradrenergic action, more notable side effects include headaches, anxiety, and insomnia. There is also a dose-dependent increase in diastolic blood pressure (~5mmHg). 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

Monitoring

  • Blood pressure (especially diastolic)
  • EKG monitoring: because of venlafaxine’s association with ↑ DBP and its prominent noradrenergic activity at higher doses, some authorities recommend that this be considered for some patients

Discontinuation Syndrome

Some patients may have severe problems with discontinuation of venlafaxine, compared with other antidepressants. Do not mistake withdrawal symptoms for relapse!

Overdose

Venlafaxine overdose causes sympathomimetic symptoms and QTc prolongation.[10] Tachycardia, hypotension, seizures, coma, serotonin syndrome, and death can occur in severe overdoses.[11]

Sleep

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.


2. Stahl's Essential Psychopharmacology, 2nd Edition, pg. 290