1. Venlafaxine and Desvenlafaxine

2. Venlafaxine and Desvenlafaxine – Overview
SNRIs: Venlafaxine is metabolized to o-desmethylvenlafaxine (desvenlafaxine).
Similarities:
Efficacy & Indications
Pharmacodynamics
Side effects profile
Differences:
Pharmacokinetics
Dosing

3. MOA and Pharmacodynamics

4. Venlafaxine and Desvenlafaxine – MOA
SERT inhibition
NET inhibition
SERT inhibition: 5 times more potent than NET inhibition
Schatzberg, Alan F., and Charles B. Nemeroff, eds. The American psychiatric publishing textbook of psychopharmacology. American Psychiatric Pub, 2009.

5. Venlafaxine Dose response: 75 mg/day: serotonergic AD
Clinical efficacy
Affinities
75 mg/day: serotonergic AD
mg/day: dual activity (SNRI)
Need for in vivo clinical studies
Schatzberg, Alan F., and Charles B. Nemeroff, eds. The American psychiatric publishing textbook of psychopharmacology. American Psychiatric Pub, 2009.

6. Desvenlafaxine
50 mg/day
100 mg/day
May not show the ascending dose response of venlafaxine:
50 mg/day SERT/ NET
100 mg/day SERT/ NET
Schatzberg, Alan F., and Charles B. Nemeroff, eds. The American psychiatric publishing textbook of psychopharmacology. American Psychiatric Pub, 2009.

7. Indications

8. FDA-approved indications
Venlafaxine
Desvenlafaxine
Major depressive disorder
Generalized anxiety disorder
Social anxiety disorder
Panic disorder
Effexor XR (venlafaxine HCl) [package insert]. Philadelphia, Pennsylvania: Wyeth Pharmaceuticals, Inc.; 2014.
Pristiq (desvenlafaxine succinate) [package insert]. Philadelphia, Pennsylvania: Wyeth Pharmaceuticals, Inc.; 2014.

9. Venlafaxine - Non-approved use: PTSD
Two trials of more than 800 participants:
Effective and improves resilience
Similar effectiveness to sertraline
VA/DoD Clinical Practice Guideline:
Venlafaxine for PTSD - Strength of recommendation: A
The net benefit of the intervention is good, quality of evidence is good
Davidson J, et al Venlafaxine extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled study. Journal of clinical psychopharmacology. 2006;26(3):
Davidson J, et al Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Archives of general psychiatry. 2006;63(10):

10. Pharmacokinetics

11. Venlafaxine/ Desvenlafaxine Pharmacokinetics
O-desmethylvenlafaxine (ODV)= desvenlafaxine
Venlafaxine
metabolized by CYP2D6 to
Weak CYP2D6 inhibitor
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

12. Venlafaxine/ Desvenlafaxine pharmacokinetics
Metabolizer type
Enzime activity
Ultrarapid metabolizers
Significantly increased
Extensive metabolizers
Not clinically relevant
Intermediate metabolizers
Poor metabolizers
Significantly decreased
Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Nuanyn Schmiedebergs Arch Pharmacol. 2004;369(1):23-37.

13. Venlafaxine/ Desvenlafaxine pharmacokinetics
Poor metabolizers
(less than 10% of the population)
Metabolism significantly decreased
Poor metabolizers of CYP2D6 may be at greater risk for side effects.
McAlpine DE, O'Kane DJ, Black JL, Mrazek DA. Cytochrome P450 2D6genotype variation and venlafaxine dosage. Mayo Clin Proc. 2007;82:1065–8.

14. Venlafaxine/Desvenlafaxine Pharmacokinetics
Desvenlafaxine: no significant effect on CYP2D6
Venlafaxine XR: unlikely to significantly affect CYP2D6 substrates.
Venlafaxine XR and desvenlafaxine have similar effects on substrates of CYP2D6. 
Colvard MD. Key Differences Between Venlafaxine XR and Desvenlafaxine: An Analysis of Pharmacokinetic and Clinical Data. Ment Health Clin. 2014;4(1):50.

15. Adverse Effects

16. Venlafaxine Adverse Effects
Nausea, insomnia, tremor sexual dysfunction.
SERT inhibition
Hypertension, sweating, dry mouth.
NET inhibition
Thase, M. SNRIs, in Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: LWW , 2009.
Nemeroff

17. Venlafaxine Adverse Effects
One of the antidepressants most commonly associated with discontinuation syndrome.
XR formulation: somewhat lower incidence of nausea
Thase, M. SNRIs, in Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: LWW , 2009.

18. Venlafaxine IR and Hypertension
Dose related effect
Immediate release studies:
Venlafaxine mg/day
Incidence
<100 3%
> 100 to ≤200 5%
>200 to ≤300 7%
>300
13%
Effexor (venlafaxine HCl) [package insert]. Philadelphia, Pennsylvania: Wyeth Pharmaceuticals, Inc.;

19. Venlafaxine XR and Hypertension
Hypertension can occur with venlafaxine XR
Caution: patients with preexisting hypertension
Recommended: blood pressure monitoring, especially when ≥ 225mg/day
Khawam EA, Laurencic G, Malone DA, Jr. Side effects of antidepressants: an overview. Cleveland Clinic journal of medicine. 2006;73(4):351-3, 6-61.

20. Dosing

21. Venlafaxine Dosing Guidelines
Usual dosage range: mg/day (can be dosed higher)
XR: once daily
IR: divided into 2-3 doses
Dosage forms:
Capsule (XR): 37.5 mg, 75 mg, 150 mg
Tablet: 37.5 mg, 75 mg, 150 mg, 225 mg
Scored tablets: 25 mg, 37.5 mg 75 mg, 100 mg
Stahl, S M. The Prescriber's Guide. 4th ed. New York: Cambrigde University Press; 2011
Effexor XR (venlafaxine HCl) [Prescribing Information]. Philadelphia, Pennsylvania: Wyeth Pharmaceuticals, Inc.; 2014.

22. Venlafaxine XR Dosing Guidelines: Depression
Starting dose (manufacturer): 75 mg/day.
Some patients may be better to start at 37mg/day
Patients not responding to 75mg/day might benefit from dose increases to 225 mg/day
Effexor XR (venlafaxine HCl) [package insert]. Philadelphia, Pennsylvania: Wyeth Pharmaceuticals, Inc.; 2014.

23. Desvenlafaxine – Dosing Guidelines
Dosage : 50 mg/day
Dosage forms:
XR Tablets: 50 mg, 100 mg
No evidence that doses greater than 50 mg/day confer any additional benefit.
mg/day effective, but adverse reactions and discontinuations more frequent.
Pristiq (desvenlafaxine succinate) [package insert]. Philadelphia, Pennsylvania: Wyeth Pharmaceuticals, Inc.; 2013.

24. Venlafaxine / Desvenlafaxine Differences
Notable differences:
Metabolism
FDA approved dosage