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Year : 2009  |  Volume : 51  |  Issue : 4  |  Page : 320-323
Desvenlafaxine


Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, India

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Date of Web Publication10-Dec-2009
 

How to cite this article:
Andrade C. Desvenlafaxine. Indian J Psychiatry 2009;51:320-3

How to cite this URL:
Andrade C. Desvenlafaxine. Indian J Psychiatry [serial online] 2009 [cited 2019 Dec 13];51:320-3. Available from: http://www.indianjpsychiatry.org/text.asp?2009/51/4/320/58303


Desvenlafaxine (DV) succinate (Pristiq; Wyeth) is a recent serotonin-norepinephrine reuptake-inhibiting (SNRI) antidepressant drug. DV is O-desmethylvenlafaxine, the principal active metabolite of venlafaxine, formed by the action of CYP 2D6 on the parent drug. In February 2008, DV (50 mg/day) was approved for the treatment of depression by the Food and Drug Administration (FDA) in the USA. [1]

If patients receive venlafaxine, DV is formed in their bodies; so, what is gained if venlafaxine is eliminated from the treatment chain and DV is administered directly? A cynical answer is that DV extends the patent life of venlafaxine. Whereas venlafaxine went out of patent in 2008, the extended-release formulation of the drug will go out of patent in 2010. In India, unless a substantial advantage for DV over venlafaxine is demonstrated, the introduction of DV will be considered to be evergreening; i.e., merely an incremental modification of an existing molecule. Evergreening is not recognized for the grant of patents under the Indian Patents Act as modified by the Parliament in 2005. [2]

Therefore, does DV have any advantages over venlafaxine? At present, it is too early to say. There are both positives and negatives for DV. Positives for DV over venlafaxine are:

  1. In clinical trials of patients with major depressive disorder, assessments using a visual analogue scale showed that DV (100-400 mg/day) has a greater efficacy than placebo against painful symptoms associated with depression. [1]
  2. In clinical trials of patients with major depressive disorder, assessments using the Sheehan Disability Scale showed that DV (50-400 mg/day) has a greater efficacy than placebo against disability associated with depression. [1]
  3. DV has demonstrated efficacy against the vasomotor symptoms (hot flushes) of menopause. [3],[4],[5]


It is likely, however, that these properties of DV constitute a class action of all antidepressants and are not unique to DV. More specific advantages with DV over venlfaxine are:

  1. In order to maximize tolerance, clinicians usually take 7-10 days or longer to uptitrate the dose of venlafaxine to the target of 150-225 mg/day, at which doses venlafaxine becomes dual-acting. In contrast, DV is started at the target dose of 50 mg/day from the very first day. [1] Should it be considered necessary, an escalation to 100 mg/day can be effected within 4-7 days.
  2. CYP 2D6 poor metabolizers constitute about 10% of the population. Such persons would not tolerate standard doses of venlafaxine. [6] Unless clinicians order blood levels or pharmacogenomic tests, they will have no way of knowing whether a patient who develops adverse effects with venlafaxine is a poor metabolizer (in whom lower doses would achieve effective blood levels with fewer adverse effects) or merely does not tolerate standard doses of the drug (necessitating drug withdrawal). Venlafaxine will therefore (unnecessarily) be withdrawn in the former subgroup. In contrast, DV is negligibly metabolized in the liver. [7],[8] Therefore, genetic variations in metabolic capacity will not influence the tolerability of the drug or influence adverse effect-related drug withdrawal decisions.
  3. Venlafaxine is associated with an up to 10% or greater dose-dependent risk of treatment-emergent hypertension. In contrast, in patients who receive DV (50-400 mg/day), there is only an approximately 1-2% risk of sustained increase in diastolic blood pressure to values .90 mmHg or values .10 mmHg above baseline (as compared with a 0.5% risk in patients receiving placebo). [1]
  4. Sexual adverse effects are common with venlafaxine. In contrast, sexual adverse effects are placebo-level with DV 50-100 mg/day, rising to noticeably above placebo level (more in men than in women) only with the 400 mg/day dose. [7],[9] A caveat here is that sexual adverse effects with DV were recorded based on spontaneous reports and had not been formally evaluated in the clinical trials available so far, and could therefore be underestimated.
  5. Venlafaxine is commonly associated with an unpleasant drug discontinuation reaction because its (terminal) half-life is short - about 5 h. This half-life does not vary as a function of immediate-release vs. extended-release formulation. As a result, the drug is substantially washed out of the body 24 h after a single missed dose. This is why discontinuation symptoms may emerge after even a single missed dose of venlafaxine, and why venlafaxine is best dosed at the same time of day each day. Whereas DV is also associated with a discontinuation syndrome, [1] from a theoretical perspective, because its terminal half-life is longer at around 10 h, [1] a drug discontinuation reaction could be less of a problem as compared with venlafaxine. A caveat here is that, as one molecule of venlafaxine yields one molecule of DV upon metabolism, this putative advantage assumes that venlafaxine and DV have subtle pharmacodynamic differences, and that DV does not compensate pharmacodynamically for the hiatus arising from the washout of venlafaxine. The issue can only be resolved through a head-to-head comparison of discontinuation symptoms between the two drugs; these data have so far not been released.


The above notwithstanding, there are some concerns about DV and some regards in which it has yet to establish itself relative to venlafaxine:

  1. Many doses of DV in many trials failed to separate from placebo for the primary outcome measure. This failure was more marked in the flexible-dose (200-400 mg/day) studies and with the 200 mg/day dose in the fixed-dose studies; however, failure at the primary outcome measure was also recorded with the 50 and 100 mg/day doses in certain fixed-dose studies. Clearcut separation for all outcome measures with all doses in all studies, and in both fixed- and flexible-dose designs, emerged only in pooled analyses. However, effect sizes remained low (around 0.30 or less) and onset of separation from placebo was late (2-4 weeks). [10],[11],[12]
  2. Data exist to suggest that venlafaxine is associated with better treatment outcomes than the selective serotonin reuptake inhibitors (SSRIs), and that venlafaxine may benefit patients who fail SSRI trials. No such studies have so far been conducted with DV.


DV is about 11 times more potent an inhibitor of serotonin reuptake than of norepinephrine reuptake. [13] Just as venlafaxine becomes a dual-acting SNRI drug only at higher doses (e.g., 150 mg/day and above), might it be possible that DV is merely an SSRI at lower doses? If so, this might, at least in part, explain some of the disappointing results with the drug in the clinical trials conducted to date. Such a possibility is supported by the adverse effect profile of the drug in 50-100 mg/day doses: nausea and dizziness, which are serotonergic adverse effects, are noticeably present whereas dysuria and hypertension, which are noradrenergic adverse effects, are negligible or absent. [7]

Here, it may be noted that strongly noradrenergic drugs such as reboxetine and more balanced SNRIs such as duloxetine and milnacipran have both found poor acceptance in clinical practice and/or have evidenced unimpressive results relative to SSRIs in meta-analyses. If DV is more strongly noradrenergic than venlafaxine, this may explain the somewhat unimpressive clinical trial results. However, as noted above, the adverse effect profile of the drug does not seem to suggest a noradrenergic bias.

With this background, mark True or False against each of the following statements:

  1. The dose-dependent risk of dry mouth and constipation with DV is due to muscarinic receptor blockade.
  2. Patients prescribed DV may lose weight.
  3. DV results in a clinically significant increase in the QTc interval.
  4. DV inhibits CYP 2D6.
  5. DV should be avoided in patients with liver disease.
  6. DV should be avoided in patients with renal disease.
  7. DV separates from placebo by week 1 in menopausal women with hot flushes.
  8. The 100 mg/day dose of DV optimizes safety and adverse effects in the treatment of the vasomotor symptoms of menopause.




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   References Top

1.Perry R, Cassagnol M. Desvenlafaxine: A new serotonin-norepinephrine reuptake inhibitor for the treatment of adults with major depressive disorder. Clin Ther 2009;31:1374-404.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Andrade C, Shah N, Chandra S. The new patent regime: Implications for patients in India. Indian J Psychiatry 2007;49:56-9.  Back to cited text no. 2    Medknow Journal  
3.Speroff L, Gass M, Constantine G, Olivier S, for the Study 315 Investigators. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms. Obstet Gynecol 2008;111:77-87.  Back to cited text no. 3      
4.Archer DF, Seidman L, Constantine G, Pickar JH, Olivier S. A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause. Am J Obstet Gynecol 2009;200:172.e1-172.e10.  Back to cited text no. 4      
5.Archer DF, Dupont C, Constantine GD, Pickar JH, Olivier S; for the Study 319 Investigators. Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: A double-blind, randomized, placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol 2009;200:238e1-e10.  Back to cited text no. 5      
6.McAlpine DE, O′Kane DJ, Black JL, Mrazek DA. Cytochrome P450 2D6genotype variation and venlafaxine dosage. Mayo Clin Proc 2007;82:1065-8.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Lourenco MT, Kennedy SH. Desvenlafaxine in the treatment of major depressive disorder. Neuropsychiatric Dis Treat 2009;5:127-36.  Back to cited text no. 7      
8.Preskorn S, Patroneva A, Silman H, Jiang Q, Isler JA, Burczynski ME, et al. Comparison of the pharmacokinetics of venlafaxine extended release and desvenlafaxine in extensive and poor cytochrome P450 2D6 metabolizers. J Clin Psychopharmacol 2009;29:39-43.   Back to cited text no. 8      
9.Clayton AH, Kornstein SG, Rosas G, Guico-Pabia C, Tourian KA. An integrated analysis of the safety and tolerability of desvenlafaxine compared with placebo in the treatment of major depressive disorder. CNS Spectr 2009;14:183-95.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Lieberman DZ, Montgomery SA, Tourian KA, Brisard C, Rosas G, Padmanabhan K, et al. A pooled analysis of two placebo-controlled trials of desvenlafaxine in major depressive disorder. Int Clin Psychopharmacol 2008;23:188-97.  Back to cited text no. 10      
11.Thase ME, Kornstein SG, Germain JM, Jiang Q, Guico-Pabia C, Ninan PT. An integrated analysis of the efficacy of desvenlafaxine compared with placebo in patients with major depressive disorder. CNS Spectr 2009;14:144-54.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Tourian KA, Padmanabhan K, Groark J, Brisard C, Farrington D. Desvenlafaxine 50 and 100mg/d in the treatment of major depressive disorder: An 8-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial and a post hoc pooled analysis of three studies. Clin Ther 2009;31:1405-23.  Back to cited text no. 12      
13.Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, et al. Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Expt Ther 2006;318:657-65.  Back to cited text no. 13      
14.Patroneva A, Connolly SM, Fatato P, Pedersen R, Jiang Q, Paul J, et al. An assessment of drug-drug interactions: The effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects. Drug Metab Dispos 2008;36:2484-91.   Back to cited text no. 14      
15.Nichols AI, Fatato P, Shenouda M, Paul J, Isler JA, Pedersen RD, et al. The effects of desvenlafaxine and paroxetine on the pharmacokinetics of the cytochrome P450 2D6 substrate desipramine in healthy adults. J Clin Pharmacol 2009;49:219-28.  Back to cited text no. 15      
16.Preskorn SH, Nichols AI, Paul J, Patroneva AL, Helzner EC, Guico-Pabia CJ. Effect of desvenlafaxine on the cytochrome P450 2D6 enzyme system. J Psychiatr Pract 2008;14:368-78.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]  
17.Baird-Bellaire S, Patat AA, Fauchoux N, Reh C, Nichols AI, Behrle A. Effects of chronic hepatic impairment on the pharmacokinetics and safety of devenlafaxine succinate extended release. Clin Pharmacol Ther 2006;79:26.  Back to cited text no. 17      
18.Oganesian A, Shilling AD, Young-Sciame R, Tran J, Watanyar A, Azam F, et al. Desvenlafaxine and venlafaxine exert minimal in vitro inhibition of human cytochrome p450 and p-glycoprotein activities. Psychopharmacol Bull 2009;42:47-63.  Back to cited text no. 18      

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Correspondence Address:
Chittaranjan Andrade
Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5545.58303

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