Out Of The Pipeline

Desvenlafaxine for depression

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New SNRI may have more predictable effects and a lower risk of drug-drug interactions.



Compared with other antidepressants, desvenlafaxine might have more predictable effects and a lower risk of drug-drug interactions because of the way it is metabolized. The FDA approved this selective serotonin-norepinephrine reuptake inhibitor (SNRI)—a major active metabolite of venlafaxine—for treating major depressive disorder (MDD, Table 1). In clinical trials, desvenlafaxine was more effective than placebo in improving patients’ scores on scales of depressive symptoms and overall improvement.1

Table 1

Desvenlafaxine: Fast facts

Brand name: Pristiq
Class: Serotonin-norepinephrine reuptake inhibitor
Indication: Major depressive disorder
Approval date: February 2008
Availability date: May 2008
Manufacturer: Wyeth Pharmaceuticals
Dosing forms: 50- and 100-mg tablets
Recommended dose: 50 to 100 mg/d

Clinical implications

Unlike other SNRIs (venlafaxine and duloxetine), desvenlafaxine does not depend on cytochrome P450 (CYP) 2D6 for bio-transformation. As a result plasma concentrations vary less among individual patients, which should result in more predictable efficacy and tolerability. In addition, unlike bupropion, duloxetine, fluoxetine, and paroxetine, desvenlafaxine does not affect the functional activity of CYP 2D6. This translates into a lower risk of drug-drug interactions and more predictable effects on coadministered drugs that are cleared by CYP 2D6.

How it works

Serotonin, norepinephrine, and dopamine in the CNS are involved in mood and neurovegetative functions that are disturbed in patients with MDD. Desvenlafaxine selectively inhibits serotonin and norepinephrine reuptake pumps, therefore increasing serotonin and norepinephrine concentration in the synaptic cleft.2 The drug has weak binding affinity for the dopamine transporter and does not cause substantial changes in extracellular dopamine concentration. Decreased presynaptic serotonin and norepinephrine uptake increases the synaptic concentration of these neurotransmitters. These effects are thought to be responsible for desvenlafaxine’s antidepressant efficacy.


Desvenlafaxine’s single-dose pharmacokinetics are linear and dose-proportional over the recommended 50 to 100 mg/d dosing range. The half-life is approximately 11 hours. Steady-state plasma concentration is achieved in 4 to 5 days with once-daily dosing.

Food does not affect intestinal absorption. Bioavailability after oral administration is 80%, and time to reach maximum concentration (Tmax) is 7.5 hours. Plasma protein binding is 30% and is independent of desvenlafaxine concentration.1

Desvenlafaxine is excreted renally:

  • unchanged (45% at 72 hours after administration)
  • as desvenlafaxine-glucuronide
  • as N-desvenlafaxine-glucuronide.

Desvenlafaxine-glucuronide is the final metabolite of conjugation reaction with glucuronic acid. N-desvenlafaxine-glucuronide is an end product of a 2-step metabolic reaction that starts with oxidation by CYP 3A4 to produce N-desvenlafaxine, which is conjugated with glucuronic acid to create N-desvenlafaxine-glucuronide. As a result of these metabolic and elimination pathways, dosing adjustment is recommended for patients with severe renal impairment or who are taking a CYP 3A4 inhibitor.


Desvenlafaxine is available as 50-mg and 100-mg tablets. The recommended dosage is 50 mg/d, and the maximum recommended dosage in patients with hepatic impairment is 100 mg/d.

No dosing adjustment is necessary for patients with moderate renal impairment. The recommend regimen for those with severe renal impairment or end-stage renal disease is 50 mg every other day.

Instruct patients to take desvenlafaxine at approximately the same time each day, with or without food. Tell them not to discontinue the drug abruptly and to immediately report any adverse effects (AEs).


Desvenlafaxine’s antidepressant efficacy was established in four 8-week, randomized, double-blind, placebo-controlled, fixed-dose (50 mg to 400 mg once daily) studies in adult outpatients who met DSM-IV-TR criteria for MDD.1,2,4

In the first study,3 461 patients received desvenlafaxine, 100 mg, 200 mg, or 400 mg, or placebo. In the second study,4 369 patients received 200 mg or 400 mg or placebo. In 2 additional studies, a total of 930 patients received 50 mg or 100 mg or placebo.1

All studies used the 17-item Hamilton Rating Scale for Depression (HAM-D17) to measure depressive symptom improvement and the Clinical Global Impressions-Improvement (CGI-I) scale to measure overall improvement. Desvenlafaxine was more effective than placebo in HAM-D17 score improvement in all 4 studies and in CGI-I score improvement in 3 studies.

In studies comparing 50 mg/d with 100 mg/d, doses >50 mg/d provided no additional benefit. Higher starting fixed doses were associated with more frequent AEs and discontinuation.

Gender or age had no effect on treatment outcome. There was no difference in safety in elderly vs younger patients. Data are insufficient to establish a relationship between race and desvenlafaxine responsiveness. Desvenlafaxine’s safety and effectiveness in children and adolescents was not evaluated, and the drug is not approved for these patients.

Tolerability and safety

Desvenlafaxine’s tolerability is comparable to that of other SNRIs. In premarketing studies, 12% of patients receiving desvenlafaxine (50 mg/d to 400 mg/d) discontinued treatment because of AEs, compared with 3% in the placebo group. The discontinuation rate in patients receiving 100 mg/d was 8.7% compared with 4.1% in patients taking 50 mg/d.


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