Desvenlafaxine for Depression

Out of the Pipeline

pSYCHIATRY

Desvenlafaxine for depression

Jana Lincoln, MD, and Sheldon H. Preskorn, MD

Table 1 ompared with other antidepressants, New SNRI may have desvenlafaxine might have more pre- Desvenlafaxine: Fast facts more predictable dictable effects and a lower risk of C Brand name: Pristiq eﬀ ects and a lower drug-drug interactions because of the way it is metabolized. The FDA approved this se- Class: Serotonin-norepinephrine reuptake risk of drug-drug lective serotonin-norepinephrine reuptake inhibitor interactions inhibitor (SNRI)—a major active metabolite Indication: Major depressive disorder of venlafaxine—for treating major depres-® DowdenApproval date: Health February 2008 Media sive disorder (MDD, Table 1). In clinical tri- Availability date: May 2008 als, desvenlafaxine was more effective than placebo in improving patients’Copyright scoresFor on personalManufacturer: use Wyeth Pharmaceuticals only scales of depressive symptoms and overall Dosing forms: 50- and 100-mg tablets improvement.1 Recommended dose: 50 to 100 mg/d

Clinical implications reuptake pumps, therefore increasing sero- Unlike other SNRIs (venlafaxine and du- tonin and norepinephrine concentration in loxetine), desvenlafaxine does not depend the synaptic cleft.2 The drug has weak bind- on cytochrome P450 (CYP) 2D6 for bio- ing affi nity for the dopamine transporter transformation. As a result plasma con- and does not cause substantial changes in centrations vary less among individual extracellular dopamine concentration. De- patients, which should result in more pre- creased presynaptic serotonin and norepi- dictable effi cacy and tolerability. In addi- nephrine uptake increases the synaptic con- tion, unlike bupropion, duloxetine, fl uox- centration of these neurotransmitters. These etine, and paroxetine, desvenlafaxine does effects are thought to be responsible for des- not affect the functional activity of CYP venlafaxine’s antidepressant effi cacy. 2D6. This translates into a lower risk of drug-drug interactions and more predictable effects on coadministered drugs that Pharmacokinetics are cleared by CYP 2D6. Desvenlafaxine’s single-dose pharmacokinetics are linear and dose-proportional over the recommended 50 to 100 mg/d How it works dosing range. The half-life is approximately Serotonin, norepinephrine, and dopamine

in the CNS are involved in mood and neu- Dr. Lincoln is a clinical instructor and Dr. Preskorn is a rovegetative functions that are disturbed in professor of psychiatry, University of Kansas Medical Center, Wichita. Dr. Preskorn also is the psychopharmacology patients with MDD. Desvenlafaxine selec- Section Editor of CURRENT PSYCHIATRY and president and CEO Current Psychiatry tively inhibits serotonin and norepinephrine of Clinical Research Institute, Wichita. Vol. 7, No. 6 89

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11 hours. Steady-state plasma concentra- outpatients who met DSM-IV-TR criteria for tion is achieved in 4 to 5 days with once- MDD.1,2,4 daily dosing. In the fi rst study,3 461 patients received Food does not affect intestinal absorp- desvenlafaxine, 100 mg, 200 mg, or 400 mg, tion. Bioavailability after oral administra- or placebo. In the second study,4 369 patients tion is 80%, and time to reach maximum received 200 mg or 400 mg or placebo. In 2

concentration (Tmax) is 7.5 hours. Plasma additional studies, a total of 930 patients re- protein binding is 30% and is independent ceived 50 mg or 100 mg or placebo.1 of desvenlafaxine concentration.1 All studies used the 17-item Hamilton Desvenlafaxine is excreted renally: Rating Scale for Depression (HAM-D17) • unchanged (45% at 72 hours after ad- to measure depressive symptom improve- ministration) ment and the Clinical Global Impressions- • as desvenlafaxine-glucuronide Improvement (CGI-I) scale to measure • as N-desvenlafaxine-glucuronide. overall improvement. Desvenlafaxine was Clinical Point Desvenlafaxine-glucuronide is the fi nal more effective than placebo in HAM-D17 To avoid nausea and metabolite of conjugation reaction with gluc- score improvement in all 4 studies and in dizziness consider uronic acid. N-desvenlafaxine-glucuronide CGI-I score improvement in 3 studies. starting with every- is an end product of a 2-step metabolic In studies comparing 50 mg/d with 100 reaction that starts with oxidation by CYP mg/d, doses >50 mg/d provided no addi- other-day dosing 3A4 to produce N-desvenlafaxine, which is tional benefi t. Higher starting fi xed doses conjugated with glucuronic acid to create were associated with more frequent AEs N-desvenlafaxine-glucuronide. As a result and discontinuation. of these metabolic and elimination path- Gender or age had no effect on treat- ways, dosing adjustment is recommended ment outcome. There was no difference in for patients with severe renal impairment safety in elderly vs younger patients. Data or who are taking a CYP 3A4 inhibitor. are insuffi cient to establish a relationship between race and desvenlafaxine respon- siveness. Desvenlafaxine’s safety and ef- Dosing fectiveness in children and adolescents Desvenlafaxine is available as 50-mg and was not evaluated, and the drug is not ap- 100-mg tablets. The recommended dosage proved for these patients. is 50 mg/d, and the maximum recommended dosage in patients with hepatic impairment is 100 mg/d. Tolerability and safety No dosing adjustment is necessary for Desvenlafaxine’s tolerability is comparable patients with moderate renal impairment. to that of other SNRIs. In premarketing stud- The recommend regimen for those with ies, 12% of patients receiving desvenlafaxine severe renal impairment or end-stage renal (50 mg/d to 400 mg/d) discontinued treat- disease is 50 mg every other day. ment because of AEs, compared with 3% in Instruct patients to take desvenlafaxine the placebo group. The discontinuation rate at approximately the same time each day, in patients receiving 100 mg/d was 8.7% with or without food. Tell them not to dis- compared with 4.1% in patients taking 50 continue the drug abruptly and to immedi- mg/d. ately report any adverse effects (AEs). AEs generally occur during the fi rst week of treatment. In the 8-week trials, the most common AEs were nausea and dizzi- Eﬃ cacy ness (Table 2, page 95). In a long-term study Desvenlafaxine’s antidepressant effi cacy (up to 9 months), the most common AE was was established in four 8-week, randomized, vomiting. Although the recommended start- double-blind, placebo-controlled, fi xed-dose ing dose is 50 mg/d, to avoid AEs consider Current Psychiatry 90 June 2008 (50 mg to 400 mg once daily) studies in adult beginning with every-other-day dosing. continued on page 95

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continued from page 90 Table 2 Desvenlafaxine trials: Rates of adverse eff ects Desvenlafaxine dose Adverse effect 50 mg/d 100 mg/d Placebo Nausea 22% 26% 10%

Dizziness 13% 10% 5%

Insomnia 9% 12% 6%

Hyperhidrosis 10% 11% 4%

Constipation 9% 9% 4%

Somnolence 4% 9% 4%

Decreased appetite 5% 8% 2% Erectile dysfunction 3% 6% 1% Clinical Point Decreased libido 4% 5% 1% Desvenlafaxine is Anxiety 3% 5% 2% excreted in breast Source: Reference 1 milk and may cause AEs in infants who Abruptly discontinuing desvenlafaxine In clinical trials, patients taking desven- are breast-fed can cause withdrawal symptoms, includ- lafaxine experienced increased cholesterol, ing dizziness, nausea, headache, irritabil- triglycerides, and blood pressure. Monitor ity, insomnia, diarrhea, anxiety, abnormal these parameters closely in patients taking dreams, fatigue, and hyperhidrosis. The fre- desvenlafaxine, and use the drug with cau- quency of withdrawal symptoms is higher tion in patients with cerebrovascular and with longer treatment duration. Gradually cardiovascular disease. reducing the dose by administering 50 mg Other concerns in patients taking des- of desvenlafaxine less often can reduce venlafaxine include: withdrawal symptoms. • Antidepressant medications can trigger hypomania or mania in patients with bipolar disorder. Clinical issues • Patients—particularly those who are All SNRIs and selective serotonin reuptake elderly or taking diuretics—may develop inhibitors (SSRIs) have a “black-box” warn- hyponatremia as a result of syndrome of in- ing about the potential for clinical worsen- appropriate antidiuretic hormone. ing and increased suicidality early in treat- • Patients with an increased risk of glau- ment. Closely monitor patients for suicidal coma need to be monitored because of the ideation/behaviors during the fi rst months drug’s effect on blood pressure. of treatment and with dose changes. When taken in the third trimester of Drug interactions. Coadministering des- pregnancy, SNRIs and SSRIs can cause venlafaxine with serotonergic medications— serious neonatal complications—includ- such as triptans, other antidepressants, and ing respiratory distress, cyanosis, apnea, tramadol—can cause serotonin syndrome, a and seizures—that may require longer potentially life-threatening condition charac- hospitalization, respiratory support, or terized by mental status changes, autonomic tube feeding for the infant. Carefully con- instability, neuromuscular aberrations, and sider risks and benefi ts of third-trimester gastrointestinal symptoms. Concomitant antidepressant use.5 Desvenlafaxine is ex- use of desvenlafaxine and blood-thinning creted in breast milk and may cause AEs in medications such as warfarin, aspirin, and Current Psychiatry infants who are breast-fed. nonsteroidal anti-infl ammatory drugs may Vol. 7, No. 6 95

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result in abnormal bleeding. Patients taking a potent CYP 3A4 inhibitor such as ketocon- Related Resource azole may have increased desvenlafaxine • Pristiq (desvenlafaxine) prescribing information. www.wyeth.com/content/showlabeling.asp?id=497. concentration. Drug Brand Names Bupropion • Wellbutrin Paroxetine • Prozac Desvenlafaxine • Pristiq Tramadol • Ultram Contraindications Duloxetine • Cymbalta Venlafaxine • Eff exor Fluoxetine • Prozac Warfarin • Coumadin Do not prescribe desvenlafaxine to patients Ketoconazole • Nizoral who are: Disclosures • hypersensitive to venlafaxine chloride, Dr. Lincoln reports no fi nancial relationship with any company desvenlafaxine succinate, or any parts whose products are mentioned in this article or with of the desvenlafaxine formulation manufacturers of competing products. • taking a monoamine oxidase inhibi- Dr. Preskorn has in the past year received research/ grant support from and served as a speaker for Wyeth tor (MAOI), or have discontinued an Pharmaceuticals. Previously, he has received research/grant Clinical Point MAOI within 14 days. support from or served as a speaker for or consultant to Concomitant use Patients who stop taking desvenlafax- Abbott Laboratories, AstraZeneca, Aventis, Biovail, Boehringer Ingleheim, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, of desvenlafaxine ine should wait 7 days before starting an GlaxoSmithKline, Hoff man LaRoche, Janssen, L.P., Johnson & MAOI. Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfi zer and blood-thinning Inc., Solvay, Somerset, Sumitomo, and Yamanouchi. agents may result in References 1. Pristiq [package insert]. Philadelphia, PA: Wyeth Pharma- abnormal bleeding ceuticals; 2008. 4. Septien-Velez L, Pitrosky B, Padmanabhan SK, et 2. Deecher DC, Beyer CE, Johnston G, et al. Desvenlafaxine al. A randomized, double-blind, placebo-controlled succinate: a new serotonin and norepinephrine reuptake trial of desvenlafaxine succinate in the treatment of inhibitor. J Pharmacol Exp Ther 2006;318(2):657-65. major depressive disorder. Int Clin Psychopharmacol 2007;22(6):338-47. 3. DeMartinis NA, Yeung PP, Entsuah R, Manley AL. A double-blind, placebo-controlled study of the effi cacy and 5. Lennestål R, Källén B. Delivery outcome in relation to safety of desvenlafaxine succinate in the treatment of major maternal use of some recently introduced antidepressants. depressive disorder. J Clin Psychiatry 2007;68(5):677-88. J Clin Psychopharmacol 2007;27(6):607-13.

Bottom Line In 4 clinical trials, desvenlafaxine, 50 mg/d, safely and eff ectively reduced depressive symptoms. Dosages >50 mg/d showed no evidence of added benefi t. The drug’s metabolic profi le—metabolism independent of CYP 2D6 and substantial renal excretion of unchanged medication—makes desvenlafaxine suitable for patients with liver impairment, in dosages ≤100 mg/d. Patients with severe renal impairment need every-other-day dosing.

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