Vortioxetine: Atypical antidepressant
Novel serotonin modulator and stimulator approved for major depressive disorder
Vortioxetine, a novel serotonin modulator and stimulator marketed under the trade name Brintellix (Takeda; Lundbeck), has received FDA approval for the treatment of adults with major depressive disorder.
Although its mechanism of action is not fully understood, vortioxetine is an inhibitor of serotonin (5-hydroxytryptamine [5-HT]) reuptake and an agonist at 5-HT1A receptors; a partial agonist at 5-HT1B receptors; and an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors. According to Takeda, it is the first and only antidepressant that increases the availability of serotonin by this unique combination of pharmacodynamic activity. The contribution of each of these mechanisms of action to vortioxetine’s antidepressant effect has not been established; however, they may represent an improvement over other antidepressants currently on the market, said Takeda.
Key clinical trials
In five short-term studies of 6 to 8 weeks—including a dedicated study with older adults—vortioxetine was effective in treating depression, demonstrating statistically significant improvements in overall symptoms compared with placebo. The primary efficacy measure was mean change from baseline to endpoint in the Hamilton Depression Scale total score in two short-term studies, including the study of older adults, and the Montgomery–Asberg Depression Rating Scale total score in the other studies.
In addition, the clinical trial program included a 24- to 64-week long-term maintenance study in which vortioxetine treatment resulted in a statistically significant longer time to recurrence of depressive episodes compared with placebo. Studies evaluated for safety included more than 4,700 patients aged 18 to 88 years.
Risks and adverse effects
The most commonly observed adverse effects in patients treated with vortioxetine in the 6- to 8-week placebo-controlled studies were nausea, constipation, and vomiting. Overall, 5% to 8% of the patients who received vortioxetine 5 to 20 mg once daily in short-term trials discontinued treatment due to an adverse reaction, the most common being nausea, compared with 4% of patients on placebo.
Vortioxetine had no significant effect on body weight as measured by the mean change from baseline in the 6- to 8-week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of the long-term study in patients who had responded to vortioxetine during the initial 12-week, open-label phase, there was no significant effect on body weight between vortioxetine and placebo. In addition, vortioxetine was not associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate.
Like SSRIs and a range of older antidepressant medications, vortioxetine will carry a boxed warning alerting patients and physicians that with children, adolescents, and young adults between 18 and 24 years, antidepressants can increase the risk of suicidal thoughts and behavior. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients older than 24 years.
Vortioxetine comes in 5-, 10-, 15-, and 20-mg tablets and will be available to patients by the end of 2013.
Manufacturer: Takeda; Lundbeck
Drug class: Serotonin modulator and stimulator (SMS)
Indication: Treatment of adults with major depressive disorder
Dosage: Recommended starting dose is 10 mg orally once daily, with or without food.
Dose may be increased to 20 mg daily as tolerated; for patients who do not tolerate higher doses, dose may be decreased to 5 mg once daily.
Vortioxetine can be discontinued abruptly. However, doses of 15 or 20 mg daily should be reduced to 10 mg daily for 1 week prior to full discontinuation if possible. Maximum recommended dose is 10 mg daily in known poor metabolizers of cytochrome P450 2D6.
Of note: Contraindications include hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in some patients. Use of MAOIs with vortioxetine or within 21 days of stopping the drug is contraindicated because of an increased risk of serotonin syndrome, as are starting vortioxetine with MAOIs such as linezolid or I.V. methylene blue and use of vortioxetine within 14 days of stopping an MAOI.
Review the Medication Guide with patients. Explain that antidepressants, including vortioxetine, carry an increased risk of suicidal thoughts and behavior in children, adolescents, and young adults, particularly at the start of treatment. Inform patients of common adverse effects and possible drug interactions such as serotonin syndrome, as well as abnormal bleeding when taken with NSAIDs, aspirin, or other drugs that affect coagulation.