vortioxetine

Last edited 07/2022 and last reviewed 07/2022

Vortioxetine

• is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder (1)
  • is a 5-HT3, 5-HT1D, and 5-HT7 antagonist, a 5-HT1A agonist, and a 5-HT1B partial agonist with a chemical formula of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]-piperazine
  • hypothesized that vortioxetine works via blockade of serotonin reuptake; however, vortioxetine is pharmacologically different than other SSRIs because it also works by direct modulation of various serotonin receptors (2)
    • chronic therapy with early approved antidepressants causes a desensitization of 5-hydroxytryptamine (5-HT1A) on the presynaptic neuron, thereby creating a negative feedback loop and possibly reducing their antidepressive effects
    • vortioxetine is an agonist of 5-HT1A on the presynaptic neuron, which can accelerate the antidepressant effects, similar to pindolol, and incorporate serotonin transporter (SERT) blockade
• is orally administered once daily at 5- to 20-mg doses
• pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing
  • mean absolute oral bioavailability of vortioxetine is 75%
  • no food effect on pharmacokinetics was observed with vortioxetine (1)
• is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase
  • major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity (1)
  • dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved
    • except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way (1)

NICE state:

• Vortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to 2 antidepressants within the current episode

Reference:

• Chen G et al. Vortioxetine: Clinical Pharmacokinetics and Drug Interactions. Clin Pharmacokinet. 2018 Jun;57(6):673-686. doi: 10.1007/s40262-017-0612-7. PMID: 29189941; PMCID: PMC5973995.
• D'Agostino A, English CD, Rey JA. Vortioxetine (brintellix): a new serotonergic antidepressant. P T. 2015 Jan;40(1):36-40.
• NICE (November 2015). Vortioxetine for treating major depressive episodes