Introduction
Vortioxetine is a novel multimodal antidepressant approved by the FDA in 2013 for the treatment of major depressive disorder (MDD) in adults. Unlike traditional antidepressants that primarily target monoamine reuptake, vortioxetine combines serotonin reuptake inhibition with direct modulation of several serotonin receptors, offering a unique pharmacological profile that may provide both antidepressant and cognitive benefits.
Mechanism of Action
Vortioxetine exerts its therapeutic effects through multiple mechanisms:
- Serotonin transporter (SERT) inhibition: Potently inhibits serotonin reuptake (Ki = 1.6 nM)
- 5-HT1A receptor agonism: Enhances serotonin transmission
- 5-HT1B receptor partial agonism: Modulates neurotransmitter release
- 5-HT1D, 5-HT3, and 5-HT7 receptor antagonism: 5-HT3 antagonism may reduce nausea and improve cognitive function, while 5-HT7 antagonism may contribute to antidepressant and procognitive effects
This multimodal activity results in enhanced serotonin, norepinephrine, dopamine, acetylcholine, and histamine transmission in specific brain regions.
Indications
- FDA-approved: Treatment of major depressive disorder (MDD) in adults
- Off-label uses: Generalized anxiety disorder (supported by clinical trials)
- Not approved for pediatric use
Dosage and Administration
Initial dose: 10 mg once daily Dose titration: May increase to 20 mg daily after at least 2 weeks based on response and tolerability Maximum dose: 20 mg daily (10 mg daily in patients with CYP2D6 poor metabolizers) Special populations:- Hepatic impairment: Maximum 10 mg daily in patients with severe hepatic impairment
- Renal impairment: No dose adjustment necessary for mild to moderate impairment; use caution in severe renal impairment
- Elderly: No dose adjustment necessary based on age alone
- CYP2D6 poor metabolizers: Maximum 10 mg daily
Pharmacokinetics
Absorption: Well absorbed with absolute bioavailability of 75%. Tmax = 7-11 hours. Food does not affect absorption. Distribution: Volume of distribution ~26 L. Plasma protein binding ~98%. Metabolism: Primarily hepatic via CYP2D6 (and to lesser extent CYP3A4/5, CYP2C9, CYP2C19, CYP2A6, CYP2C8, and CYP2B6). Forms pharmacologically inactive metabolites. Elimination: Half-life ~66 hours. Excreted primarily in urine (59%) and feces (26%).Contraindications
- Hypersensitivity to vortioxetine or any component of the formulation
- Concomitant use with MAOIs or within 21 days of MAOI discontinuation
- Initiation of MAOI therapy within 14 days of vortioxetine discontinuation
Warnings and Precautions
Suicidal thoughts and behaviors: Monitor for clinical worsening and suicide risk, especially during initiation and dose adjustments Serotonin syndrome: Risk particularly with concomitant serotonergic drugs Activation of mania/hypomania: Screen for bipolar disorder Discontinuation syndrome: Taper gradually when discontinuing treatment Angle-closure glaucoma: May occur due to pupillary dilation Hyponatremia: May occur due to SIADH Bleeding risk: Increased risk of bleeding, especially with concomitant NSAIDs, aspirin, or other anticoagulantsDrug Interactions
Strong CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine): Reduce vortioxetine dose by half Strong CYP inducers (e.g., carbamazepine, phenytoin, rifampin): May decrease vortioxetine concentrations Serotonergic drugs (e.g., other SSRIs, SNRIs, triptans, tramadol): Increased risk of serotonin syndrome NSAIDs, aspirin, warfarin: Increased bleeding risk MAOIs: Contraindicated due to risk of serotonin syndromeAdverse Effects
Common (≥5% and twice placebo):- Nausea (21-32%)
- Constipation (3-6%)
- Vomiting (3-6%)
- Sexual dysfunction (decreased libido, delayed ejaculation, anorgasmia)
- Serotonin syndrome
- Suicidal ideation
- Hyponatremia
- Abnormal bleeding
- Angle-closure glaucoma
- Mania/hypomania
Monitoring Parameters
- Mental status and suicide risk assessment at initiation and during dose changes
- Signs and symptoms of serotonin syndrome
- Serum sodium in elderly patients and those on diuretics
- Bleeding parameters in patients on concomitant anticoagulants
- Mood changes suggesting mania/hypomania
- Treatment response using standardized depression scales (PHQ-9, MADRS)
- Adverse effects, particularly gastrointestinal symptoms and sexual dysfunction
Patient Education
- Take medication as prescribed at the same time each day
- Do not stop abruptly; work with provider to taper if discontinuation needed
- May take several weeks to experience full therapeutic benefit
- Report any worsening depression, suicidal thoughts, or unusual behavior changes
- Be aware of potential side effects, especially nausea (which often improves with continued treatment)
- Inform all healthcare providers about vortioxetine use, especially before surgical procedures
- Avoid alcohol during treatment
- Use caution when driving or operating machinery until effects are known
- Report any signs of bleeding or bruising easily
References
1. FDA Prescribing Information: Trintellix (vortioxetine). 2022 2. Sanchez C, et al. Vortioxetine: a novel multimodal antidepressant for the treatment of major depressive disorder. Expert Opin Pharmacother. 2015;16(3):385-395 3. McIntyre RS, et al. The effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials. Int J Neuropsychopharmacol. 2016;19(10):pyw055 4. Baldwin DS, et al. A meta-analysis of the efficacy of vortioxetine in patients with major depressive disorder (MDD) and high levels of anxiety symptoms. J Affect Disord. 2016;206:140-150 5. Thase ME, et al. Efficacy and safety of vortioxetine on cognitive function in major depressive disorder: a systematic review and meta-analysis of randomized controlled trials. CNS Spectr. 2022;27(4):416-425 6. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010 (with 2022 updates)