Trintellix (Vortioxetine)
vortioxetine hydrobromide
Vortioxetine Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major depressive disorder (MDD) | Adults (18+ years) | Monotherapy | FDA Approved |
Vortioxetine was approved by the FDA in September 2013 (initially marketed as Brintellix, renamed to Trintellix in 2016 to avoid confusion with Brilinta). Efficacy was demonstrated in six randomized, double-blind, placebo-controlled trials of 6–8 weeks (five in adults 18–75 years, one in elderly 64–88 years) and two maintenance studies. Trintellix is the first antidepressant with FDA-approved labelling that includes DSST (Digit Symbol Substitution Test) data, a validated measure of processing speed in acute MDD. Vortioxetine is not approved for pediatric use; two studies in patients aged 7–17 failed to demonstrate efficacy.
Generalized anxiety disorder (GAD) — Evidence quality: Low. Development for GAD was discontinued. Meta-analyses have yielded mixed results; a 2019 analysis found no statistically significant superiority over placebo. Post-hoc subgroup analyses suggest benefit limited to severe GAD (HAM-A ≥25).
Cognitive impairment in MDD — Although DSST improvement data appear in the FDA label, vortioxetine was not approved as a standalone treatment for cognitive symptoms. Path analyses suggest half to two-thirds of the cognitive effect is independent of mood improvement.
OCD (SSRI-resistant) — Evidence quality: Very low. A 2025 retrospective multicenter study showed promising Y-BOCS reductions, but no prospective RCTs have been completed. An ongoing RCT is evaluating adjunctive vortioxetine in OCD.
Vortioxetine Dosing
Adult Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD — initial treatment | 10 mg once daily | 20 mg once daily | 20 mg/day | Increase to 20 mg as tolerated; higher doses showed better effects in U.S. trials Can take with or without food |
| MDD — dose-sensitive patient | 5 mg once daily | 5–10 mg once daily | 20 mg/day | For patients who do not tolerate higher doses Two U.S. studies at 5 mg failed to show effectiveness |
| MDD — CYP2D6 poor metabolizer or strong CYP2D6 inhibitor | 5 mg once daily | 5–10 mg once daily | 10 mg/day | PMs have ~2x plasma levels; halve dose with bupropion, fluoxetine, paroxetine, quinidine Resume original dose when inhibitor stopped |
| MDD — strong CYP inducer (>14 days) | 10 mg once daily | Up to 3× original dose | 3× original | Rifampin, carbamazepine, phenytoin; reduce to original within 14 days of stopping inducer |
| MDD — switching from MAOI | 10 mg once daily | 10–20 mg once daily | 20 mg/day | 14-day washout after stopping MAOI 21-day washout required after stopping vortioxetine before starting MAOI |
| MDD — discontinuation | 15–20 mg → 10 mg/day × 1 week → stop | — | Can be abruptly discontinued per label; gradual reduction recommended at higher doses Patients on ≤10 mg may stop without tapering | |
Special Populations
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Elderly (>65 years) | 5–10 mg once daily | 5–20 mg once daily | 20 mg/day | No PK-based adjustment; 5 mg efficacy shown in dedicated elderly trial (ages 64–88) Higher hyponatremia risk; monitor sodium |
| Renal impairment (mild–severe, ESRD) | 10 mg once daily | 10–20 mg once daily | 20 mg/day | No dose adjustment; clearance not affected |
| Hepatic impairment (mild–severe) | 10 mg once daily | 10–20 mg once daily | 20 mg/day | No dose adjustment; clearance not affected |
Due to vortioxetine’s very long half-life (~66 hours), the FDA requires a minimum 21-day washout after stopping vortioxetine before starting an MAOI — significantly longer than the 14 days required for most SSRIs/SNRIs. Conversely, when switching from an MAOI to vortioxetine, the standard 14-day washout applies. This asymmetry is unique to vortioxetine and is one of the most commonly overlooked prescribing details.
Pharmacology
Mechanism of Action
Vortioxetine is classified as a multimodal serotonin modulator because it combines serotonin reuptake inhibition with direct activity at several serotonin receptor subtypes. It potently inhibits the serotonin transporter (SERT; Ki = 1.6 nM, IC50 = 5.4 nM for reuptake inhibition) while simultaneously acting as a 5-HT3 receptor antagonist (Ki = 3.7 nM), 5-HT1A receptor agonist (Ki = 15 nM), 5-HT7 receptor antagonist (Ki = 19 nM), 5-HT1B receptor partial agonist (Ki = 33 nM), and 5-HT1D receptor antagonist (Ki = 54 nM). In PET studies, SERT occupancy is approximately 50% at 5 mg/day, 65% at 10 mg/day, and 80% at 20 mg/day. The multimodal pharmacology is hypothesized to modulate downstream glutamate and GABA release, which may contribute to cognitive benefits observed on measures of processing speed. Vortioxetine has negligible affinity for norepinephrine (Ki = 113 nM) and dopamine (Ki >1000 nM) transporters and does not prolong QTc at doses up to 40 mg.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 7–11 h; bioavailability 75%; food has no effect | Can be taken with or without food; no dietary restrictions |
| Distribution | Vd ~2,600 L; protein binding 98% (concentration-independent) | Extensive extravascular distribution; dialysis unlikely effective; may displace highly bound drugs |
| Metabolism | Extensively via CYP2D6 (primary) + CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, CYP2B6 + glucuronidation; major metabolite (carboxylic acid) is inactive | CYP2D6 PMs have ~2x exposure (cap 10 mg/day); halve dose with strong CYP2D6 inhibitors; up to 3x dose with strong CYP inducers |
| Elimination | t½ ~66 h; steady state ~2 weeks; 59% urine + 26% feces (as metabolites); negligible unchanged drug in urine | Once-daily dosing; very long t½ requires 21-day washout before MAOI; no renal/hepatic adjustment needed |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 21–32% | Dose-related (21% at 5 mg to 32% at 20 mg vs 9% placebo); usually mild-moderate; median duration 2 weeks; 15–20% experience it within first 1–2 days; ~10% still affected at end of 6–8 wk studies; more common in females |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | 6–9% | Dose-related; similar to placebo (6%) at 5 mg; no impairment on driving test |
| Diarrhea | 7–10% | Mild excess over placebo (6%); generally transient |
| Dry mouth | 6–8% | Comparable to placebo (6%); minimal clinical significance |
| Constipation | 3–6% | Dose-related; vs 3% placebo |
| Vomiting | 3–6% | Dose-related; vs 1% placebo; usually in first week |
| Flatulence | 1–3% | Mild; at 10 mg 3% vs 1% placebo |
| Pruritus | 1–3% | Dose-related; includes generalized pruritus |
| Abnormal dreams | 2–3% | At 15–20 mg; vs 1% placebo |
| Sexual dysfunction (males) | 3–5% (self-reported); 16–29% (ASEX) | Dose-related; ASEX placebo rate 14%; may be lower than traditional SSRIs; switching from SSRI improved prior TESD vs escitalopram switch |
| Sexual dysfunction (females) | <1–2% (self-reported); 22–34% (ASEX) | ASEX placebo rate 20%; proactive assessment recommended |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serotonin syndrome | Rare | Hours to days; higher risk with combinations | Discontinue vortioxetine and serotonergic agents; supportive care |
| Suicidal thoughts and behaviors | Class effect | First months or after dose changes; highest in <25 yrs | Close monitoring; consider discontinuation if worsening |
| Hyponatremia / SIADH | Rare | Days to weeks | Discontinue; manage electrolytes |
| Mania/hypomania | <0.1% | Days to weeks | Discontinue; screen for bipolar disorder |
| Hypersensitivity (anaphylaxis, angioedema) | Very rare (postmarketing) | Any time | Discontinue permanently; emergency care; rechallenge contraindicated |
| Abnormal bleeding | Rare (class effect) | Any time; additive with anticoagulants | Monitor; check INR if on warfarin |
| Seizures | Very rare (postmarketing) | Variable | Discontinue; evaluate etiology |
| Angle-closure glaucoma | Very rare (class effect) | Any time | Avoid in untreated narrow angles; urgent ophthalmology referral |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Nausea | Most common | Only individual AE cited as leading cause across all dose groups |
| Other (GI, dizziness) | <1% each | Rarely severe enough to warrant stopping |
Nausea is the most significant tolerability barrier, affecting up to one-third of patients at 20 mg/day. It peaks within the first 1–2 days, has a median duration of about two weeks, and is more common in females. Starting at 10 mg and allowing tolerance before escalating is standard. For highly sensitive patients, consider starting at 5 mg. Taking with food may help symptomatically but is not pharmacokinetically required.
Drug Interactions
Vortioxetine is metabolized by multiple CYP enzymes with CYP2D6 as the primary pathway. It does not significantly inhibit or induce other CYP enzymes and has no clinically meaningful effects on substrates for CYP2B6, CYP2C9, CYP2C19, or CYP3A4. A notable laboratory interaction is that vortioxetine can produce false-positive results for methadone on urine enzyme immunoassays.
Monitoring
- Suicidality screeningWeekly × 4 wk, biweekly × 4 wk, then as indicated
RoutineAssess for emergent suicidal ideation, especially in patients under 25 and after dose changes. - Depressive symptomsEvery 2–4 wk during titration, then 1–3 months
RoutineFull effect generally not until week 4+. Effect on processing speed (DSST) may emerge earlier. - Serum sodiumBaseline in at-risk; as clinically indicated
Trigger-basedCheck in elderly, diuretic users, and volume-depleted patients. - Sexual functionBaseline, then 4–6 wk and periodically
RoutineTESD can occur at all doses but may be lower than traditional SSRIs. Switching from SSRI may improve prior TESD. - CYP2D6 statusBefore initiation if feasible
Trigger-basedPMs have ~2x exposure. Max 10 mg/day in known PMs. Consider pharmacogenomic testing. - WeightBaseline, then every 3 months
RoutineNo significant weight effect in trials. Postmarketing reports of weight gain exist. - Bleeding signsEach visit if on anticoagulants
Trigger-basedMonitor INR when starting/stopping vortioxetine in warfarin users.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to vortioxetine or any formulation component — Anaphylaxis, angioedema, and urticaria reported. Rechallenge contraindicated.
- Concurrent MAOI use or within required washout periods — 14 days after stopping MAOI; 21 days after stopping vortioxetine. Includes linezolid and IV methylene blue.
Relative Contraindications (Specialist Input Recommended)
- Bipolar disorder (unscreened or uncontrolled) — May precipitate mania. Screen before initiation.
- Untreated anatomically narrow angles — Risk of angle-closure glaucoma.
Use with Caution
- Elderly or volume-depleted / diuretic users — Higher hyponatremia risk.
- CYP2D6 poor metabolizers — Cap at 10 mg/day.
- Active bleeding or anticoagulant therapy — SRI-mediated platelet impairment.
- Third trimester pregnancy — Neonatal withdrawal and PPHN risk.
Antidepressants increased suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. In pooled analyses, 14 additional cases per 1,000 under 18 and 5 per 1,000 aged 18–24 compared with placebo. Closely monitor all patients. Vortioxetine is not approved for pediatric use.
Patient Counselling
Purpose of Therapy
Vortioxetine is prescribed to treat major depressive disorder. It works by increasing serotonin activity and modulating several serotonin receptors, which may help improve both mood and aspects of thinking ability such as processing speed. Full benefit generally takes 4 weeks or longer.
How to Take
Take vortioxetine once daily at the same time, with or without food. Swallow the tablet whole. If you miss a dose, take it as soon as you remember unless near the next dose. Do not stop without consulting your prescriber, as gradual reduction is recommended at higher doses.
Sources
- Takeda Pharmaceuticals America, Inc. TRINTELLIX (vortioxetine) tablets, for oral use. Full prescribing information. Revised 8/2023. FDA LabelPrimary source for all dosing, adverse reaction rates, drug interactions, contraindications, and PK parameters cited in this monograph.
- FDA. Trintellix (vortioxetine) NDA 204447. Initial approval September 30, 2013. Approval HistoryRegulatory timeline covering initial approval as Brintellix and 2016 name change.
- Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15(5):589–600. doi:10.1017/S1461145711001027Pivotal trial demonstrating vortioxetine 5 mg and 10 mg superiority over placebo on MADRS (Study 1 in label).
- Boulenger JP, Loft H, Florea I. A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder. J Psychopharmacol. 2012;26(11):1408–1416. doi:10.1177/0269881112441866Maintenance study (Study 9) demonstrating relapse prevention with vortioxetine 5–10 mg vs placebo.
- McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557–1567. doi:10.1017/S1461145714000546Landmark DSST trial (Study 7) showing vortioxetine 10 mg and 20 mg improvement in processing speed in MDD.
- Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, Clayton AH. Effect of vortioxetine vs. escitalopram on sexual functioning in adults with well-treated MDD experiencing SSRI-induced sexual dysfunction. J Sex Med. 2015;12(10):2036–2048. doi:10.1111/jsm.12980Study 11 in label demonstrating improvement in SSRI-induced TESD when switching to vortioxetine vs escitalopram.
- Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27(4):215–223. doi:10.1097/YIC.0b013e3283542457Dedicated elderly trial (Study 6) demonstrating vortioxetine 5 mg efficacy in patients aged 64–88.
- Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 update on clinical guidelines for management of major depressive disorder in adults. Can J Psychiatry. 2024;69(9):641–687. doi:10.1177/07067437241245384Current guideline listing vortioxetine as a first-line antidepressant option for MDD.
- Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–1366. doi:10.1016/S0140-6736(17)32802-7Landmark network meta-analysis ranking vortioxetine among the top agents for efficacy and acceptability.
- Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther. 2015;145:43–57. doi:10.1016/j.pharmthera.2014.07.001Comprehensive review of vortioxetine’s multimodal mechanism including receptor pharmacology and downstream effects.
- Stahl SM. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA). CNS Spectr. 2015;20(4):331–336. doi:10.1017/S1092852915000334Translational review linking receptor pharmacology to glutamate/GABA modulation and potential cognitive benefits.
- Huang IC, Chang TS, Chen C, Sung JY. Effect of vortioxetine on cognitive impairment in patients with major depressive disorder: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2022;25(12):969–978. doi:10.1093/ijnp/pyac054Meta-analysis confirming cognitive benefits in MDD, with path analysis showing partial independence from mood improvement.
- Baldwin DS, Florea I, Jacobsen PL, Zhong W, Nomikos GG. A meta-analysis of the efficacy of vortioxetine in patients with major depressive disorder and high levels of anxiety symptoms. J Affect Disord. 2016;206:140–150. doi:10.1016/j.jad.2016.07.035Post-hoc meta-analysis showing vortioxetine efficacy in anxious depression subgroup.
- Kambeitz JP, Howes OD. The serotonin transporter in depression: meta-analysis of in vivo and post mortem findings and implications for understanding and treating depression. J Affect Disord. 2015;186:358–366. doi:10.1016/j.jad.2015.07.034Meta-analysis of SERT changes in depression, contextualizing vortioxetine’s PET-measured occupancy data.