Vortioxetine

Indications

• FDA-approved for major depressive disorder in adults, started at 10 mg once daily and increased to 20 mg/day as tolerated.
• Not approved for any pediatric indication; adolescent depression trials did not consistently separate from placebo.
• Off-label for generalized anxiety disorder, where the trial results were mixed and did not support a US anxiety indication.
• Randomized trials show improvement in processing speed and executive function in depression that is partly independent of mood change.
• A reasonable off-label choice when residual cognitive complaints persist after mood symptoms have improved on another antidepressant.
• Sometimes selected off-label after SSRI-induced sexual dysfunction, since switching to vortioxetine improved sexual function in a comparative trial.

Mechanism of action

• Inhibits the serotonin transporter while also acting directly at several serotonin receptor subtypes, which is why it is called multimodal.
• Antagonizes 5-HT3 and 5-HT7 receptors, actions linked in preclinical work to procognitive and antidepressant effects beyond reuptake blockade.
• Acts as a 5-HT1A agonist and 5-HT1B partial agonist, further increasing serotonergic tone and modulating raphe autoreceptor feedback.
• Downstream disinhibition of acetylcholine, norepinephrine, dopamine, and glutamate release is the proposed basis for its cognitive effects.
• 5-HT3 antagonism paradoxically coexists with high rates of nausea, which appears to be centrally rather than peripherally mediated.

Pharmacokinetics

• Bioavailability is about 75 percent and is unaffected by food, so it can be taken at any consistent time of day.
• Half-life is approximately 66 hours, the longest among the newer antidepressants, so steady state takes about two weeks to reach.
• That long half-life makes discontinuation symptoms uncommon, though the label still advises reducing 15 to 20 mg doses to 10 mg for a week.
• Metabolized mainly by CYP2D6 with several minor enzymes contributing; the carboxylic acid metabolite is pharmacologically inactive.
• CYP2D6 poor metabolizers reach roughly twice the exposure of extensive metabolizers, which caps their dose at 10 mg/day.

Dosing

• Start 10 mg PO once daily with or without food; increase to 20 mg/day as tolerated, since higher doses were more effective in trials.
• Use 5 mg/day for patients who cannot tolerate 10 mg, and treat 20 mg/day as the maximum recommended dose.
• Halve the dose when a strong CYP2D6 inhibitor such as bupropion, fluoxetine, paroxetine, or quinidine is added.
• With a strong CYP inducer used beyond 14 days the dose may be increased, but not to more than three times the original dose.
• Available as 5, 10, and 20 mg film-coated tablets; there is no liquid or extended-release formulation.
• No adjustment is needed for renal impairment or mild to moderate hepatic impairment, and it is not recommended in severe hepatic impairment.

Adverse effects

• Nausea is the dominant adverse effect, rising from about 21 percent at 5 mg/day to roughly 32 percent at 20 mg/day and more frequent in women.
• Nausea usually appears in the first week and resolves within two weeks; taking the dose with food and titrating slowly both help.
• Constipation, vomiting, dry mouth, dizziness, and abnormal dreams are the other common tolerability complaints.
• Sexual dysfunction is dose-related and appears lower than with SSRIs at 5 to 10 mg/day but approaches SSRI rates at 20 mg/day.
• Hyponatremia, serotonin syndrome, treatment-emergent mania, and increased bleeding with NSAIDs or anticoagulants are the serious risks.
• Weight change is minimal in short-term and one-year extension studies, an advantage over mirtazapine and paroxetine.

Monitoring

• Assess suicidality, activation, and agitation weekly for the first four weeks and after each dose change, especially in patients under 25.
• Ask specifically about nausea at week one and week two, since it peaks early and is the main driver of early discontinuation.
• Track mood with the PHQ-9 or MADRS every two to four weeks and consider a cognitive measure such as the DSST when cognition is the target.
• Check serum sodium at baseline and within two to four weeks in older adults and in patients on diuretics.
• Review the medication list for strong CYP2D6 inhibitors and for strong inducers whenever a new prescription is started.

Interactions

• Contraindicated with MAOIs and within 14 days of stopping one, and with linezolid or intravenous methylene blue.
• Strong CYP2D6 inhibitors, most commonly bupropion, fluoxetine, and paroxetine, double exposure and require halving the vortioxetine dose.
• Strong inducers such as rifampin, carbamazepine, and phenytoin can reduce exposure by more than half over two weeks of co-administration.
• Additive serotonin syndrome risk with triptans, tramadol, fentanyl, lithium, tryptophan, and other serotonergic antidepressants.
• Increases bleeding risk with aspirin, NSAIDs, warfarin, and direct oral anticoagulants, as with the SSRIs.

Special populations

• Pregnancy data are limited to registry and cohort reports without a clear teratogenic signal; better-studied agents are preferred if possible.
• Lactation data are sparse, so an antidepressant with established infant safety should generally be chosen when starting during breastfeeding.
• Not approved in pediatric patients, and the two adolescent depression trials did not establish efficacy over placebo.
• No dose adjustment is required by age, although older adults face greater hyponatremia and falls risk and may prefer 5 to 10 mg/day.
• No adjustment is needed in any degree of renal impairment, and severe hepatic impairment remains unstudied and not recommended.

Clinical pearls

• Nausea is dose-related and peaks in week one; start at 10 mg and take it with food.
• Best antidepressant evidence for improving processing speed independent of mood improvement.
• Halve the dose if bupropion, fluoxetine, or paroxetine is added, since all are strong 2D6 inhibitors.