Vilazodone (Viibryd)

Mechanism of action

• Blocks SERT, increasing synaptic serotonin, and simultaneously partially stimulates presynaptic 5-HT1A autoreceptors.
• The theoretical advantage: partial (rather than full) 5-HT1A agonism may desensitize these autoreceptors faster, reducing the initial negative-feedback dampening of serotonin release that normally delays SSRI onset - and the added post-synaptic 5-HT1A stimulation is thought to further boost net serotonergic tone. This was hypothesized to give a faster onset and fewer sexual side effects than plain SSRIs, though large trials have not shown consistent superiority over standard SSRIs (psychiatrist.com review; Psychopharmacology Institute).

Indication

• FDA-approved for Major Depressive Disorder (MDD) in adults. Not approved for pediatric use - safety/efficacy in children has not been established (Kaplan & Sadock's Synopsis of Psychiatry).
• Used off-label for generalized anxiety disorder, social anxiety, and OCD.

Dosing and administration

• Requires titration: typically started low and increased over about 2 weeks to the target dose to minimize GI side effects.
• Must be taken with food. Without food, absorption is markedly reduced and effectiveness may be diminished (Kaplan & Sadock's Synopsis of Psychiatry).

Pharmacokinetics / drug interactions

• Metabolized primarily by CYP3A4.
• Strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) can raise vilazodone plasma levels by 50% or more, requiring dose reduction; CYP3A4 inducers can lower levels (Katzung's Basic and Clinical Pharmacology; Kaplan & Sadock's Comprehensive Textbook of Psychiatry).
• Vilazodone itself is neither a potent inhibitor nor strong inducer of CYP enzymes.

Adverse effects

• Diarrhea (~28% vs 9% placebo in phase III trials)
• Nausea (~23% vs 5% placebo)
• Dizziness, insomnia, vomiting, abnormal dreams, akathisia/restlessness, palpitations, tremor, feeling jittery

Safety signals / precautions

• Like other serotonergic antidepressants, carries a risk of serotonin syndrome when combined with other serotonergic agents (MAOIs, SSRIs, SNRIs, triptans, tramadol, buspirone, tryptophan) - contraindicated with MAOIs or within 14 days of MAOI use.
• In vitro, vilazodone was clastogenic in some mammalian cell assays though not mutagenic in bacterial reverse mutation testing (per package insert data cited in Kaplan & Sadock's).
• Standard antidepressant class warnings apply (suicidality risk in young adults, discontinuation syndrome if stopped abruptly - see Maudsley Deprescribing Guidelines for tapering advice).

Vilazodone's dual action at SERT and 5-HT1A receptors (Stahl's Essential Psychopharmacology).

Evidence check

Vilazodone Dosing

• Available as 10 mg, 20 mg, and 40 mg tablets (a 30-day starter kit contains 7x10mg, 7x20mg, and 16x40mg tablets to facilitate titration).
• Titration schedule:
  • Days 1-7: 10 mg once daily
  • Days 8-14: 20 mg once daily
  • Day 15 onward: 40 mg once daily (target/maintenance dose)
• Must be taken with food - without food, drug absorption is significantly reduced and efficacy may be diminished.
• No additional benefit was shown in trials with doses beyond the standard target.

Special population adjustments

Dose adjustment for drug interactions

• If co-administered with a strong CYP3A4 inhibitor (e.g., ketoconazole, regular grapefruit juice intake), limit the dose to 20 mg/day maximum, since CYP3A4 inhibition can raise vilazodone plasma levels by 50% or more.
• Caution with CYP3A4 inducers, which may lower efficacy.

Rationale for titration

Vortioxetine (Trintellix)

• Agonist at 5-HT1A receptors
• Partial agonist at 5-HT1B receptors
• Antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors

Dosing

Dose adjustments for drug interactions (CYP2D6 is the primary metabolic pathway)

• CYP2D6 potent inhibitors co-administered (e.g., bupropion, fluoxetine, paroxetine, quinidine): reduce vortioxetine dose by half.
• CYP2D6 poor metabolizers: max dose 10 mg/day.
• CYP inducers co-administered >14 days (e.g., rifampin, carbamazepine, phenytoin): may need to increase dose up to 3x the original dose; once the inducer is stopped, taper back down to the original dose within 14 days.
• Older adults, poor 2D6 metabolizers, or with a 2D6 inhibitor on board: starting dose should be 5 mg/day (Kaplan & Sadock's Comprehensive Textbook of Psychiatry).

Discontinuation

• Can technically be stopped abruptly, but for doses of 15-20 mg/day, tapering is recommended: decrease to 10 mg/day for 1 week before full discontinuation, to avoid transient withdrawal effects (headache, muscle tension) seen in placebo-controlled trials.
• Given its long terminal half-life, a bothersome side effect can be managed by withholding the dose for 3 days and restarting at half-dose rather than stopping altogether.

Side effects

• Nausea is the most common treatment-emergent adverse event (roughly one-fourth to one-third of patients), and the leading cause of discontinuation (dose-dependent, reaching rates comparable to duloxetine 60 mg/day).
• Other common effects: constipation, vomiting, sexual dysfunction (dose-dependent, worse at higher doses).
• Considered to have a comparatively favorable overall tolerability profile among antidepressants otherwise.

Overdose data

Evidence check

• PMID 39891526 - efficacy meta-analysis in acute MDD treatment (2025)
• PMID 39121757 - umbrella review of dose-response relationship (2024)
• PMID 41058029 - efficacy/adverse effect meta-analysis (2025)

FDA-Approved Use of Vortioxetine (Trintellix)

• Original approval: September 30, 2013, initially marketed as Brintellix, renamed Trintellix in the US in 2016 to avoid confusion with the anticoagulant Brilinta (drugs.com; Takeda newsroom).
• The FDA approval was supported by an initial clinical development program of eleven placebo-controlled trials (five active-referenced) (Kaplan & Sadock's Comprehensive Textbook of Psychiatry).
• As of current labeling, MDD in adults remains the only FDA-approved indication - "To this day, the only approved indication for vortioxetine is for the treatment of MDD in adults" (Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Therapeutic Indications).

Label expansion: cognitive function claim (2018)

• Note: Katzung's Basic and Clinical Pharmacology states vortioxetine is "approved in Europe and the USA to treat cognitive dysfunction associated with depression" - this reflects the cognition-related labeling data added to the existing MDD indication, not a separate stand-alone indication for cognitive dysfunction as a distinct disorder. The formal indication remains MDD; the cognition data is additional supporting information within that indication.

Not FDA-approved for:

• Generalized anxiety disorder, other anxiety disorders, or any indication outside adult MDD - these would be off-label uses.
• Pediatric use - not established/approved in children or adolescents.

Global context