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protriptyline

Adjunctive therapy

Brand: Vivactil

Published 2025-09-28 · Last reviewed 2025-10-05 · 5 references

Content sourced from FDA labeling (DailyMed) and peer-reviewed literature.

Print sheet Review evidence

At a glance

Class: Adjunctive therapy·Typical dose: Initiate 5 mg three to four times daily (15–20 mg/day) and increase by 5 mg every 3–5 days as tolerated to a usual target of 20–40 mg/day (maximum 60 mg/day).·Half-life: Single-dose mean 54 h·TDM range: 70–250 ng/mL·LAI available: No

Class: Adjunctive therapy
Typical dose: Initiate 5 mg three to four times daily (15–20 mg/day) and increase by 5 mg every 3–5 days as tolerated to a usual target of 20–40 mg/day (maximum 60 mg/day).
Half-life: Single-dose mean 54 h
TDM range: 70–250 ng/mL
LAI available: No

Quick answers

What is protriptyline?: Protriptyline (Vivactil) is an activating secondary amine tricyclic antidepressant reserved for legacy treatment-resistant depression regimens and, rarely, narcolepsy-related hypersomnolence or cataplexy due to its pronounced anticholinergic and cardiotoxic risks.
What is Vivactil?: Vivactil is a brand name for protriptyline.
What is Vivactil (protriptyline) used for?: Label indications include: Depression; off-label adjunct for narcolepsy-related cataplexy.
What drug class is Vivactil (protriptyline)?: Tricyclic Antidepressant.
What is the mechanism of action of Vivactil (protriptyline)?: Secondary amine tricyclic antidepressant; enhances norepinephrine with minimal sedative effect.
What strengths does Vivactil (protriptyline) come in?: Oral tablets: 5 mg, 10 mg (brand Vivactil; limited generic supply that often requires special ordering).

General information

Protriptyline (Vivactil) is an activating secondary amine tricyclic antidepressant reserved for legacy treatment-resistant depression regimens and, rarely, narcolepsy-related hypersomnolence or cataplexy due to its pronounced anticholinergic and cardiotoxic risks.

Continuation therapy should involve clinicians comfortable with therapeutic drug monitoring, ECG surveillance, and constipation management because safer antidepressants are usually preferred first-line.

The compare view and the Protriptyline evidence feed can help contextualize activation, anticholinergic load, and cardiotoxicity when maintaining legacy regimens or planning cross-tapers.

U.S. approvals

Major depressive disorder (1967)

Formulations & strengths

Oral tablets: 5 mg, 10 mg (brand Vivactil; limited generic supply that often requires special ordering).

Generic availability

Generics exist but shortages are common—confirm sourcing before refills.

Because the drug has a long half-life, narrow therapeutic window, and lethal overdose potential, assess alternatives when initiating therapy and coordinate care with cardiology or sleep specialists for ongoing use.

View labelExact

Mechanism of action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Potent inhibition of the norepinephrine transporter with comparatively modest serotonin reuptake blockade creates an energizing clinical effect that may lift psychomotor retardation yet can provoke agitation or insomnia.

Quinidine-like sodium-channel blockade and antagonism of muscarinic, histamine H1, and α1 receptors explain arrhythmia risk, orthostasis, and anticholinergic toxicity.

High-affinity NET inhibition.
Moderate M1, H1, and α1 antagonism with minimal antihistamine sedation.
Weak sodium-channel blockade contributes to QRS widening in overdose.

Metabolism & pharmacokinetics

Highly protein bound (~90%) with large volume of distribution; peak concentrations occur 2–5 hours after oral dosing.
Extensively metabolized by CYP2D6 (and CYP2C19) to inactive metabolites—poor metabolizers or patients on strong CYP2D6 inhibitors can accumulate toxic levels.
Terminal half-life averages 54–120 hours; steady state requires several weeks and supports once- or twice-daily maintenance dosing after stabilization.
Therapeutic plasma range 70–250 ng/mL; levels above this increase seizure and arrhythmia risk, warranting dose reduction.

Dosing & administration

Initiate 5 mg three to four times daily (15–20 mg/day) and increase by 5 mg every 3–5 days as tolerated to a usual target of 20–40 mg/day (maximum 60 mg/day).
Once steady state is achieved, consolidate dosing to morning and early afternoon administrations (e.g., 20 mg at 0800, 10 mg at 1300) to limit insomnia.
In older adults, frail patients, or those with cardiac disease, start 5 mg twice daily, titrate cautiously with baseline/follow-up ECGs, and rely on plasma levels to keep concentrations below 150 ng/mL.

Adverse effects

FDA boxed warnings

Antidepressants increase suicidality risk in children, adolescents, and young adults; monitor closely during initiation and dose changes.

Common side effects (≥10%)

Anticholinergic effects: Dry mouth, constipation, urinary retention, blurred vision—prophylactic bowel regimens and hydration counseling recommended.
Orthostatic hypotension: Advise slow positional changes and monitor blood pressure regularly.
Tachycardia: Baseline and follow-up vitals needed, especially if combined with stimulants.
Weight change: Despite its activating profile, modest weight gain can occur; monitor BMI.

Other notable effects

Insomnia, agitation, or tremor—minimize with earlier dosing.
Cardiac conduction abnormalities (QRS/QT prolongation, ventricular arrhythmias); obtain baseline and post-titration ECGs.
Seizure threshold reduction and highly lethal overdose potential requiring limited dispensing and secure storage.
Mania/hypomania activation may emerge in bipolar spectrum disorders—monitor closely and coordinate mood stabilizer coverage through the bipolar disorder hub.

Interactions

Strong CYP2D6 or CYP2C19 inhibitors (e.g., fluoxetine, paroxetine, bupropion, quinidine, ritonavir) markedly increase concentrations—halve the dose and recheck plasma levels.
MAOIs, linezolid, and methylene blue are contraindicated; enforce a 14-day washout to prevent hypertensive crisis or serotonin toxicity.
Sympathomimetics and stimulants used for narcolepsy can amplify hypertension and tachycardia—monitor closely.
Additive QT prolongation with class Ia/III antiarrhythmics, certain antipsychotics, macrolides, or methadone warrants ECG monitoring.
Cumulative anticholinergic burden with first-generation antihistamines, clozapine, or bladder antispasmodics increases delirium and constipation risk.

Other useful information

Obtain baseline ECG, electrolytes, and weight before titration; repeat ECG after reaching target dose or if plasma levels exceed 150 ng/mL.
Order therapeutic drug monitoring after 2–3 weeks on a stable dose and after dose or interacting medication changes to maintain 70–250 ng/mL.
Educate patients on securing medication, recognizing cardiac or serotonin toxicity, and maintaining hydration/fiber to mitigate gastrointestinal hypomotility.

References

Related hubs:SMI toolkit·Support resources