protriptyline

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

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.

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 and 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 and 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

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

1. Protriptyline hydrochloride tablets prescribing information — DailyMed (2023)
2. Therapeutic drug monitoring of protriptyline — Therapeutic Drug Monitoring (2022)
3. Use of protriptyline in narcolepsy management — Sleep Medicine (2021)
4. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
5. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)