maprotiline

General Information

Maprotiline (Ludiomil) is a tetracyclic antidepressant that potently blocks norepinephrine reuptake while exerting pronounced antihistaminic and anticholinergic effects.

Because of its narrow therapeutic index and elevated seizure/cardiac risk, modern practice rarely initiates maprotiline; this profile supports clinicians managing legacy regimens.

The compare tool to contrast seizure and cardiotoxic risk against other norepinephrine-focused agents, and review the maprotiline evidence feed when considering continuing or tapering legacy regimens.

High seizure risk (notably above 150 mg/day) and cardiotoxicity often prompt reassessment of therapy and consideration of safer alternatives.

Mechanism of Action

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

Selectively inhibits the norepinephrine transporter, producing antidepressant effects similar to secondary tricyclics while offering little serotonergic activity.

Marked H1, muscarinic, and α1 antagonism underlies its sedative, anticholinergic, and orthostatic adverse effect profile.

• Potent NET inhibitor.
• Antagonist at histamine H1, muscarinic M1, and adrenergic α1 receptors.

Metabolism and Pharmacokinetics

• Slow absorption with peak concentrations 8–12 hours post-dose; elimination half-life averages 43–52 hours (range 26–71 h).
• Highly protein bound and extensively metabolized by CYP2D6 to active desmethylmaprotiline; poor metabolizers and patients on strong CYP2D6 inhibitors accumulate higher levels.
• Therapeutic plasma range 200–400 ng/mL; seizures become more likely above ≈600 ng/mL, supporting routine therapeutic drug monitoring.
• Approximately 60% of a dose is excreted renally and 30% fecally as metabolites; <5% is recovered unchanged.

Dosing and Administration

• Common initiation pattern: 25 mg at bedtime with 25 mg increases every 3–7 days based on tolerability to a typical maintenance dose of 75–150 mg/day (single HS or divided).
• Doses above 150 mg/day are generally avoided; if higher doses are used (up to 225 mg/day), ECG and seizure monitoring are typically intensified.
• Trough concentrations are sometimes obtained at steady state (≥10 days) and after dose or interacting-drug changes, targeting 200–400 ng/mL.
• Older adults or patients with cardiovascular disease generally require ≤75 mg/day with slower titration.

Monitoring & Labs

• Baseline and follow-up ECGs (QRS/QT) for patients with cardiac disease, electrolyte abnormalities, doses >150 mg/day, or QT-active co-medications; urgent evaluation is warranted for syncope or palpitations.
• Therapeutic drug monitoring at steady state (≥10 days), after dose changes, and after starting/stopping CYP2D6 inhibitors is commonly used to stay within the therapeutic window and avoid high plasma levels.
• Seizure risk review at each visit: prior seizure history, sleep deprivation, alcohol use, and other seizure-threshold–lowering drugs (bupropion, tramadol, antipsychotics).
• Orthostatic vitals, sedation, and falls risk—especially in older adults and during titration; dose timing changes and driving precautions are commonly discussed.
• Anticholinergic burden (constipation, urinary retention, confusion); bowel regimens and reduction of additive anticholinergic polypharmacy are often considered when feasible.
• Suicide risk and overdose safety: dispense limited quantities when risk is elevated and include locked-storage counseling.

Maprotiline monitoring is higher-intensity than most modern antidepressants because seizure and cardiotoxic risks rise with plasma level and dose; reassess the ongoing need for legacy therapy regularly.

Adverse Effects

Interactions

• CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) elevate serum levels—dose reduction and therapeutic drug monitoring are often used.
• MAOIs are contraindicated; a 14-day washout is typically used when switching to or from maprotiline.
• Agents that lower seizure threshold (bupropion, tramadol, antipsychotics, theophylline) increase risk—alternatives are often considered, or monitoring is intensified.
• Co-administration with other QT/QRS-prolonging drugs (class I/III antiarrhythmics, certain antipsychotics, macrolides) is generally avoided; if unavoidable, monitoring is typically intensified.
• Additive sedation and anticholinergic toxicity with benzodiazepines, opioids, and first-generation antihistamines.

Other Useful Information

• Legacy regimens are often reassessed for opportunities to transition to safer antidepressants; gradual tapering is typical to limit withdrawal.
• Baseline ECG, weight/BMI, and laboratory assessments are commonly obtained; ECGs are often repeated after dose changes or if arrhythmia symptoms occur.
• Education often covers seizure precautions, constipation management, and early toxicity signs (e.g., tremor, confusion, palpitations).

References

1. Maprotiline hydrochloride tablets prescribing information — DailyMed (2024)
2. Maprotiline Treatment in Depression — Archives of General Psychiatry (1986)
3. Therapeutic drug monitoring of maprotiline — Therapeutic Drug Monitoring (2022)
4. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical