Introduction
Nortriptyline is a tricyclic antidepressant (TCA) that has been used clinically since the 1960s. It is the active N-demethylated metabolite of amitriptyline and is primarily indicated for the treatment of major depressive disorder. Nortriptyline is also commonly used off-label for various chronic pain conditions, migraine prophylaxis, and anxiety disorders. As a secondary amine TCA, it offers a potentially more favorable side effect profile compared to tertiary amine TCAs.
Mechanism of Action
Nortriptyline exerts its therapeutic effects primarily through inhibition of norepinephrine reuptake at the presynaptic neuronal membrane, thereby increasing synaptic concentrations of norepinephrine in the central nervous system. It also moderately inhibits serotonin reuptake. Additionally, nortriptyline demonstrates antagonistic activity at various receptors including:
- Muscarinic acetylcholine receptors (anticholinergic effects)
- Histamine H₁ receptors (sedative effects)
- Alpha-1 adrenergic receptors (orthostatic hypotension)
The drug's antidepressant effects are thought to result from adaptive changes in neurotransmitter receptor systems following chronic administration.
Indications
FDA-Approved Indications:- Major depressive disorder
- Neuropathic pain (diabetic neuropathy, postherpetic neuralgia)
- Migraine prophylaxis
- Anxiety disorders
- Nocturnal enuresis in children (>6 years)
- Smoking cessation adjunct
Dosage and Administration
Depression in Adults:- Initial dose: 25 mg orally once daily or divided doses
- Maintenance dose: 75-100 mg/day in divided doses
- Maximum dose: 150 mg/day
- Initial dose: 10-25 mg at bedtime
- Titrate slowly with 10-25 mg increments
- Not recommended for depression in children
- Nocturnal enuresis: 10-20 mg 1-2 hours before bedtime
- May be administered with or without food
- Once-daily dosing at bedtime is recommended to minimize daytime sedation
- Dose adjustments should occur at ≥5-day intervals
Pharmacokinetics
Absorption: Well absorbed from GI tract; bioavailability ~50% due to first-pass metabolism Distribution: Vd: 15-30 L/kg; highly lipophilic; protein binding: 93-95% Metabolism: Extensive hepatic metabolism via CYP2D6 (primary), CYP2C19, and CYP3A4 Elimination: Half-life: 16-38 hours; excreted primarily in urine as metabolites Therapeutic Range: 50-150 ng/mL (plasma monitoring recommended)Contraindications
- Hypersensitivity to nortriptyline or other TCAs
- Concomitant use with MAOIs (within 14 days)
- Recent myocardial infarction
- Acute recovery phase following MI
- Narrow-angle glaucoma
- Urinary retention
Warnings and Precautions
Black Box Warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders- Cardiovascular Effects: May prolong QT interval; use caution in patients with cardiac disease
- Seizures: May lower seizure threshold
- Anticholinergic Effects: Use caution in elderly patients and those with benign prostatic hyperplasia
- Hepatic Impairment: Dose reduction required
- Renal Impairment: Use caution; consider dose reduction
- Elderly Patients: Increased sensitivity to adverse effects
- Pregnancy: Category D; use only if potential benefit justifies potential risk
- Lactation: Excreted in breast milk; not recommended
Drug Interactions
Major Interactions:- MAOIs: Risk of serotonin syndrome and hypertensive crisis
- CYP2D6 inhibitors (fluoxetine, paroxetine): Increased nortriptyline levels
- Other serotonergic drugs: Increased risk of serotonin syndrome
- Anticholinergic agents: Additive anticholinergic effects
- CNS depressants: Additive sedation
- Antihypertensives: May reduce antihypertensive effects
- Sympathomimetics: Increased pressor effects
Adverse Effects
Common (≥10%):- Dry mouth
- Constipation
- Drowsiness/sedation
- Dizziness
- Blurred vision
- Weight gain
- QT prolongation and arrhythmias
- Orthostatic hypotension
- Seizures
- Neuroleptic malignant syndrome
- Serotonin syndrome
- Agranulocytosis
- Hepatotoxicity
- Suicidal ideation
Monitoring Parameters
Baseline:- Comprehensive metabolic panel
- ECG (especially in patients >40 years or with cardiac risk factors)
- Blood pressure and heart rate (standing and supine)
- Depression screening (PHQ-9)
- Therapeutic drug monitoring (target 50-150 ng/mL)
- ECG every 6-12 months in long-term therapy
- Blood pressure and weight regularly
- Mental status assessment
- Liver function tests annually
Patient Education
- Take medication exactly as prescribed; do not stop abruptly
- May take 2-4 weeks to experience full therapeutic benefit
- Avoid alcohol and other CNS depressants
- Rise slowly from sitting/lying position to prevent dizziness
- Use sugar-free gum or candy for dry mouth
- Maintain good oral hygiene
- Report any chest pain, palpitations, or significant side effects
- Use caution when driving or operating machinery
- Inform all healthcare providers about nortriptyline use
- Keep medication away from children and pets
References
1. FDA Prescribing Information: Pamelor (nortriptyline) 2. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. Cambridge University Press; 2013. 3. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. 4. Finnerup NB, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173. 5. Hiemke C, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62. 6. Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health; 2023. 7. Trindade E, et al. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ. 1998;159(10):1245-1252.
Note: This monograph provides general information and should not replace professional medical advice. Always consult with a healthcare provider for personalized medical guidance.