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Sunday, July 27, 2025

Dosulepin


Dosulepin (also known as dothiepin) is a tricyclic antidepressant (TCA) that was once widely used in the treatment of major depressive disorder, anxiety disorders, and certain forms of neuropathic pain. While it shares pharmacological similarities with other TCAs, dosulepin has become less favored in clinical practice due to its narrow therapeutic index, significant cardiotoxicity risk, and lethality in overdose. In several countries, including the UK, its use has been severely restricted or discouraged.

This comprehensive professional profile outlines dosulepin’s pharmacological classification, mechanisms of action, clinical indications, dosing protocols, adverse reactions, contraindications, precautions, and pharmacodynamic considerations.

Pharmacological Classification

  • Therapeutic class: Antidepressant

  • Pharmacologic class: Tricyclic antidepressant (TCA)

  • ATC code: N06AA16

  • Legal status: Prescription-only (Rx); restricted in some countries

Chemical and Formulation Information

  • International Nonproprietary Name (INN): Dosulepin

  • USAN Name: Dothiepin (not FDA approved in the United States)

  • Common brand names: Prothiaden®, Dothep®, Thaden®, Dopress®

  • Formulations:

    • Tablets: 25 mg, 75 mg

    • Capsules: 25 mg

    • Oral liquid (elixir): 25 mg/5 mL

Mechanism of Action

Dosulepin acts primarily by inhibiting the reuptake of norepinephrine (NA) and serotonin (5-HT) at the presynaptic neuron, increasing their concentration in the synaptic cleft. This enhances mood and alleviates depressive symptoms over time.

It also exhibits additional pharmacological actions due to its non-selectivity:

  • Anticholinergic (muscarinic antagonist) → dry mouth, blurred vision, constipation

  • Antihistaminic (H1 antagonist) → sedation

  • Alpha-1 adrenergic blockade → hypotension, dizziness

  • Sodium and calcium channel blockade → contributes to cardiotoxicity, especially in overdose

Indications

Approved Indications

  • Major depressive disorder (moderate to severe depression)

  • Depression with coexisting anxiety

  • Nocturnal enuresis (off-label, historical use)

  • Chronic neuropathic pain, including postherpetic neuralgia and fibromyalgia (off-label)

  • Tension-type headaches or migraine prophylaxis (off-label)

Dosage and Administration

Adults (Depression)

  • Initial dose: 75 mg/day (usually in divided doses or at bedtime)

  • Maintenance dose: 75–150 mg/day

  • Maximum dose: 225 mg/day (hospitalized patients only)

For elderly or frail patients:

  • Start with 25–50 mg/day, titrate slowly to reduce risk of anticholinergic and cardiac effects

Neuropathic Pain (off-label)

  • Starting dose: 25 mg at night

  • Increase gradually to 75 mg/day based on response and tolerability

Duration

  • Antidepressant effect may take 2–4 weeks to appear

  • Once remission is achieved, treatment usually continues for at least 6 months to prevent relapse

Administration Notes

  • Take with or without food

  • Preferably given at bedtime to reduce daytime sedation

  • Avoid abrupt discontinuation to prevent withdrawal symptoms

Contraindications

  • Known hypersensitivity to dosulepin or TCAs

  • Recent myocardial infarction

  • Cardiac arrhythmias, particularly heart block

  • Mania or bipolar disorder (unless used with a mood stabilizer)

  • Severe liver disease

  • Narrow-angle glaucoma

  • Urinary retention, particularly due to prostatic hypertrophy

  • Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation

Warnings and Precautions

  • Narrow therapeutic index: Even small overdoses can be fatal due to cardiotoxicity and CNS toxicity

  • Suicidal ideation: Risk especially high during early treatment phase

  • QT prolongation: May lead to torsades de pointes; ECG monitoring recommended in at-risk patients

  • Hepatic metabolism: Use caution in patients with impaired liver function

  • Serotonin syndrome: Possible when used with serotonergic agents (e.g., SSRIs, tramadol)

  • Orthostatic hypotension: Particularly in elderly patients

  • Lowering of seizure threshold: Risk increased in predisposed individuals

  • Photosensitivity: Rare but reported with long-term use

Adverse Effects

Very Common (≥10%)

  • Dry mouth

  • Drowsiness, sedation

  • Constipation, blurred vision, urinary retention

  • Dizziness, orthostatic hypotension

Common (1–10%)

  • Weight gain

  • Tachycardia, palpitations

  • Sweating, tremor

  • Agitation, confusion

  • Sexual dysfunction (e.g., decreased libido, erectile dysfunction)

Rare but Serious

  • Cardiac arrhythmias, conduction block, sudden cardiac death

  • Seizures

  • Jaundice, elevated liver enzymes

  • Manic switching in bipolar patients

  • Leukopenia, agranulocytosis (rare hematological reactions)

Drug Interactions

  • MAOIs: Risk of hypertensive crisis or serotonin syndrome

  • SSRIs/SNRIs: Increased serotonergic effect → serotonin syndrome risk

  • CYP2D6 inhibitors (e.g., paroxetine, fluoxetine): May raise plasma dosulepin levels

  • CNS depressants (e.g., alcohol, benzodiazepines): Additive sedation

  • Anticholinergic drugs (e.g., antihistamines): Enhanced anticholinergic side effects

  • Antiarrhythmics: Increased risk of QT prolongation

  • Oral contraceptives: Estrogens may alter TCA metabolism

  • Antihypertensives: Additive hypotensive effects, especially with alpha-blockers

  • Tramadol: May increase risk of seizures and serotonin toxicity

Pregnancy and Lactation

Pregnancy

  • Not recommended unless clearly necessary

  • Animal studies show fetal harm at high doses

  • Use in third trimester may cause neonatal withdrawal or toxicity (e.g., respiratory distress, irritability)

Breastfeeding

  • Dosulepin is excreted in breast milk in small amounts

  • Use only if benefits outweigh the risk; monitor infants for drowsiness, poor feeding

Use in Special Populations

Elderly

  • Increased susceptibility to orthostatic hypotension, falls, confusion, cardiac effects

  • Start with lowest dose possible

Renal Impairment

  • No dose adjustment required, but caution is advised

Hepatic Impairment

  • Dose adjustments may be required due to hepatic metabolism

  • Monitor liver enzymes periodically

Overdose Toxicity

Dosulepin overdose is highly lethal, particularly in:

  • Intentional self-poisoning

  • Children and elderly

Symptoms of Overdose

  • Seizures, arrhythmias, delirium, hypotension

  • QRS widening, prolonged QT, torsades de pointes

  • CNS depression, coma, respiratory failure

  • Death may occur within hours of ingestion

Management

  • Immediate hospitalization

  • Activated charcoal if within 1 hour

  • Continuous ECG monitoring

  • Sodium bicarbonate for cardiac toxicity (QRS widening)

  • No specific antidote available

Regulatory and Prescribing Considerations

  • MHRA (UK): Dosulepin is not recommended for new patients

  • Prescribing is restricted to specialists or continuation for existing stable patients

  • NICE does not recommend dosulepin as a first-line antidepressant due to safety concerns

Comparison with Other Antidepressants (no tables)

Dosulepin vs. Amitriptyline

  • Both are tricyclic antidepressants with similar efficacy

  • Dosulepin may have less sedation but more cardiac risk in overdose

  • Amitriptyline is more commonly used in neuropathic pain

Dosulepin vs. SSRIs

  • SSRIs (e.g., sertraline, fluoxetine) are safer in overdose

  • Better tolerated and have fewer anticholinergic effects

  • Dosulepin is not recommended as a first-line option

Dosulepin vs. Nortriptyline

  • Nortriptyline is a secondary amine TCA with fewer side effects

  • Dosulepin has greater sedation and anticholinergic burden

  • Nortriptyline has a wider therapeutic window

Patient Counseling Points

  • Take exactly as prescribed; do not exceed the dose

  • May take 2–4 weeks to feel benefit

  • Do not stop abruptly; withdrawal symptoms include nausea, insomnia, flu-like symptoms, rebound anxiety

  • Avoid alcohol and other sedatives

  • Rise slowly from sitting or lying to prevent dizziness

  • Inform doctor of any chest pain, palpitations, or fainting

  • Inform eye doctor before cataract surgery

  • Store safely away from children and suicidal individuals




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