Dothiepin

Usage

• Dothiepin is prescribed for the treatment of major depressive disorder and the associated anxiety. It is also sometimes prescribed for pain relief or migraine prevention, although this is not its primary indication and other treatments are generally preferred.

• Pharmacological classification: Tricyclic antidepressant (TCA).

• Mechanism of action: Dothiepin inhibits the reuptake of norepinephrine and serotonin, increasing their concentration in the synaptic cleft. It also exhibits some anticholinergic properties.

Alternate Names

• Dosulepin (International Nonproprietary Name)

• Brand names: DOTHEP, Prothiaden (and others, which can vary regionally).

How It Works

• Pharmacodynamics: Dothiepin primarily affects the central nervous system by enhancing serotonergic and noradrenergic neurotransmission. Its anticholinergic effects contribute to some of its side effects.

• Pharmacokinetics:

  • Absorption: Well-absorbed orally.
  • Metabolism: Extensively metabolized in the liver, primarily by CYP2D6. Subject to genetic polymorphism, influencing individual responses. Undergoes enterohepatic circulation.
  • Elimination: Excreted mainly in urine as metabolites. Terminal half-life approximately 20 hours, though this can vary.

• Mode of action: Dothiepin binds to presynaptic reuptake transporters for serotonin and norepinephrine, inhibiting their reuptake into the presynaptic neuron. This leads to increased levels of these neurotransmitters in the synaptic cleft, prolonging their action on postsynaptic receptors.

• Receptor binding, enzyme inhibition or neurotransmitter modulation: Inhibits reuptake of serotonin and norepinephrine. Also exhibits anticholinergic activity, blocking muscarinic acetylcholine receptors.

• Elimination pathways: Primarily hepatic metabolism (CYP2D6), followed by renal excretion of metabolites.

Dosage

Standard Dosage

Adults:

• Initial: 75 mg daily, given as a single dose at night or in divided doses.
• Maintenance: May be increased gradually up to 150 mg daily, if required. In some cases (e.g., hospital settings), doses up to 225 mg/day have been used.
• For pain relief or preventing migraines: 25 mg a day, gradually increasing up to 75 mg/day (max 150mg/day).

Children:

• Not recommended for use in children and adolescents under 18 years of age for depression.

Special Cases:

• Elderly Patients: Start with a lower dose (50-75 mg/day) and increase cautiously.
• Patients with Renal Impairment: Reduce dosage and use with caution due to the risk of accumulation.
• Patients with Hepatic Dysfunction: Contraindicated in severe liver disease. Reduce dosage and use cautiously in mild to moderate hepatic impairment.
• Patients with Comorbid Conditions: Use with caution in patients with cardiovascular disease, epilepsy, glaucoma, urinary retention, or hyperthyroidism.

Clinical Use Cases

• Dothiepin is not typically indicated for use in clinical settings like intubation, surgical procedures, mechanical ventilation, or the ICU. Its primary role is in the management of depression and associated anxiety in outpatient settings. In emergency situations, other medications are generally preferred.

Dosage Adjustments:

• Dosage adjustments are based on individual response and tolerability. Close monitoring is necessary, especially when initiating therapy or modifying the dose. Therapeutic drug monitoring can be helpful in certain cases.

Side Effects

Common Side Effects:

• Drowsiness, dizziness
• Dry mouth, constipation
• Blurred vision
• Weight gain
• Nausea, vomiting
• Increased sweating
• Tremor

Rare but Serious Side Effects:

• Cardiac arrhythmias (including QTc prolongation)
• Seizures
• Severe allergic reactions (e.g., skin rash, swelling)
• Urinary retention
• Jaundice
• Hallucinations, confusion
• Suicidal ideation

Long-Term Effects:

• Chronic complications are rare but can include tardive dyskinesia.

Adverse Drug Reactions (ADR):

• Serotonin syndrome (rare but potentially life-threatening)
• Neuroleptic malignant syndrome (very rare but life-threatening)
• Cardiotoxicity (especially in overdose).

Contraindications

• Hypersensitivity to dothiepin
• Recent myocardial infarction
• Heart block or other cardiac arrhythmias
• Mania
• Severe liver disease
• Concomitant use of MAOIs (or within 14 days of discontinuing MAOIs)

Drug Interactions

• MAOIs: Increased risk of serotonin syndrome.
• Alcohol: Potentiates sedative effects.
• CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): Increased dothiepin levels.
• CYP inducers (e.g., carbamazepine, phenytoin): Decreased dothiepin levels.
• Anticholinergics: Additive anticholinergic effects.
• Sympathomimetics: Enhanced sympathomimetic effects.
• Antihypertensives (e.g., guanethidine): Antagonism of antihypertensive effects.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Limited data are available. Use only if potential benefit outweighs risk.

• Fetal risks: Potential for neonatal withdrawal symptoms.

• Breastfeeding: Small amounts are excreted in breast milk. Potential for adverse effects in the infant, though generally considered safe.

Drug Profile Summary

• Mechanism of Action: Inhibits serotonin and norepinephrine reuptake.
• Side Effects: Drowsiness, dry mouth, constipation, blurred vision, weight gain.
• Contraindications: Recent MI, heart block, mania, severe liver disease, MAOI use.
• Drug Interactions: MAOIs, alcohol, CYP2D6 inhibitors/inducers.
• Pregnancy & Breastfeeding: Use with caution. Monitor infant.
• Dosage: Adults: 75-150 mg/day. Elderly: 50-75 mg/day initially.
• Monitoring Parameters: ECG, mental status, liver function tests, blood pressure, weight.

Popular Combinations

• Dothiepin is not commonly used in combination with other antidepressants.

Precautions

• General Precautions: Monitor for suicidal ideation, especially early in treatment. Screen for cardiac, hepatic, and renal dysfunction.

• Specific Populations: See “Dosage - Special Cases”.

• Lifestyle Considerations: Avoid alcohol. May impair driving or operating machinery.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dothiepin?

A: Adults: Initial dose is 75 mg daily, adjusted as needed up to 150 mg/day, and maximum dose: 225mg/day (rare). Elderly: 50-75 mg/day initially. Children: Not recommended.

Q2: What are the most common side effects of Dothiepin?

A: Drowsiness, dry mouth, constipation, blurred vision, weight gain, dizziness, and nausea.

Q3: Is Dothiepin safe to use during pregnancy?

A: Use with caution. Limited data are available. Potential risk of neonatal withdrawal symptoms. Discuss risks and benefits with the patient.

Q4: Can Dothiepin be used with alcohol?

A: No. Alcohol can potentiate the sedative effects of Dothiepin and should be avoided.

Q5: What should I do if a patient overdoses on Dothiepin?

A: Seek immediate medical attention. Overdose can be life-threatening. Supportive care and symptomatic treatment are the mainstays of management.

Q6: Can Dothiepin be used to treat anxiety disorders other than those associated with depression?

A: While dothiepin has some anxiolytic effects, it is not a first-line treatment for other anxiety disorders. Other medications, such as SSRIs or SNRIs, are generally preferred.

Q7: How long does it take for Dothiepin to start working?

A: It can take 2-4 weeks for the full therapeutic effects to be seen.

Q8: Does Dothiepin interact with any other medications?

A: Yes. See the “Drug Interactions” section for a list of potentially significant interactions.

Q9: What is the mechanism of action of Dothiepin?

A: Dothiepin primarily inhibits the reuptake of norepinephrine and serotonin, along with exhibiting anticholinergic properties.

Q10: Is there a genetic test available to guide dothiepin dosing?

A: CYP2D6 testing is available to identify slow metabolisers who may be at a higher risk for increased drug concentrations.