Dosulepin

Dosulepin, also known by its generic name dothiepin, is a tricyclic antidepressant (TCA) that has been used in the treatment of various mood disorders, particularly depression. It belongs to the class of medications known as tricyclic antidepressants, which were among the first generation of antidepressants developed and widely prescribed before the advent of selective serotonin reuptake inhibitors (SSRIs) and other newer classes of antidepressants. Dothiepin works by modulating the levels of certain neurotransmitters in the brain, primarily serotonin and norepinephrine, which are believed to play a key role in regulating mood.

Chemical Structure and Mechanism of Action

Dothiepin is chemically classified as a tricyclic compound due to its three-ring molecular structure. It functions primarily as a serotonin-norepinephrine reuptake inhibitor (SNRI), meaning it increases the levels of serotonin and norepinephrine in the synaptic cleft by inhibiting their reuptake into presynaptic neurons. This action enhances neurotransmission and is thought to alleviate symptoms of depression. Additionally, dothiepin has anticholinergic, antihistaminergic, and sedative properties, which contribute to its side effect profile.

Indications and Uses

Dothiepin is primarily indicated for the treatment of major depressive disorder (MDD). It has also been used off-label for other conditions, such as anxiety disorders, neuropathic pain, and insomnia, due to its sedative effects. However, its use has declined in recent years due to the development of newer antidepressants with fewer side effects and a better safety profile.

Dosage and Administration

The dosage of dothiepin varies depending on the severity of the condition, patient response, and tolerability. It is typically administered orally in tablet form. The initial dose is usually low (e.g., 75 mg per day) and gradually increased to a therapeutic dose (up to 150–225 mg per day) under medical supervision. It is often recommended to take dothiepin at bedtime due to its sedative effects, which can help with sleep disturbances commonly associated with depression.

Pharmacokinetics

Dothiepin is well-absorbed from the gastrointestinal tract after oral administration. It undergoes extensive hepatic metabolism, primarily via the cytochrome P450 enzyme system, and has an active metabolite, northiaden. The half-life of dothiepin is approximately 14–24 hours, allowing for once-daily dosing in most cases. It is excreted primarily in the urine as metabolites.

Side Effects

Like other tricyclic antidepressants, dothiepin is associated with a range of side effects, which can limit its use in some patients. Common side effects include:

• Anticholinergic effects: Dry mouth, blurred vision, constipation, urinary retention, and increased heart rate.

• Sedation: Drowsiness and fatigue, which can be beneficial for patients with insomnia but may impair daytime functioning.

• Cardiovascular effects: Orthostatic hypotension (a drop in blood pressure upon standing) and arrhythmias.

• Weight gain: Due to its effects on appetite regulation.

• Sexual dysfunction: Reduced libido and difficulty achieving orgasm.

Contraindications and Precautions

Dothiepin is contraindicated in patients with a history of hypersensitivity to tricyclic antidepressants, recent myocardial infarction, or certain cardiac arrhythmias. It should be used with caution in patients with a history of seizures, glaucoma, urinary retention, or liver/kidney impairment. Due to its sedative effects, patients should avoid driving or operating heavy machinery until they know how the medication affects them.

Drug Interactions

Dothiepin can interact with a wide range of medications, including:

• Monoamine oxidase inhibitors (MAOIs): Concurrent use can lead to serotonin syndrome, a potentially life-threatening condition.

• Other CNS depressants: Alcohol, benzodiazepines, and opioids can enhance the sedative effects of dothiepin.

• Antihypertensive medications: Dothiepin can counteract the effects of blood pressure-lowering drugs.

• Serotonergic drugs: Combining with SSRIs or SNRIs increases the risk of serotonin syndrome.

Withdrawal and Discontinuation

Abrupt discontinuation of dothiepin can lead to withdrawal symptoms, including nausea, headache, dizziness, irritability, and sleep disturbances. To minimize these effects, the dose should be tapered gradually under medical supervision.

Special Populations

• Elderly patients: Older adults are more susceptible to the anticholinergic and sedative effects of dothiepin, increasing the risk of falls and cognitive impairment.

• Pregnancy and lactation: Dothiepin should be used during pregnancy only if the potential benefits outweigh the risks. It is excreted in breast milk, so breastfeeding is generally not recommended while taking this medication.

• Pediatric patients: The safety and efficacy of dothiepin in children and adolescents have not been well-established.

Historical Context and Decline in Use

Dothiepin was widely prescribed in the mid-to-late 20th century as a first-line treatment for depression. However, its use has declined significantly with the introduction of SSRIs (e.g., fluoxetine, sertraline) and SNRIs (e.g., venlafaxine, duloxetine), which have fewer side effects and are better tolerated by patients. Additionally, the risk of overdose with tricyclic antidepressants like dothiepin is higher compared to newer antidepressants, contributing to its decreased popularity.

Overdose and Toxicity

Tricyclic antidepressants, including dothiepin, are highly toxic in overdose. Symptoms of overdose may include severe anticholinergic effects, cardiac arrhythmias, seizures, coma, and even death. Immediate medical attention is required in cases of suspected overdose. Treatment may involve gastric lavage, activated charcoal, and supportive care, including monitoring of cardiac and respiratory function.

Conclusion

Dothiepin (dosulepin) is a tricyclic antidepressant with a long history of use in the treatment of depression. While effective, its use has been largely supplanted by newer antidepressants due to its side effect profile and risk of toxicity. However, it remains an option for certain patients, particularly those who do not respond to other treatments or who benefit from its sedative properties. As with all medications, the decision to use dothiepin should be made on an individual basis, weighing the potential benefits against the risks.