Dosulepin, also called dothiepin, is sold under the brand name Prothiaden and other names. It is a type of medication called a tricyclic antidepressant (TCA), used to treat depression. In the past, it was the most commonly prescribed antidepressant in the United Kingdom. However, it is not used as often now because it can be very dangerous if taken in large amounts, and it does not work better than other TCAs. Dosulepin works by blocking the reabsorption of serotonin and norepinephrine in the brain. It also has other effects, such as acting as an antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and blocking sodium channels in the body.

Medical uses

Dosulepin helps treat serious depression. There is strong proof that it works for a type of facial pain called psychogenic facial pain, but it might need to be taken for up to one year.

Contraindications

Contraindications include:

• Seizure disorders, as the medication may increase the risk of seizures
• Tricyclic antidepressants (TCAs) should not be taken at the same time as monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI treatment, due to the risk of serotonin syndrome
• The period right after a heart attack, as TCAs may cause heart rhythm problems
• Liver failure
• Allergic reaction to dosulepin

Side effects

Common adverse effects:

Less common adverse effects:

• Thrombocytopenia (not enough platelets in the blood. This can lead to easier bleeding)
• Eosinophilia (too many eosinophils in the blood)
• Agranulocytosis (very low number of white blood cells, which can make infections more dangerous)
• Galactorrhea (producing milk without being pregnant or breastfeeding)

Overdose

The symptoms and treatment for an overdose are similar to those for other TCAs. Dosulepin may be more harmful in an overdose compared to other TCAs. Harmful effects usually begin about 4 to 6 hours after dosulepin is swallowed. To reduce the risk of overdose, patients should receive only a small number of tablets at one time. It is also important not to give patients other medicines that could increase the risk of harm when taken with dosulepin, as this might lead to a more serious overdose. The medication should be stored in a place where children cannot reach it.

Interactions

Dosulepin can increase the effects of alcohol. At least one death has been linked to using these together. Tricyclic antidepressants (TCAs) can strengthen the sleepiness caused by barbiturates, tranquilizers, and central nervous system (CNS) depressants. Guanethidine and other drugs that block adrenergic neurons may have their ability to lower blood pressure reduced by dosulepin. Sympathomimetic drugs may increase the effects of dosulepin on the nervous system. Because dosulepin has anticholinergic and antihistamine effects, medications with similar actions may become more effective when combined with dosulepin. These combinations are not recommended. Diuretics may increase the risk of postural hypotension caused by dosulepin. Anticonvulsants may become less effective when used with dosulepin, as dosulepin can lower the seizure threshold.

Pharmacology

Dosulepin stops the reabsorption of serotonin and norepinephrine by blocking their transporters, making it an SNRI. It also blocks several receptors, including histamine H1, α1-adrenergic, serotonin 5-HT2, and muscarinic acetylcholine receptors. Additionally, it prevents sodium from moving through voltage-gated channels in nerve cells. The antidepressant effects of dosulepin are likely due to its ability to stop the reabsorption of norepinephrine and possibly serotonin.

Dosulepin forms three metabolites: northiaden (desmethyldosulepin), dosulepin sulfoxide, and northiaden sulfoxide. These metabolites stay in the body longer than dosulepin itself. However, northiaden is active and works similarly to dosulepin, while the sulfoxide metabolites are mostly inactive and do not contribute to the drug’s effects or side effects. Compared to dosulepin, northiaden is less effective at stopping serotonin reabsorption and has weaker antihistamine and anticholinergic effects. It is more effective at stopping norepinephrine reabsorption, similar to other secondary amine tricyclic antidepressants.

Studies by Heal & Cheetham (1992) found that dosulepin and northiaden had high K_i values (12 and 15 nM) at the rat α2-adrenergic receptor, suggesting they might block this receptor. However, Richelson & Nelson (1984) found a much lower K_D value (2,400 nM) for dosulepin in human brain tissue, indicating it has weak activity at this receptor, similar to other tricyclic antidepressants.

Dosulepin is absorbed quickly from the small intestine and is broken down in the liver into its main active form, northiaden. Peak levels in the blood range from 30.4 to 279 ng/mL (103–944 nmol/L) within 2–3 hours after taking the drug. It enters breast milk, crosses the placenta, and passes through the blood–brain barrier. Dosulepin binds strongly to plasma proteins (84%), and it takes about 51 hours for the drug to leave the body completely.

Chemistry

Dosulepin is a tricyclic compound, specifically a dibenzothiepine, which means it has three rings connected together with a side chain attached. It is the only tricyclic antidepressant (TCA) with a dibenzothiepine ring system that has been sold as a medicine. Dosulepin is a tertiary amine TCA, and its side chain produces a metabolite called northiaden (desmethyldosulepin), which is a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, doxepin, and trimipramine. Dosulepin exists in two forms called (E) and (Z) stereoisomers, like doxepin. However, only the pure (E) or trans isomer is used in medicine. The drug is sold as the hydrochloride salt; the free base form is not used.

History

Dosulepin was created by SPOFA. It was patented in 1962 and first written about in scientific papers in the same year. The drug began being used by doctors in the United Kingdom in 1969.

Society and culture

Dosulepin is the common name for the drug in English and German. It is also called the International Nonproprietary Name (INN) and the British Approved Name (BAN). Dosulepin hydrochloride is the British Approved Name and Japanese Accepted Name (JAN) for the drug. Dothiepin was the previous British Approved Name for the drug, and dothiepin hydrochloride was the previous British Approved Name and is still the current United States Adopted Name (USAN). In Spanish and Italian, the drug is called dosulepina. In French, it is called dosulépine. In Latin, it is called dosulepinum.

Dosulepin is sold worldwide mainly under the brand name Prothiaden. It has also been sold under other brand names, including Altapin, Depresym, Dopress, Dothapax, Dothep, Idom, Prepadine, Protiaden, Protiadene, Thaden, and Xerenal.

In Europe, the drug is sold as Prothiaden, Protiaden, and Protiadene. In Australia, it is sold as Dothep and Prothiaden. In New Zealand, it is sold as Dopress. In South Africa, it is sold as Thaden. It is also available in Japan, Hong Kong, Taiwan, India, Singapore, and Malaysia. The drug is not available in the United States or Canada.