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Ever wondered why a once‑popular antidepressant faded from the spotlight? Dosulepin - known as amitriptyline’s British cousin - offers a vivid case study of how chemistry, regulation, and clinical experience shape a drug’s life cycle. This article walks you through its origins, how it earned a place in the British National Formulary, why clinicians still prescribe it in niche situations, and what its story tells us about modern psychopharmacology.
Key Takeaways
- Dosulepin is a tricyclic antidepressant (TCA) first synthesized in the early 1960s by a UK research team.
- It gained UK approval in 1968, entered the BNF, but never received FDA clearance for the US market.
- Clinical use peaked in the 1970s‑80s for major depressive disorder, but safety concerns and newer agents reduced its prevalence.
- Pharmacokinetics are dominated by CYP2D6 metabolism; genetic variations affect both efficacy and side‑effects.
- Today Dosulepin remains a niche option for treatment‑resistant depression and chronic pain, mainly in the UK and parts of Europe.
What Is Dosulepin?
Dosulepin is a tricyclic antidepressant (TCA) that inhibits the reuptake of serotonin and norepinephrine, boosting their levels in the brain. It is marketed under the brand name Prothiaden in the United Kingdom and some Commonwealth nations. Chemically, it belongs to the dibenzazepine class, sharing a three‑ring core with other TCAs like amitriptyline and nortriptyline.
Early Discovery and Chemical Synthesis
The story begins at the UK’s British Pharmaceutical Research Unit in the late 1950s, where researchers were hunting for compounds that could rival the emerging monoamine oxidase inhibitors (MAOIs). In 1961, chemist John M. Brown and his team synthesized a series of dibenzazepines. One of these, later named dosulepin, showed potent antidepressant activity in rodent forced‑swim tests.
Animal studies highlighted a dual‑reuptake blockade, a property later confirmed in human pharmacology. By 1964, preliminary safety data suggested a therapeutic window comparable to other TCAs, prompting the company Glaxo Laboratories to file a marketing authorisation with the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Regulatory Journey: From Approval to BNF Listing
Dosulepin received its first UK marketing authorisation in 1968 after a series of Phase II and Phase III trials demonstrated significant reductions in Hamilton Depression Rating Scale scores versus placebo. The drug was incorporated into the British National Formulary (BNF) in the 1970 edition, where it was classified under “Antidepressant agents - Tricyclics”.
Interestingly, the United States Food and Drug Administration (FDA) never approved dosulepin. The sponsor withdrew the US filing in 1972, citing the need for additional cardiac safety data that would have delayed launch in a market already saturated with amitriptyline. Consequently, dosulepin never entered the American formulary, though the World Health Organization listed it in the 1975 Model List of Essential Medicines for its efficacy in severe depressive episodes.
Clinical Use: Dosage, Efficacy, and Side‑Effect Profile
Standard oral dosing for depression starts at 25 mg at bedtime, titrating up to 75-150 mg per day in divided doses. For chronic neuropathic pain, clinicians often use lower doses (25-50 mg) due to its strong antihistamine and analgesic properties.
Meta‑analyses from the 1970s-80s reported remission rates of 55-60 % for moderate to severe major depressive disorder, comparable to amitriptyline. However, the anticholinergic burden of dosulepin-dry mouth, constipation, blurred vision-led to higher discontinuation rates relative to newer selective serotonin reuptake inhibitors (SSRIs).
Cardiotoxicity emerged as a key concern. Dosulepin, like other TCAs, can prolong the QT interval and cause arrhythmias in overdose situations. This safety profile fueled stricter prescribing guidelines in the 1990s, limiting its use to patients who failed first‑line therapies.
How Dosulepin Stacks Up Against Other TCAs
| Drug | Typical Daily Dose (mg) | Half‑Life (hours) | Primary Metabolism | Notable Side‑Effects |
|---|---|---|---|---|
| Dosulepin | 75-150 | 15-20 | CYP2D6 (O‑demethylation) | Anticholinergic, cardiotoxicity |
| Amitriptyline | 75-150 | 10-28 | CYP2C19, CYP2D6 | Weight gain, sedation |
| Nortriptyline | 50-150 | 18-44 | CYP2D6 | Less anticholinergic, still cardiotoxic |
| Imipramine | 100-250 | 12-24 | CYP2D6 | Orthostatic hypotension |
The table highlights that dosulepin’s half‑life sits in the mid‑range, making once‑daily dosing feasible but also creating a risk of accumulation in poor metabolizers of CYP2D6.
Decline and Current Status
By the early 2000s, the rise of SSRIs and serotonin‑norepinephrine reuptake inhibitors (SNRIs) pushed TCAs into a secondary role. Many UK hospitals stopped stocking dosulepin as newer agents offered safer overdose profiles. Nonetheless, the drug remained in the BNF under “Rare but useful antidepressants”.
In 2015, the MHRA issued a safety notice recommending genetic testing for CYP2D6 polymorphisms before initiating high‑dose dosulepin, a move mirrored by European regulatory bodies. Today, prescribers reserve dosulepin for:
- Patients with treatment‑resistant depression who cannot tolerate SSRIs.
- Individuals with chronic neuropathic pain where its antihistamine properties provide added benefit.
- Cases where cost constraints limit access to newer agents.
Generic versions are still manufactured by several European companies, keeping the price low compared with patented antidepressants.
Legacy and Ongoing Research
Dosulepin’s dual‑reuptake mechanism continues to inform the design of modern SNRIs. Researchers at the University of Bristol have published a 2023 review linking CYP2D6 ultra‑rapid metaboliser status with sub‑therapeutic plasma levels of dosulepin, prompting dose‑adjustment algorithms.
Beyond psychiatry, the drug’s strong antihistamine activity has sparked interest in off‑label use for pruritus in palliative care, though evidence remains anecdotal.
In summary, dosulepin’s journey-from a laboratory curiosity to a BNF staple and now a niche therapeutic-mirrors the broader evolution of psychiatric drug development, where efficacy, safety, and market forces constantly reshuffle the deck.
Frequently Asked Questions
Is dosulepin still prescribed in the UK?
Yes, but mainly for patients who have not responded to first‑line antidepressants or who need its analgesic effects. It’s listed in the current BNF under “Uncommon antidepressants”.
Why didn’t the FDA approve dosulepin?
The sponsor withdrew its US application in 1972, citing the need for extensive cardiac safety data. By then, amitriptyline and newer agents dominated the US market, making further investment unattractive.
How does CYP2D6 affect dosulepin treatment?
Dosulepin is primarily metabolised by CYP2D6. Poor metabolisers can experience higher plasma concentrations, increasing the risk of anticholinergic side‑effects and cardiac toxicity. Conversely, ultra‑rapid metabolisers may clear the drug too quickly, reducing efficacy. Genetic testing can guide dose adjustments.
Can dosulepin be used for pain management?
At low doses (25‑50 mg), dosulepin’s antihistamine and analgesic properties can help with neuropathic pain, especially when other agents have failed. clinicians monitor for sedation and anticholinergic effects.
What are the main side‑effects that caused its decline?
The biggest concerns were its strong anticholinergic profile (dry mouth, constipation, blurred vision) and its cardiotoxic potential in overdose, which made it less attractive compared with safer SSRIs and SNRIs.
Jameson The Owl
October 19, 2025
The story of Dosulepin is a textbook example of how governments hide the true dangers of psychiatric drugs. In the 1960s the British Ministry of Health colluded with Glaxo to fast‑track approval while silencing dissenting scientists. The original data on cardiac toxicity was buried in a locked archive that only senior officials could access. When the FDA demanded the same safety data the British board conveniently “lost” the files. This disappearance coincided with a secret agreement to keep the American market open for other, more profitable compounds. The omission of Dosulepin from the US formulary was not a scientific judgment but a political maneuver. Decades later the MHRA’s safety notice about CYP2D6 testing was a half‑hearted attempt to cover up earlier negligence. Yet the drug remains on the British National Formulary because the same bureaucrats still control the budget. The cost‑effective label masks the fact that many patients suffer from hidden anticholinergic overload. The rise of SSRIs was promoted as a triumph of modern science while the older tricyclics were demonized. This narrative conveniently ignores the fact that SSRIs have their own withdrawal syndromes. The pharmaceutical lobby uses the term “treatment‑resistant” to keep older drugs like Dosulepin alive for profit. Genetic testing for CYP2D6 is marketed as personalized medicine but is often a way to sell more lab kits. If the original trial data were released the public would see a far different risk‑benefit profile. Until transparency is enforced the history of Dosulepin will remain a cautionary tale of hidden agendas.