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Dothiepin

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Depressive Illness

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Summary

Synopsis

Dothiepin is a tricyclic antidepressant that is structurally related to amitriptyline. It appears that the antidepressant activity of dothiepin is mediated through facilitation of noradrenergic neurotransmission by uptake inhibition and possibly also by enhancement of serotoninergic neurotransmission. The overall therapeutic efficacy of dothiepin is very similar to that of amitriptyline. In addition, dothiepin appears to be comparable to imipramine, doxepin, maprotiline, mianserin, fluoxetine, fluvoxamine and trazodone.

Dry mouth is the most commonly reported side effect of therapeutic doses but the incidence of this and other anticholinergic side effects is less among patients treated with dothiepin than with amitriptyline. However, the sedative/anxiolytic activity of dothiepin is similar to that of amitriptyline. Dothiepin has not been associated with cardiotoxicity at therapeutic doses.

Thus, many years of extensive clinical use have shown that dothiepin is now an established and effective antidepressant in both inpatients and outpatients with depressive symptoms of varying severity and coexisting anxiety. Its therapeutic equivalence to other tricyclics ensures its place as a treatment alternative in these disorders.

Pharmacodynamic Studies

In vitro dothiepin and its metabolite northiaden facilitate noradrenergic neurotransmission through inhibition of the neuronal uptake of noradrenaline (norepinephrine). Dothiepin is a more potent inhibitor of 14C-serotonin uptake in human platelets in vitro than its metabolites, and may enhance brain serotonin synthesis by inhibition of the tryptophan-degrading enzyme tryptophan pyrrolase.

Neurotransmitter receptor binding studies have indicated that dothiepin has low affinity at α1-and α2-adrenoceptors and serotonin 5HT1 and 5HT2-receptors. In comparison with other antidepressants, dothiepin has a relatively high affinity for guinea-pig ileum muscarinic receptors in vitro but in common with other antidepressants it is a relatively potent antagonist of histamine H1-receptors in vitro.

Repeated, but not acute, administration of dothiepin to rats preferentially antagonised serotonin-mediated behaviour despite the fact that in in vitro studies dothiepin and its metabolites were more effective inhibitors of noradrenaline uptake than serotonin uptake.

Single oral doses of dothiepin and amitriptyline 25mg produced comparable increases in heart rates, and reductions in blood pressures, in both young and elderly healthy subjects. However, in a 6-week double-blind study in 184 outpatients with neurotic depression, amitriptyline produced significant increases in heart rate and electrocardiographic QT intervals in comparison with both dothiepin and placebo.

A double-blind study involving administration of single oral doses of dothiepin and amitriptyline 25mg indicated that in elderly healthy subjects both dothiepin and amitriptyline produced marked reductions in salivary flow rate.

Pharmacokinetic Studies

Following oral administration to healthy subjects dothiepin is readily absorbed and peak plasma concentrations are achieved within 2 to 4 hours. Steady-state serum concentrations are achieved within 12 days with either 3 times daily or once daily administration. Dothiepin undergoes extensive hepatic metabolism to dothiepin-S-oxide, northiaden and northiaden-S-oxide, and its oral bioavailability is about 30% after first-pass hepatic metabolism. In healthy subjects the mean terminal elimination half-lives of dothiepin and its metabolites are 14 to 24 hours and 23 to 46 hours, respectively.

In elderly healthy subjects the time to peak plasma concentration and the elimination half-life are prolonged, the AUC is increased and the absorption rate constant, volume of distribution and plasma clearance of dothiepin are reduced, compared with younger individuals

Therapeutic Trials

Dothiepin is an effective antidepressant that has an onset of action of about 2 weeks when administered in doses up to 225 mg/day to patients with depression of different aetiologies. A single 50 to 150mg dose of dothiepin at night was as effective as 3 times daily administration.

Double-blind controlled studies have demonstrated that the overall antidepressant efficacy of dothiepin is indistinguishable from that of amitriptyline. Other studies have suggested equivalence with imipramine, doxepin, maprotiline, mianserin, fluoxetine, fluvoxamine and trazodone. In studies comparing dothiepin with amitriptyline, reductions in Hamilton Depression Rating Scale scores after 4 to 6 weeks were in the range 40 to 70%, with 66 to 74% of patients showing at least some improvement with both drugs. In addition, the sedative/anxiolytic activity of dothiepin appears to be equivalent to that of amitriptyline, mianserin, trazodone and the benzodiazepine alprazolam, and greater than that of chlordiazepoxide in patients with anxiety associated with depression.

Preliminary studies have indicated that dothiepin has significant analgesic activity, compared with placebo, in patients with psychogenic facial pain, idiopathic fibromyalgia syndrome or rheumatoid arthritis.

Adverse Effects

The most commonly reported adverse effects of treatment with dothiepin among 5755 patients evaluated for tolerability in non-comparative and double-blind comparative studies were dry mouth (24%), drowsiness (17%), gastrointestinal disorders (11%) and dizziness (10%). Overall, 52% of patients reported adverse effects of varying degrees of severity and 5% were withdrawn from treatment because of side effects. The results of comparative studies indicate that dothiepin treatment produces a lower incidence of side effects than treatment with amitriptyline.

Dosage and Administration

The usual starting dosage of dothiepin is 75 mg/day in divided doses, or as a single dose at night, increasing to 150 mg/day according to the severity of the depressive illness. In certain circumstances daily doses of up to 225mg may be used in hospital inpatients. Treatment of the elderly should be initiated with doses in the range 50 to 75 mg/day and increased thereafter with caution. Dosage recommendations for the United States include an initial dose of 50mg twice daily in most adult outpatients increasing to a maximum of 300 mg/day. Alternatively, 100mg increasing to 150mg could be administered once at night, with a total daily dose of 300mg. Higher doses should only be administered to hospitalised patients under supervision. Improvement in the symptoms of depression may be delayed for 2 to 4 weeks and patients should be closely monitored until their individual reaction to treatment has been defined. Dothiepin and other tricyclic antidepressants are contraindicated in patients receiving monoamine oxidase inhibitors, sympathomimetic agents or adrenergic neurone blocking drugs.

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  1. ADIS Drug Information Services, Manchester, England

    Simon G. Lancaster & John P. Gonzalez

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  1. Simon G. Lancaster
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Various sections of the manuscript reviewed by: F.J. Ayd, Baltimore, Maryland, USA; A.A.B. Badawy, Whitchurch Hospital, Cardiff, Wales; R.J. Baldessarini, Mailman Research Center, McLean Hospital, Belmont, Massachusetts, USA; W.F. Boyer, Feighner Research Institute, Encinitas, California, USA; G.D. Burrows, Department of Psychiatry, University of Melbourne, Victoria, Australia; J.P. Feighner, Feighner Research Institute, Encinitas, California, USA; S. Garattini, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; L.E. Hollister, Harris County Psychiatric Center, Houston, Texas, USA; M. Lader, Institute of Psychiatry, London, England; S. Montgomery, Academic Department of Psychiatry, St Mary’s Hospital Medical School, London, England; T.R. Norman, Department of Psychiatry, University of Melbourne, Victoria, Australia; C. Ogura, Department of Neuropsychiatry, Tottori University School of Medicine, Yonago, Japan; M.B. Scharft, The Center for Research in Sleep Disorders, Cincinnati, Ohio, USA.

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Lancaster, S.G., Gonzalez, J.P. Dothiepin. Drugs 38, 123–147 (1989). https://doi.org/10.2165/00003495-198938010-00005

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