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Doxepin Up-to-Date: A Review of its Pharmacological Properties and Therapeutic Efficacy with Particular Reference to Depression

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Summary

Synopsis: Doxepin1 is closely related in structure and general pharmacological properties to other tricyclic antidepressant drugs such as amitriptyline and imipramine. It combines antidepressant activity with a sedative effect and in this respect resembles amitriptyline, with which it shares a similar profile of clinical action.

The mood elevating effect of doxepin appears to be similar to that of amitriptyline but is probably less marked than that of imipramine and in some studies has been slower to take effect than imipramine. At dosages which have achieved a similar overall response rate, doxepin tends to cause fewer or less troublesome side-effects than imipramine, amitriptyline or amitriptyline-perphenazine. The more marked sedative properties of doxepin make it more useful than imipramine in depressed patients with sleep disturbances and in depression associated with anxiety. The benzodiazepines remain the drugs of choice in anxiety states, but when anxiety is accompanied by significant depression, doxepin is more effective than chlordiazepoxide or diazepam.

Doxepin is usually well tolerated, and in particular by the elderly and those with cardiovascular disease. Side-effects are similar in nature to those of other tricyclic antidepressants, with dry mouth, drowsiness and constipation being the most common. Postural hypotension is uncommon. Although doxepin appears to cause fewer cardiovascular side-effects in usual therapeutic doses, it has an intrinsic cardiotoxicity on overdosage similar to other tricyclics.

Pharmacodynamic studies: In rodents, doxepin has been shown to antagonize the central depressant effects of reserpine and tetrabenazine, to suppress spontaneous motility and conditioned avoidance behaviour, and to potentiate and prolong the stimulant actions of amphetamine and levodopa, to an extent similar to that observed with amitriptyline. Doxepin also possesses tranquillizing properties similar to the benzodiazepines, but it lacks muscle relaxant properties. Its central and peripheral anticholinergic properties are less than those of amitriptyline, and the cardiovascular effects are similar to other tricyclics — lowered blood pressure, increased heart rate, reduced total peripheral resistance and, at higher doses, cardiac arrhythmias. Compared with other tricyclic antidepressants, doxepin is only a weak inhibitor of norepinephrine or serotonin uptake into peripheral organs or the brain, although it potentiates pressor responses to norepinephrine and blocks those to tyramine.

In man, doxepin produces EEG changes typical of the tricyclic antidepressants. Its cardiovascular effects are minimal, even in patients with myocardial disease, and hypotension has occurred in only a small proportion of patients during therapy. Doxepin, unlike other tricyclic antidepressants, appears to have little effect on intracardiac conduction, but like other tricyclic antidepressants, it disturbed cardiac rhythm on overdosage. Doxepin potentiates pressor responses to epinephrine, blocks those to tyramine, and at doses above 200mg daily reverses the antihypertensive effects of adrenergic neuron blocking agents like guanethidine and bethanidine. A major metabolite of doxepin, desmethyldoxepin, is pharmacologically active. Thus in the body, pharmacological effects are exerted by a mixture of doxepin and its active metabolite(s).

Pharmacokinetic studies: Results of experiments in rats and dogs using radio-labelled doxepin, show it to be well absorbed after oral administration, rapidly distributed to various tissues including liver, kidney, lung and brain, and rapidly metabolised by pathways similar to amitriptyline and imipramine. About 50 to 60 % of an oral dose was excreted in the urine in 24 hours. In a preliminary study in elderly patients, therapeutic plasma levels of total drug (doxepin plus desmethyldoxepin) appeared to be about 110ng/ml, and were associated with a dose range of 50 to 300mg daily. Another study in depressed patients suggests that clinical response correlates with plasma levels of desmethyldoxepin of 20ng/ml or above, but not with plasma levels of doxepin alone.

Therapeutic trials: When confounding effects due to study population differences are eliminated and the similar overall response rate in uncontrolled and comparative trials is taken into account, together with the superior results of doxepin over a placebo, one must conclude that doxepin is an active antidepressant. Whether it is definitely as effective overall as amitriptyline and imipramine in depression must await clarification in studies involving a large number of patients. Trials involving relatively small numbers of patients in wellmatched treatment groups have not been able to detect a statistically significant overall difference between doxepin and amitriptyline or imipramine. Nevertheless, trends for differences in certain types of depression have emerged. From both the comparative trials and the clinical experience in uncontrolled trials, doxepin seems to have mood elevating activity probably less marked than that of imipramine but similar to that of amitriptyline. Thus in the largest uncontrolled trial doxepin was most effective in agitated depressives and of lesser benefit in retarded depressives. In the largest comparative trial, doxepin tended to be more effective than imipramine in neurotic depression, while imipramine was more effective in endogenous depression. Doxepin also tends to be more effective than imipramine in depressed patients with sleep disturbances. Similar differences between doxepin and amitriptyline have been less evident, possibly because both have mood elevating properties as well as pronounced sedative activity. Doxepin cannot be regarded as superior to other tricyclic antidepressants in the treatment of severe, endogenous depressions.

It is possible that doxepin may have a more prominent sedative effect than amitriptyline because in general, doxepin has tended to produce a more favorable response than amitriptyline in patients with depression associated with anxiety or the mixed depression-anxiety syndrome. Doxepin has achieved a similar response as amitriptyline-perphenazine in these patients, but appears to be better tolerated. The antianxiety effect of doxepin occurs earlier than its antidepressant effect, and more rapidly than that of amitriptyline or amitriptylineperphenazine. The onset of antidepressant effect of doxepin is similar to that of amitriptyline or amitriptyline-perphenazine, but in some studies was less rapid than that of imipramine. Preliminary findings suggest that the onset of antidepressant effect of doxepin may be more rapid with a single daily bedtime dosage regimen than with a divided daily dose schedule.

In preliminary studies, doxepin appears to have a lesser depressive effect on intracardiac conduction than imipramine or amitriptyline. It has been well tolerated by patients with myocardial disease, although patient numbers have not been very large, and by the elderly in whom postural hypotension and anticholinergic side-effects have not proved a problem.

The effects of doxepin in anxiety states are not such that it can be considered in preference to the benzodiazepines, but when a predominant anxiety state is accompanied by depression, doxepin has proved superior to chlordiazepoxide and diazepam and to be associated with a much smaller incidence of ataxia.

Side-effects are generally mild and tend to disappear with continued treatment, or if necessary, reduction of dosage. The most common side-effects have been dry mouth, drowsiness, constipation and dizziness. Excessive daytime drowsiness or sedation can be overcome by giving the major portion or the total daily dose at bedtime. Other side-effects are typical of tricyclic antidepressants and have occurred much less frequently. Hypotension and tachycardia in particular have been uncommon with doxepin. The usual precautions for use of tricyclic antidepressants also apply to doxepin.

Doxepin has only a moderate effect on the norepinephrine pump. Consequently, only at doses of 200mg or more daily has it antagonised the antihypertensive effect of guanethidine or bethanidine. In cases where doxepin has antagonized the antihypertensive effect of guanethidine or bethanidine, and the blood pressure has returned to pretreatment hypertensive levels, abrupt withdrawal of doxepin has been followed by a rebound increase in diastolic pressure to dangerously high levels above the pretreatment value.

Dosage should be individualised. The usually effective dosage for most depressed patients has been 75 to 150mg daily for outpatients and 150 to 300mg daily for hospitalised patients. A few patients have required larger doses. Doses for the elderly should be smaller initially, with smaller progressive increases. Patients with anxiety have usually been treated with 75 to 150mg daily, but hospitalised patients and some other patients may require larger doses. A dosage regimen based on the major portion or total daily dose given at bedtime has been of benefit in depressed patients with sleep disturbances, in the elderly and when it has been necessary to avoid any excessive daytime drowsiness. Dosage increases of tricyclic antidepressants should always be gradual, particularly in bedtime-based schedules.

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Various sections of the manuscript reviewed by: F.J. Ayd, Baltimore, Md. USA; T.A. Ban, Tennessee Neuropsychiatric Institute, Nashville, Tenn. USA; G. Bianchi, Bardon West, Australia; K.H. Boysen, Vienna, Austria; G.D. Burrows, Department of Psychiatry, University of Melbourne, Australia; B. Davies, Department of Psychiatry, University of Melbourne, Australia; J.M. Davis, Illinois State Psychiatric Institute, Chicago, III. USA; E. Ebnen, Department of Pharmacology, University of Helsinki, Finland; W.E. Fann, Department of Psychiatry, Baylor College of Medicine, Houston, Texas, USA; R.O. Friedel, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Wash. USA; H.L. Goldberg, West-Ros-Park Mental Health Center, Hyde Park, Mass. USA; B.J. Goldstein, Departments of Psychiatry and Pharmacology, University of Miami, Florida, USA; L.H. Hollister, Veterans Administration Hospital, Palo Alto, Calif. USA; J.W. Jefferson, Department of Psychiatry, University of Wisconsin-Madison, USA; I. Karacan, Department of Psychiatry, Sleep Disorders Center, Baylor College of Medicine, Houston, Texas, USA; A. Kiev, Cornell University Medical College, New York, NY, USA; M. Kimura, Psychotherapeutic Internal Department, Kyushu University, Fukuoka, Japan; N.S. Kline, Department of Mental Hygiene, Rockland Research Institute, Orangeburg, New York, USA; A.J. Krakowski, Plttsburgh, NY, USA; M. Lader, Institute of Psychiatry, De Crespigny Park, London, England; M. Manila, Department of Pharmacology, University of Helsinki, Finland; E. Radmayr, Facharzt fur Neurologie und Psychiatrie, Dornbirn, West Germany; K. Rickels, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa. USA; M. Toru, Department of Neuropsychiatry, Tokyo Medical and Dental School, Japan; J.K. Vohra, Cardiac Department, Royal Melbourne Hospital, Australia.

‘Sinequan’, ‘Sinquan’ (Pfizer); ‘Adapin’ (Pennwalt); ‘Aponal’, ‘Curatin’, ‘Quitaxon’ (Boehringer Mannheim)

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Finder, R.M., Brogden, R.N., Speight, T.M. et al. Doxepin Up-to-Date: A Review of its Pharmacological Properties and Therapeutic Efficacy with Particular Reference to Depression. Drugs 13, 161–218 (1977). https://doi.org/10.2165/00003495-197713030-00001

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  • DOI: https://doi.org/10.2165/00003495-197713030-00001

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