What is the available information about trazodone?

Fråga: What is the available information about trazodone?

Sammanfattning: Trazodone is a 2nd generation antidepressant, not registered in Sweden. It differs chemically and pharmacologically from tricyclics and MAOIs. Its main advantage compared to classic antidepressants seems to be its relatively low frequency of anticholinergic and cardiotoxic effects. However the quality of theclinical documentation is inferior to that of the established first generation antidepressants.

Svar: Trazodone is a member of the so called 2nd generation antidepressants not registered in Sweden. It is a triazolopyridine derivative which differs chemically in its pharmacological profile from tricyclics and MAOI antidepressants. It is a weak but specific inhibitor of the synaptosomal uptake of serotonin (1). It possesses an antiserotonin and alpha adrenergic blocking effects (2,4). It is practically devoid of anticholinergic effects. It down-regulates beta-adrenergic and serotonin 1 and 2 receptors in long term treatment (2). The mode of action of trazodone in depression is not fully understood.

Trazodone is well absorbed after oral administration, and the mean peak plasma concentration is attained around 2 (plus minus 0.5) hours after ingestion. It is extensively metabolised, less than one per cent of a dose is excreted unchanged in the urine. The metabolites are predominantly excreted via the kidney (70-75 percent recovered in 72 hs). The elimination half life for the unchanged drug has been reported as about 6.3 h, and for total drug and metabolites about 13 h (1,3,4). There are no adequate data on the association between plasma drug levels and clinical effects.

Trazodone is an antidepressant with sedative and antianxiety activities. Its efficacy as an antidepressant has been shown both in open trials as in controlled trials. In these, it was generally shown that the efficacy of trazodone was superior to placebo and equal to that of imipramine, amitriptyline and desipramine. It showed less side effects compared to imipramine andmore antianxiety effects compared to desipramine (1,7,8).

There are no consistent differences between the drugs with respect to the rapidity of onset of their antidepressant activity. The claims that trazodone has an earlier onset of effect are probably due to its antianxiety properties.

In geriatric patients as in younger patients, trazodone was comparable in therapeutic efficacy with imipramine, but was better tolerated. Trazodone 75 to 150 mg daily was more effective than placebo and comparable with 50 to 150 mg of thioridazine in depressed geriatric patients (1). There are few well designed studies demonstrating its efficacy in other than endogenous depression. At lower doses, it appears to be effective in treating anxiety neuroses. It has also been used in combination with antipsychotic drugs in depressed schizophrenics, as it usually does not aggravate schizophrenia. There is some evidence suggesting it may be of help in the treatment of drug induced tardive dyskinesias and Parkinsonism in some patients (1).

The initial oral dosage is 50 to 150 mg daily in divided doses, and it should be gradually increased according to response. The usual adult therapeutic dosage is 150 to 400 mg daily for outpatients and up to 600 mg daily for inpatients or more severly depressed patients (exceptionally, up to 800 mg daily have been used) (1,3,9).

Drowsiness has been the most frequently reported adverse effect (around 10 percent, maximum report 45 percent). Dizziness, fatigue, gastrointestinal discomfort follow (the latter occur more frequently than with tricyclic antidepressants and may include nausea, indigestion, "burning", vomiting). Hypotension, headache and insomnia have also been reported. Agitation is confined largely to schizophrenic patients. Priapism is a rare side effect. There have been occasional reports of tachycardia and bradycardia (1,3,4,5).

The low incidence of cardiovascular side effects reported, along with findings in dog and rat studies, and limited studies in humans, suggest that important adverse effects on the heart may be less likely with trazodone than with tricyclic antidepressants (1,5). The same could be said about anticholinergic side effects, which occur less frequently than with imipramine and amitriptyline (1,5).

Trazodone produces a dose dependent inhibition of the antihypertensive effect of clonidine in animals, but it is not known whether the antihypertensive effect of clonidine or guanethidine are significantly reduced by therapeutic doses of trazodone in human beings (1,5).

Increased sedation could result with concomitant administration of other sedatives, antidepressants or alcohol.

In view of all these characteristics, trazodone has been recommended by the manufacturers and some authors (1,2,3,6,7,8) in favour to tricyclics in:

-depression in the elderly,

-depression in schizophrenics,

-depressive syndromes concomitant to organic disease such as narrow angle glaucoma, prostatic hyperplasia, cardiac disease, alcoholism and tremor.