S. Jue, G. Dawson, R. N. Brogden
Jul 1, 1982
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Influential Citations
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Quality indicators
Journal
Drugs
Abstract
SummarySynopsis: Amoxapine is an N-demethylated dibenzoxazepine closely related to the neuroleptic loxapine. Its tricyclic structure appears to give it antidepressant properties resembling imipramine and amitriptyline. In uncontrolled trials it was shown to have antidepressant activity in usual doses up to 200 to 400mg daily. In placebo and double-blind controlled studies comparing amoxapine with the standard tricyclic antidepressants imipramine and amitriptyline, it was shown to be comparable in efficacy with a possibly somewhat faster onset of improvement of selected symptoms of depression in some studies. Because of the small study groups and lack of placebo control, many reports do not show statistically significant differences of treatment over standard drugs. To date there have been no studies comparing amoxapine with electroconvulsive therapy. Side effects were qualitatively similar to standard drugs with a suggestion that in standard doses or overdose myocardial effects are mild. However, the final place of amoxapine in the therapy of depressed states is still to be decided. Pharmacodynamic Studies: The pharmacological profile of amoxapine does not generally differ significantly from imipramine with the possible exception that amoxapine demonstrates a relatively weak central anticholinergic activity and also has no effect on 5-hydrox-ytryptamine. There are 2 active metabolites of amoxapine, one of which (7-hydroxyamox-apine) demonstrates weak neuroleptic activity similar to that seen with amoxapine itself. Pharmacokinetic Studies: Amoxapine is readily absorbed after oral administration with peak levels being attained in 1 to 2 hours. The half-lives of amoxapine and its 2 active metabolites, 7-hydroxyamoxapine and 8-hydroxyamoxapine, are 8, 6 and 30 hours, respectively. Little unchanged drug is found in the urine. No clear relationship between plasma concentrations and clinical benefit has been established. Therapeutic Trials: Results of open and controlled trials in patients (mostly outpatients) with depressive illness reveal that amoxapine has antidepressant activity at dosages of 75 to 600mg daily. The controlled therapeutic trials have generally involved relatively small numbers of patients, a factor which prevents establishing statistically significant differences between amoxapine and the tricyclic antidepressants in published studies. In trials where the diagnosis is homogeneous, amoxapine 150 to 300mg has not been shown to be superior to the standard drugs amitriptyline or imipramine given in doses of at least 150mg. The drug does appear to be beneficial in both reactive and endogenous depressed patients in acute and chronic cases. Other types of depressed patients have been treated in too small numbers to conclude that amoxapine is superior to standard amitriptyline or imipramine treatment.The antianxiety activity of this drug appears to be minimal, but further studies in suitably selected patients are required to determine its role in patients with anxiety associated with primary depression.Some open trials and controlled clinical trials suggest a more rapid onset of antidepressant activity than with imipramine or amitriptyline, but more clinical experience is needed to confirm this observation.Amoxapine has not been used in children, but elderly persons have been included in open and controlled trials and appear to have tolerated the drug well.To date the efficacy of amoxapine has not been compared with that of the more recently marketed antidepressant drugs such as nomifensine, trazodone, maprotiline, zimelidine and mianserin. Side Effects: These are generally mild and have seldom required withdrawal of therapy. Anticholinergic side effects occurred as frequently as with imipramine in placebo-controlled trials. However, sedation seems to be intermediate between imipramine and amitriptyline. Tachycardia occurred commonly, but without changes in blood pressure. Serious cardiotoxic effects were not reported frequently in either amoxapine-treated or amitriptyline/ imipramine-treated groups of carefully selected patients. This is not unexpected, since the patients at high risk for cardiovascular problems were generally excluded from these comparative studies. Extrapyramidal side effects such as akathisia, ataxia and tremor have occurred rarely at usual therapeutic dosages.Experience with overdosage is extremely limited, but serious adverse events have not been reported thus far.Galactorrhoea and hyperprolactinaemia were reported in a limited number of patients following acute administration of amoxapine, but one chronic study failed to confirm any prolonged effect. More studies are required to elucidate the clinical importance of this finding. Dosage: Dosage should be individualised, but should begin with 50mg in divided doses (halved in elderly patients) and increased at 3-day intervals up to 300mg daily. Once the effective dosage is established, maintenance dosage may be given once daily at bedtime. Higher doses up to 600mg daily may be required occasionally, but should be given in divided doses with the largest fraction being given at bedtime. Single doses greater than 300mg have led to convulsive episodes in 2 patients.