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Drugs

, Volume 18, Issue 1, pp 1–24 | Cite as

Nomifensine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Depressive Illness

  • R. N. Brogden
  • R. C. Heel
  • T. M. Speight
  • G. S. Avery
Evaluations on New Drugs

Summary

Synopsis: Nomifensine1 is a tetrahydroisoquinoline antidepressant which is chemically unrelated to the tricyclic or tetracyclic antidepressants, the monoamine oxidase inhibitors or the recently introduced agents. Nomifensine resembles the tricyclic antidepressants in many of its pharmacological effects in animal models of depressive illness, but differs from them in that it strongly inhibits the re-uptake of dopamine as well as noradrenaline and is a relatively weak inhibitor of serotonin uptake. It has an overall efficacy comparable with that of imipramine and amitriptyline in depressive illness, but at dosages which have achieved a similar overall clinical improvement, nomifensine causes little or no sedation, fewer and milder anticholinergic side effects, and also appears less likely than these drugs to cause serious cardiotoxicity on over-dosage. Nomifensine may aggravate the psychopathology of patients with schizo-affective disorders and intensification of the psychosis may require neuroleptic therapy. Nomifensine also has antianxiety activity, but its role in treating anxiety associated with primary depression has still to be clarified. Nomifensine appears to be well tolerated by the elderly.

Pharmacodynamic Studies: The profile of action of nomifensine differs from that of the tricyclic and other antidepressant drugs in that it is a strong inhibitor of dopamine as well as of noradrenaline re-uptake in vitro and is only a relatively weak inhibitor of 5-hydroxytryptamine (serotonin). Low doses have a slight sedative effect, but higher doses of nomifensine and its 4-hydroxyphenyl (M1) and 3-methoxy-4-hydroxyphenyl (M2) metabolites may produce dose-related stereotyped behaviour in animals.

Studies in animals and in man indicate that nomifensine has little anticholinergic or sedative activity and is less likely to produce adverse cardiovascular effects than certain of the tricyclic antidepressants. At a dose of 10mg/kg nomifensine was less liable to produce seizures in photosensitive epileptic baboons than equal doses of imipramine or clomipramine, but at a dosage of 20mg/kg, results were less conclusive. However, recent reports of nomifensine overdose suggest that the incidence of convulsions may be low when the drug is taken in overdose amounts.

Pharmacokinetic Studies: Nomifensine is readily absorbed after oral administration in man and is present in plasma mainly as the glucuronide conjugate. Steady-state plasma concentrations are attained within the first 5 days of repeated administration. There is a short distribution phase of 2 to 4 hours and a relatively large (up to 14L/kg) apparent volume of distribution. About 96 % of a dose is recovered in the urine and 3.7 % in the faeces. The plasma half-life is about 2 to 4 hours, but is prolonged in severe renal impairment and accumulation may occur when the creatinine clearance is below 25ml/min.

Therapeutic Trials: Results of open and controlled trials in patients (mostly outpatients) with depressive illness indicate that nomifensine has antidepressant activity at dosages of 50 to 150mg daily in divided doses. The controlled therapeutic trials have generally involved relatively small numbers of patients, a factor which may have contributed to the lack of statistically significant differences between the efficacy of nomifensine and the tricyclic anti-depressants in the published studies. Nevertheless, it appears that the mood elevating effect of nomifensine is comparable with that of equal dosages of the tricyclic antidepressants. There is evidence that nomifensine possesses some antianxiety activity, although further studies in suitably selected patients comparing nomifensine with doxepin or with an antidepressant plus antianxiety drug are needed to determine its role in patients with anxiety associated with primary depression.

Although open trials have reported a rapid onset of antidepressant effect, there is no convincing evidence in controlled trials that the onset of the antidepressant action of nomifensine is more rapid than that of the tricyclic antidepressants.

Nomifensine has been used in children in one study, in elderly patients in open and controlled studies and has generally been well tolerated by both age groups. To date, the efficacy of nomifensine has not been compared with that of electroconvulsive therapy, or mianserin or some of the other recently marketed antidepressant drugs. Although reports of clinical impressions, and the pharmacological properties of nomifensine suggest that the drug may be of particular value in ‘retarded’ depression, the evidence in controlled trials is meagre. Further trials involving larger numbers of patients are necessary to determine the type of depressive illness which will respond best to nomifensine and the profile of activity of the drug relative to that of other recently introduced antidepressant drugs.

Generally, the frequency and/or severity of adverse effects has been lower with nomifensine than with the tricyclic antidepressants.

Side Effects: These are generally mild and have seldom necessitated withdrawal of therapy. Anticholinergic side effects and sedation have occurred less frequently than with the tricyclic antidepressants, and in one of the few studies which attempted to differentiate between side effects and symptoms associated with the depressive illness itself, tachycardia occurred less frequently with nomifensine than with nortriptyline. There have been few reports of cardiovascular side effects associated with therapeutic dosages of nomifensine, but in the trials comparing nomifensine with the tricyclic antidepressants such effects have seldom occurred with the tricyclics either. This is not unexpected, since those patients most likely to be at risk (e.g. the elderly or those with cardiovascular disease) were usually excluded from such comparative studies. However, recent reports on overdosage suggest that important adverse effects on the heart are less likely with nomifensine than with the standard tricyclic anti-depressants.

Dosage should be individualised but initially should be 25mg 2 or 3 times daily. The effective dosage is usually 75 to 150mg daily but higher dosages can be given where necessary. Lower initial dosages should be given in elderly patients.

Keywords

Tricyclic Imipramine Amitriptyline Clomipramine Nortriptyline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© ADIS Press Australasia Pty Ltd 1979

Authors and Affiliations

  • R. N. Brogden
    • 1
  • R. C. Heel
    • 1
  • T. M. Speight
    • 1
  • G. S. Avery
    • 1
  1. 1.Australasian Drug Information ServicesBirkenhead, Auckland 10New Zealand

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