Nomifensine was first introduced in Germany in 1976 and in the United Kingdom in 1977 and was finally registered in 98 countries.
BACKGROUND
Nomifensine
was first introduced in Germany in 1976 and in the United Kingdom in 1977 and
was finally registered in 98 countries. It was a novel chemical entity, a
tetrahydroisoquinoline, unrelated chemically to any other antidepressant. Like
tricyclic antidepres-sants, however, its supposed mode of action was the
inhibition of the presynaptic reuptake of biogenic amines in the brain,
enhancing their concentration with the aim of combating depression (thought to
be mediated by a relative deficiency of these amines). Nomifensine was also a
powerful inhibitor of the reup-take of dopamine, with lesser effects on
noradrenaline and, through its metabolites, on serotonin (Nicholson and Turner,
1977).
Its
preclinical properties, which were confirmed in clinical use, showed the drug
to have few anti-cholinergic and sedative effects. It was therefore a possible
safer alternative to tricyclic antidepressants, which could be especially
troublesome when taken in overdose. Nomifensine proved to be well tolerated in
overdose and was not associated with significant cardiotoxicity or
epileptogenic activity. These prop-erties meant that the drug was potentially
useful in certain depressive disorders, notably retarded depres-sion, and in
certain subgroups, such as those associ-ated with cardiovascular disease and
epilepsy. It was also considered to be of value in the treatment of elderly
depressed patients and, through its dopaminer-gic properties, patients with
early Parkinson’s disease.
Depression
is a very common condition with approximately one in seven general practitioner
(GP) encounters being a follow-up appointment of a patient with depressive
symptoms, and one in 25 encoun-ters a new case. Only 10% of cases seen by GPs
are referred to psychiatrists (Beaumont, 1984). The mainstays of
pharmacological treatment during the 1980s, the tricyclic antidepressants and
monoamine oxidase inhibitors, were associated with a consider-able number of
adverse reactions in most physiologi-cal systems (Edwards, 1981).
Nomifensine
joined mianserin as a representative of a new generation of antidepressants
that caused fewer side effects. Other drugs of this category intro-duced into
practice at or near this time were maproti-line, viloxazine, tryptophan,
zimeldine, trazodone and lofepramine, each with its own subsequent history of
benefit and risk.
In
the decade up to 1980, the total number of deaths from drug poisoning in
England and Wales remained steady at about 3000 per year, two-thirds of which
occurred outside hospital. During this time, the proportions due to different
groups of drugs changed considerably, with deaths due to barbiturates falling
by half and those due to analgesics and tricyclic antidepressants doubling. In
1980, tricyclic antide-pressants were second only to barbiturates in causing
death by poisoning (Crome and Chand, 1980). An antidepressant with low toxicity
in overdose would thus have life-saving potential if a patient, despite all
efforts at prevention, decided to attempt suicide with the medication.
Nomifensine proved to be excep-tionally well tolerated in overdose in many
published reports (Crome and Chand, 1980; Garnier et al., 1982; Ali and Crome, 1984).
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