- Antidepressant
- The concept of drugs thought to work specifically against a disease called depression is probably a misnomer because depression often includes anxiety and other symptoms as well. Yet, "antidepressant" has claimed a firm place in the nomenclature of psychopharmacology, and drugs called antidepressants have evolved over the arc of several generations.First-generation antidepressants: the amphetamines and mixed amphetamine– barbiturates. There is a good deal of evidence that the amphetamines, launched in 1936 with Smith Kline & French’s Benzedrine (racemic amphetamine sulfate), have efficacy in community (nonhospital) depression. The firm began advertising Benzedrine for "mild depression" in 1942. In 1946, Smith Kline brought outdextro-amphetamine sulfate (Dexedrine) for mild depression, among other indications, and 2 years later they were billing the compound—used widely as well in weight reduction—as "the antidepressant of choice." In 1950, Smith Kline launched a combination product, Dexamyl—a mixture of dextro-amphetamine and Lilly’s amobarbital (Amytal) (see Barbiturates), informing medical readers of its "smooth and profound antidepressant action": the "smooth" was emphasized because many patients found unpleasant the revved-up feeling they got from amphetamines alone. (This was not mere marketing hype. In 1963, Ruth Rushton and Hannah Steinberg, members of the Department of Pharmacology, University College London, found that, "The combined effect of the two drugs can be regarded as true potentiation, since the maximal effects produced by the mixtures are considerably greater than the maximal effects produced by . . . either constituent alone and are greater than would be expected from simple addition" [British Journal of Pharmacology, p. 304].) (See WOMEN IN PSYCHIATRY: Steinberg.) Finally, the member of this first generation of antidepressants later to be the most deeply stigmatized was methamphetamine, launched by several firms in 1950 (Burroughs Wellcome’s "Methedrine"; Endo Products’ "Norodin": "psychomotor stimulant and antidepressant").Subsequently, indications for all of the amphetamines became tightly circumscribed, and methamphetamine vanished entirely from the pharmacopoeia. Yet, for more than a decade they represented the beginning of "antidepressant" therapy. The amphetamines started to become drugs of abuse when they were widely prescribed for obesity; an article in 1938 by Mark Falcon Lesses (1903–), a research associate at Boston State Hospital, and Abraham Myerson (1881–1948), director of research at the hospital, on "Benzedrine Sulfate as an Aid in the Treatment of Obesity" in the New England Journal of Medicine launched this rather fateful evolution.Second-generation antidepressants: the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs)The MAOIs, the first of which was iproniazid, were introduced for tuberculosis in 1952 (Roche’s Marsilid) and used in psychiatry after 1957. Imipramine, the first of the tricyclic antidepressants (Geigy’s Tofranil), was first marketed in Switzerland in 1957; in the United States in 1959. (For details, see the main entries for these two drugs.) Here it is reminded that iproniazid was initially billed as a "psychic energizer," only later as an antidepressant; Geigy brought out imipramine (Tofranil) as a "thymoleptic, specific in depression."Third-generation antidepressants: the first compounds developed on the basis of neurotransmitter theories about "reuptake inhibition." The Organon company developed (but did not design) the antidepressant drug mianserin with a view to inhibiting the reuptake of the monoamine neurotransmitters serotonin and norepinephrine. It was patented in The Netherlands in 1967 and by 1979, when the company launched it in France as Athymil (Norval in the United Kingdom), Organon realized that it inhibited the reuptake of monoamines. Because of confusion surrounding several American trialists who submitted fraudulent data, it was never registered in the United States.The Italian pharmacologist Bruno Silvestrini in Rome synthesized the antidepressant drug trazodone; he speculated that it might affect serotonin but did no biochemical or pharmacological testing. It was patented in the United States in 1968 by the Italian firm Angelini Francesco, who developed it as an anxiolytic. The license for the United States was sold to the Mead Johnson company, and by the time the company marketed it as Desyrel in 1982, the penny had dropped about reuptake inhibition, and the company claimed that it "selectively inhibits serotonin uptake in the brain." (In fact, its effect on serotonin is weak.)Also in 1968, Ciba patented their antidepressant drug maprotiline. It was launched in France in 1975 as Ludiomil and in the United States in 1981 under the same name: "Acts primarily by blocking re-uptake of norephinephrine [sic] at nerve endings to produce a significant therapeutic response on depressed mood," the company said. (The misspelling in the ad copy shows how new these concepts were.) All three of these third-generation antidepressants, and other compounds as well, were developed as designer drugs, tested clinically with specific neurohumoral actions in mind; namely, inhibiting the reuptake of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine.Fourth-generation antidepressants
Edward Shorter. 2014.
