psychiatric applications of Iproniazid. Ernst Zeller found Iproniazid to be a potent Monoamine oxidase inhibitor. Nevertheless, Iproniazid remained relatively obscure until Nathan S. Kline, the influential head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer". Roche put a significant marketing effort behind Iproniazid. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity. The antidepressant effect of a Tricyclic, a three-ringed compound, was first discovered in 1957 by Roland Kuhn in a Swiss psychiatric hospital. Antihistamine derivatives were used to treat surgical shock and later as neuroleptics. Although in 1955, Reserpine was shown to be more effective than a placebo in alleviating anxious depression, neuroleptics were being developed as sedatives and antipsychotics. Attempting to improve the effectiveness of Chlorpromazine, Kuhn in conjunction with the Geigy Pharmaceutical Company discovered the compound "G 22355", later renamed Imipramine. Imipramine had a beneficial effect on patients with depression who showed mental and motor retardation. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA. Antidepressants became prescription drugs in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic about marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers, which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use. By the 1960s, it was thought that the mode of action of Tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later Tricyclics were thought to affect serotonin as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug. Second-generation antidepressants Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was Zimelidine in 1971, while the first released clinically was Indalpine. Fluoxetine was approved