A method that contributed to the discovery of chlorpromazine was a descendant of the rat rope climbing studies. A rat cage had a grid floor. A rope hung from the roof of the cage. A rat was put in the cage. A single ring of a bell was sounded and a few seconds later a small AC current was applied across the grid. The current was sufficient to prompt escape by the rat but not, of course, sufficiently strong to cause any harm. If the rat climbed the rope, it removed itself from the current. After a few experiences the rat began climbing the rope promptly when the bell sounded. The effects of drugs on consistency and speed of climbing were studied.

It was known in the 1940s that clinically available antihistamine drugs caused a side effect of "drowsiness" even though the various drugs belonged to many different chemical classes. Sometime before the end of 1950, a group at a French drug company had the insight to consider that perhaps the drowsiness is indicative of interesting new pharmacology. Therefore, starting with an antihistamine, 3277RP (promethazine) marketed by the company, the group helped guide the synthetic program of chemists in the team toward compounds with potent behavioral effects using, inter alia, the method just described as one of their tests. They selected a compound designated 4560RP, which became chlorpromazine. They found many effects of the drug but in particular the following: In the rope (or pole) climbing test, with increasing dose, the latency from the sound to the rat climbing increased progressively until the rat sometimes remained on the grid until onset of the current, whereupon the rat promptly climbed the rope. As dosage was further increased, the rat increasingly did not climb the rope after the sound but continued to do so at onset of the current. The climbing at onset of the current showed that the lack of climbing during the sound was not due to motor incapacity to climb. A barbiturate at increasing dose caused increased latency, but at dose levels at which the rat failed to climb after the sound, it also failed to climb at onset of current. The investigators thought that the dissociation produced by chlorpromazine was indicative of a new and interesting pharmacology. Indeed they were right.

After an inauspicious beginning, chlorpromazine found its way into psychiatric wards in Paris as Largactil. Within a few years it was in use worldwide (as Thorazine in the United States) and had produced the most profound therapeutic revolution that psychiatry has experienced, certainly since the cessation of the punitive treatment of the insane. Chlorpromazine has beneficial effects in psychoses such as schizophrenia and manic-depressive psychoses that previously had no effective treatment. Chlorpromazine is said to have "antipsychotic" properties. What it does particularly well is quieten agitated, disoriented, difficult to handle psychotics. As a result, the large, custodial psychiatric hospitals run by states and cities became quieter and more manageable places. In a relatively short amount of time, a large fraction of the population of hospitals was able to be discharged for care in the community. The hospitals were consolidated and many closed. There have been problems, of course, because many families and communities lack the knowledge, resources, or willingness to continue the level of care that the ex-hospitalized psychotics still require since chlorpromazine is not curative. Still, anyone who remembers the bleak and dreadful hopelessness of the large public so-called mental hospitals can only regard the problem as an acceptable price to pay for the great emancipation.

Chlorpromazine had a major impact on attitude in psychiatry. Hitherto, the mission of psychiatry was to help patients cope with their disorders and be more comfortable. Chlorpromazine came without warning and showed that it was possible to help psychotics with drugs not just by "sedating" them but by moving them toward normality. The question now asked was, if chlorpromazine can do this, for what other beneficial effects can agents be discovered? An optimism about future therapies permeated psychiatry, even though a minority of psychiatrists, most with doctrinaire affiliations with old "schools," resented the advent of pharmacotherapies and regarded help from drugs as failure to persist with persuasion. Because a chemical agent could be antipsychotic, there was new faith that biological bases of psychoses could be discovered and there was increased research activity and funding. The drug companies were galvanized into developing new research and development programs, and many new phenothiazine and other chemical classes of antipsy-chotic agents were introduced.

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