Chlorpromazine discovery

The discovery of the activity of the phenothiazines such as chlorpromazine (44) against schizophrenia pointed the way to drug therapy of diseases of the mind. The intensive... 

It can be argued that the introduction of lithium salts into the practice of psychiatry in 1949 heralded the beginning of psychopharmacology, as it predated the discovery of chlorpromazine, imipramine, monoamine oxidase inhibitors and resperine. Lithium came into clinical use serendipitously, the Australian psychiatrist Cade having by chance given it to a small group of manic patients and found that it had beneficial effects. 

It is interesting to note that one of the founders of modern psychiatry, Kraepelin, listed only nine substances that were available for the treatment of psychiatric illness in the 1890s. These were opium, morphine, scopolamine, hashish, chloral hydrate, a barbiturate, alcohol, chloroform and various bromides. Later Bleuler, another founder of modern psychiatry, added paraldehyde and sodium barbitone to the list. Thus psychopharmacology is a very recent area of medicine which largely arose from the chance discovery of chlorpromazine by Delay and Deniker in France in 1952, and of imipramine by Kuhn in Switzerland in 1957. 

Detailed accounts of the discovery of chlorpromazine as an antipsychotic drug have been given by two authors (Caldwell, 1970 Swazey, 1974) an abridged... 

The discoveries of chlorpromazine and imipramine are generally regarded as greater scientific advances than that of the tranquillizers. However, in making the public aware of the fact that mental disturbances can be treated with... 

In 1954, i.e. about 2 years after the discovery of chlorpromazine in Europe, two American biochemists (Woolley and Shaw) published the hypothesis that schizophrenia and similar psychoses could be based on a disturbance of serotoninergic neurotransmission in the brain. This hypothesis was supported by some facts that had become known shortly beforehand the spectacular psychotropic actions of LSD (lysergic acid diethylamide), which can trigger disturbances in perception, thought and feelings as well as hallucinations in healthy subjects (Stoll, 1947) and the serotonin-antagonistic effects of LSD, i.e. its ability to block the actions of serotonin in various pharmacological tests. 

At the time of the discovery of chlorpromazine. dopamine could not be assayed directly and its role as a neurotransmitter was unknown (Carlsson, 1987). Chlorpromazine exerts a large number of pharmacological effects, all of which could, in principle, be considered responsible for its clinical action. Thus, it was first assumed that the antipsychotic action of chlorpromazine and similar... 

Chlorpromazine s (CPZ) efficacy was discovered primarily by chance in exploratory clinical trials after it had been initially synthesized as an antihistamine. Its discovery, however, was not entirely fortuitous, because it was chosen for human investigation since it was mildly sedating. The concept of an antipsychotic, however, was unknown. CPZ s sedative properties then led the French anesthesiologist and surgeon Henri Laborit to use it in a lytic cocktail to reduce autonomic response with surgical stress (1). He also persuaded many clinicians to try it for the treatment of a wide variety of other disorders. In this context, he encouraged John Delay and Pierre Deniker (1952), who then administered CPZ to schizophrenic patients. The rest is history ( 2, 3). 

Similar examples abound in most fields of therapeutics. For example, the major tranquilizer chlor-promazine—the first drug found to have true antipsychotic properties—is a trivial modification of phenothiazine, which was known for decades and used as a de-wormer for livestock. The parent phenothiazine, and many of its structural modifications, have no antipsychotic activity at all it is only certain minor structural modifications that have the essential pharmacologic and therapeutic properties. (Chlorpromazine also happens to be a classic example of the serendipitous empirical-clinical method of discovery of a drug s unique therapeutic value, a method described below.)... 

Phenothiazine derivatives have found many applications in todays chemical industry they have been and are used primarily as dyestuffs, antioxidants and in pharmaceutical preparations. This application is due to the discovery of their neuroleptic activity (1 ) (e.g. Chlorpromazine), but allergic skin reactions and ocular opacity are known to occur during therapy. 

Curzon G (1990) How reserpine and chlorpromazine act the impact of key discoveries on the history of psychopharmacology. Trends Pharmacol Sci 11, 61-63. 

Although the discovery that chlorpromazine and related phenothiazine neuroleptics were effective in the treatment of schizophrenia was... 

An important breakthrough in the development of novel neuroleptics arose over 25 years ago with the discovery of the dibenzazepine neuroleptic clozapine. This neuroleptic was novel because it attenuated both the positive and negative symptoms of schizophrenia without causing extrapyramidal side effects or elevating serum prolactin concentrations, effects which characterize most typical neuroleptics such as chlorpromazine and haloperidol. 

---