The story of antipsychotics: Past and present

Abstract

Byline: Chaitra. Ramachandraiah, Narayana. Subramaniam, Manuel. Tancer Antipsychotics have been broadly classified into classical/ typical, which includes phenothiazines and butyrophenones, and atypical antipsychotics, which includes benzamides. The psychiatric effects of all the progeners of these groups were discovered serendipitously. Chlorpromazine, belonging to phenothiazines, heralded the psychopharmacological era and replaced therapies such as electroconvulsive therapy, insulin coma, frontal lobotomy and simple sedation, causing an important revolution in psychiatric practice. Derivatives of phenothiazines, such as methylene blue, had been used since the nineteenth century in the dyeing industry (textile as well as histopathological preparations) and pharmaceuticals such as antiseptics and antihelmenthics. A group of phenothiazine derivatives with an aminate chain were synthesized by a team led by Paul Charpentier to exploit the antihistaminic properties as pre-anesthetic medication. In 1949, Henri-Marie Laborit, a French army surgeon, used promethazine, a phenothiazine derivative, along with barbiturates, to prevent surgical shock and called this lytic cocktail. He also noticed the patients who were extremely anxious were made calm, relaxed and indifferent to the surroundings. Agitated patients got subdued and co-operative as if they had a pharmacological lobotomy. The research on phenothiazines continued until 1950, when a chlorinated derivative of promazine was developed: RP-4560, later named chlorpromazine, which not only had antihistaminic properties but was also adrenolytic, gangliolytic and antiemetic among many other effects. Laborit tried to convince psychiatrists about the therapeutic uses of the drug in psychiatry, in line of his hypothesis and observations, especially in sleep disorders. No one in the scientific community was enthused about it. Finally, Joseph Hammon tried it for the first time in 1952 on a manic patient. The patient not only calmed down but was also able to maintain this state. He was eventually discharged after 3 weeks. Researchers almost disregarded this effect because the patient was on other medication, such as barbiturates, opiates and electro-convulsive therapy. In the same year, Jean Delay and Deniker conducted a study using chlorpromazine alone and observed a group of symptoms with decreased motor activity and affective indifference. They named the constellation of symptoms as syndrome. The word neuroleptic was suggested by Jean Delay in 1955, which meant that take the nerve. The duo further went on to present six clinical reports on 38 patients with mania and psychosis and confirmed the effectiveness of chlorpromazine. Heinz Lehmann, a psychiatrist from Berlin and a refugee residing in Canada, published similar articles on the use of chlorpromazine exhaustively over several years. He used the drug in different psychiatric conditions with psychomotor agitation (acute and chronic mania, schizophrenia, senile psychosis, post lobotomy and mentally challenged). He obtained positive results in 66%, but the response was the best in patients with manic depression, who were manageable within 24 hours, subsequently, having fewer relapses. He also cautioned that, in patients with chronic schizophrenia who were nonresponders, the possible toxic effects of the drug prevailed. In 1954, Elkes and Elkes conducted a historic study on psychotic patients, which was randomized and placebo-controlled, showing the effectiveness of chlorpromazine. Eventually chlorpromazine started being accepted by psychiatrists all over the world, although a slow start. Thus, it paved the way for the neuro- biological basis of psychiatric illnesses.[sup] [1] Haloperidol belongs to butyrophenones and was synthesized in 1958 at a Belgian laboratory by Paul Janssen. Janssen laboratories were then trying to develop a more powerful analgesic than dextromoramide. …