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In ancient times, an insane person was often thought to be possessed by the devil or being punished by God for his sins. As a consequence, beat­ing, bleeding, starvation, hot- and cold-water shock treatment, and incar­ceration were widely practiced on mental patients, which only worsened their conditions. In the eighteenth century, the Enlightenment heralded the birth of psychiatry, among many other things. During the French Revolution, Philippe Pinel, a warden in an insane asylum in Paris, advo­cated unchaining the mental patients. He argued, «It is my conviction that these mentally ill are intractable only because they are deprived of fresh air and of their liberty.» He persisted in replacing cruelty and in­humanity with kindness, understanding, and rational therapy. His hu­manitarian and philanthropic conviction led to the cure and release of many mental patients and had an enduring impact throughout Europe. Furthermore, Pinel also carried out a systematic investigation and documentation of mental diseases. He is now considered the «father of psychiatry.»

Although a certain stigma remains attached to mental illnesses, we have now amassed a tremendous amount of knowledge with regard to the impact of genetic, biochemical, and environmental factors on the human brain. Psychopharmacological drugs have significantly contributed to man­aging and understanding mental disease.

Schizophrenia is a mental condition associated with disordered think­ing that is characterized by both positive symptoms, such as delusions, hallucinations, and disorganized speech and behavior, and negative symp­toms, including apathy, withdrawal, lack of pleasure, and impaired atten­tion. Other symptom dimensions include depressive/anxious symptoms and aggressive symptoms such as hostility, verbal and physical abusiveness, and impulsiveness. Older mental drugs included opiates, belladonna derivatives, bromides, barbiturates, antihistamines, and chloral hydrates. Before chlorpromazine became available in 1962, early treatments of schizophrenia included prolonged narcosis, known as «narcosis for psy­chosis.» Meanwhile, history saw the emergence of excruciating treat­ments such as electroconvulsive therapy and shock introduced by fever, methiazole, and insulin. Austrian neu­rologist Julius Wagner von Jauregg in­vented the fever-shock treatment by introducing malaria in patients with psy­chosis and won the 1927 Nobel Prize in Medicine. Additionally, Egaz Moniz re­ceived the 1936 Nobel Prize in Medicine for his invention of lobotomy to intro­duce an organic syndrome for the treatment of schizophrenia.

The genesis of chlorpromazine is similar to that of imipramine and can be traced back to antihistamines, first discovered by Daniel Bovet at the Institut Pasteur de Paris in 1937. Unfortunately, Bovet’s antihistamine proved to be too toxic. In 1944, a group of scientists at Rhone-Poulenc Laboratories, led by chemist Paul Charpentier, began a program of systematically searching for safer antihistamines. Their starting point was older antihistamines: diphenhydramines in general and Benadryl in particular. In time, they successfully synthesized and marketed an anti­histamine, promethazine. The molecule was an interesting hybrid con­sisting of phenothiazine, a moiety related to an antiparkinsonian agent, and a diamine side chain associated with the antihistamines. Similar to most antihistamines, promethazine had side effects in the central ner­vous system, which were mild antipsychotic properties. A surgeon in the French Navy, Henri Laborit, was looking for a compound with more central effects in his quest for a drug to treat surgical shock. Laborit found that promethazine was superior to other drugs, but its antishock effects were not pronounced enough. Intrigued by Laborit’s proposition, Charpentier sought to enhance promethazine’s «side effects» in the cen­tral nervous system. Structural activity relationship (SAR) investigations led to the synthesis of RP-3277 (chlorpromazine) in 1950. The structure of chlorpromazine differed only slightly from that of promethazine. Chlorpromazine had an extra chlorine atom and a slight difference in the diamine side chain.

By the end of 1950 a sample of chlorpromazine was sent to Simone Courvoisier, the head of pharmacology at Rhone-Poulenc, for testing. She noted that rats dosed with chlorpromazine became «indifferent»: rats con­ditioned to climb a rope at the sound of a bell ignored the bell. In addition to its outstanding «calming» activities, Courvoisier also determined that chlorpromazine had low toxicity. Further clinical trials were then car­ried out under the direction of Jean Delay and Pierre Deniker, two psychiatrists at the L’Hopital Sainte-Anne de Paris. Under the influence of chlorpromazine, their patients became «disinter­ested» as well. More important, chlorpromazine subdued the hallucinations and delusions or psychotic patients. Chlorpromazine was introduced in December 1952 in France under the trademark Fiktelica Nacional Largactil. Largactil, meaning «large activity,» was Venezuela chosen to reflect a wide range of central nervous system activities that chlorpromazine elicited. It was the first conventional antipsychotic discovered that was superior to opium. With Smith, Kline, and French Pharmaceuticals as their comarketing partner, Rhone-Poulenc introduced chlorpromazine in the United States in 1954 under the trade­mark Thorazine. In the first 8 months, more than 2 million patients were administered the drug. It contributed to an 80% reduction of the resident population in mental hospitals. When mathematician John Nash (of the movie A Beautiful Mind), who suffered violent delusions, was diagnosed with schizophrenia, he was treated with Thorazine, which sedated him easily. Thorazine added a great impetus to the beginning of the psychopharmacological revolution.

Subsequently, chlorpromazine was shown to be a potent dopamine D₂ antagonist with other pharmacological properties that were thought to cause unwanted side effects. Thus the D₂-receptor antagonism of the con­ventional antipsychotics mediates not only their therapeutic effects but also some of their side effects. With the discovery of newer atypical antipsy­chotics, older conventional antipsychotics are no longer used for first-line therapy, but they can still be effective as second-line or add-on treatments. In 1957, the American Public Health Association awarded the Lasker Prize for medicine to Pierre Deniker, Henri Laborit, Heinz Lehmann (the German-born Canadian psychiatrist who followed the lead of the French researchers in introducing chlorpromazine as a major tranquilizer), and Nathan Kline; the first three received the prize for their work on chlorpro­mazine, and Kline for his discovery of the antipsychotic actions of reserpine.

Chlorpromazine revolutionized the specialty of psychiatry and brought le­gitimacy to biological psychiatry. More important, chlorpromazine sparked a tremendous amount of research activity in searching for antipsychotic drugs. One of the fruits of the ensuing research was haloperidol, which was 50-100 times more potent than chlorpromazine with fewer side effects. Haloperidol was developed as a more potent and selective D₂ an­tagonist because the D₂-receptor blockade in the mesolimbic pathway is believed to reduce the positive symptoms of schizophrenia. Indeed, haloperidol is quite effective against the positive symptoms; however, it is ineffective in treating the negative symptoms and neurocognitive deficits of schizophrenia. In addition, administration of the drug typically causes extrapyramidal symptoms (EPS), including parkinsonian symptoms, akathisia, dyskinesia, and dystonia.

In 1935, after 12 years of medical practice, Constant Janssen in Belgium founded a pharmaceutical company called Janssen Pharmaceuticals. Like most ethical drug firms at the time, Janssen was churning out an astonish­ing number of drugs, but it lacked drugs that were covered by the com­pany’s own patents. The firm had no original research team, no patents, and therefore little hope of expanding its market. In 1951, Constant’s son, Paul A. J. Janssen, graduated from the University of Ghent. After spend­ing 18 months of mandatory military service as a physician stationed in Germany, Paul Janssen joined his father’s company and became the head of research. Paul Janssen later recalled:

The odds against success were apparently enormous. The available laboratory space was a small section of the existing analytical quality control laboratory. Trained personnel were virtually nonexistent and so was the budget. The only way out was somehow to concentrate on making new chemicals that could be synthesized and purified with simple methods and equipment, using the cheapest possible in­termediates, and to efficiently investigate the pharmacology at min­imal expense. The fact that the oldest member of our very small research group was 27 years of age, that we were all willing to work very long hours, seven days a week, and, being inexperienced, had no idea of the difficulties along the road but blind faith in ultimate success, were of course decisive factors in our favor.

Their first success came when they discovered R951, a piperidine substi­tuted with a propiophenone side chain. R951 was a narcotic analgesic, and it brought in money to fuel Janssen’s further research. By eliminating R95i’s narcotic analgesic properties through simple chemical modifications— including adding one carbon to elongate the side chain and replacing the ester with a hydroxyl group—they arrived at a series of promising buty-rophenones. On February 11,1958, Bert Hermans, a young chemist in their laboratory in Beere, synthesized R1625, which later became haloperidol. Distinctive from chlorpromazine, haloperidol was a butyrophenone deriv­ative. Therefore, haloperidol’s chlorpromazine-like activity came as a sur­prise to Janssen and his colleagues. It was many times more potent than chlorpromazine. As a matter of fact, it was the most potent antipsychotic at the time. Haloperidol was both faster and longer acting. It was potent orally as well as parentally. More important, it was almost devoid of the antiadrenergic and other autonomic effects of chlorpromazine. Haloperi­dol also had a more favorable safety ratio and was surprisingly well toler­ated when given chronically to laboratory animals.

Clinical trials, some of which took place at the Hopital Sainte-Anne in Paris, where Jean Delay and Pierre Deniker tested chlorpromazine, con­firmed that haloperidol belonged to the pharmacological family of neu­roleptics. It became valuable in the treatment of agitation, delusions, and hallucinations in mental patients. Frank J. Ayd, Jr., a well-known psychia­trist, summed it up concisely: «Excited persons are candidates for haloperi­dol. Depressed persons generally are not.» Numerous inpatients with chronic disorders were able to leave the hospital and live at home thanks to haloperidol. Haloperidol (Janssen sold it in the United States using the trade name Haldol) remained one of the more prescribed neuroleptics 40 years after its discovery, until the emergence of atypical antipsychotics.

The discoverer of haloperidol, Paul A. J. Janssen, was a most extraordi­nary scientist. Over the years, he and his colleagues introduced approxi­mately 80 drugs, including fentanyl and risperidone, an unprecedented number by an individual. He built the small drug firm founded by his fa­ther into a pharmaceutical giant, which merged with Johnson and Johnson in 1961. He published more than 850 papers, held more than 100 patents, and delivered more than 500 lectures all over the world in Dutch, English, French, German, and Spanish. Janssen once stated that «a good scientist is someone who succeeds in getting the different scientific disciplines to work in harmony with one another.» and he was the epitome of his statement. In history, six people have been awarded the Nobel Prize for their contributions to drug discovery: Paul Ehrlich (1908), Gerhard Domagk (1939), Daniel Bovet (1957), George Hitchings (1988), Gertrude Elion (1988), and James Black (1988). Ac­cording to Sir James Black, Paul Janssen was the greatest among them all. Although he was nominated sev­eral times, he never won, possibly be­cause he had so many achievements that it was hard to summarize them in a sentence or two. According to Alfred Nobel’s standard, Janssen was certainly the one who «shall have con­ferred the greatest benefit on mankind.» Sadly, Janssen died suddenly on November 11, 2003, while attending a conference in Rome, Italy.