controlling paroxysms of furious excitement and turbulent maniacal outbreaks.” However, only a few psychiatrists widely accepted Drapes’s report citing observations that hyoscine and the new line of hypnotic drugs quieted rather than cured patients. During this time, the possibility of a substance affecting the brain’s circuitry, modulating behavior, and changing the clinical course of a neurological disorder was widely perceived as a mere fantasy. In 1903, barbiturates were discovered by Emil Fischer Modern Psychopharmacology (1950–1964) In 1950, Smith, Kline, and French (SKF) synthesized and commercially market chlorpromazine in the U.S. The synthesis of chlorpromazine is arguably the beginning of the modern psychopharmacology era. Compared to the early sedatives and hypnotics perceived to hold no significant clinical intervention value, the new drug was the first psychoactive substance to improve the clinical presentations of patients with psychopathy. In addition to being in an easily administered presentation form, multiple correspondences on the clinical effects of chlorpromazine also testified that the clinical effects of the new drug were reproducible. Although chlorpromazine introduced a new area of clinical management, the research interest needed to sustain this new discipline was prominently lacking. Chlorpromazine was largely discovered by chance. Its discovery was the culmination of a lengthy process starting in the mid- 1800s with the extraction of synthetic dyes from coal tars. These synthetic dyes were identified and characterized by the famous organic chemist August Berntsen. Berntsen described the chemical structures of these dyes as a phenothiazine nucleus—a chemical core earlier described in methylene blue. In the early 1940s and 1950s, clinical research on antihistamines in the biology of allergies become increasingly popular, with many scientists focused on developing synthetic antihistamines. Charpentier began an extensive research project testing for antihistaminic properties in substances with the phenothiazine chemical core earlier characterized by August Berntsen. Charpentier’s project continued until the synthesis of a substance named R.P. 4560. With a few chemical modifications and a proper description of expected physiological properties, Charpentier convinced a few physicians to trial the new substance in patients. The drug testing regulations during this era were less strict, as pharmaceutical companies and scientists could directly leverage informal contacts with physicians to get new drugs tested. In the case of R.P. 4560, physicians reported a significant calming effect in agitated patients with a low sedative effect. R.P. 4560 was later named chlorpromazine, approved by the U.S. Food Drug Administration (FDA) and marketed globally as Thorazine in 1954. Although formally approved for the management of vomiting in patients, SKF promoted and pushed chlorpromazine for the management of anxiety, tension, agitation, delirium, confusion, and hostility in patients diagnosed with schizophrenia and manic-depressive disorder. Judging from the statistics on use cases and purchases, SKF soon discovered that chlorpromazine was better indicated for psychiatric purposes rather than vomiting. In 1955 alone, SKF reported an estimated $75 million profit for chlorpromazine. A significant percentage of the sales metrics pointed to the success of chlorpromazine in psychiatric interventions. In 1954, another drug was introduced to the North American psychiatric landscape. Derived from the plant Rauwolfia serpentina, the new extract was initially reported in India for its beneficial clinical effects in the management of fevers, consistently high blood pressure, and snake bites. The active salt of the extract was first identified, isolated, and characterized in 1953. It was later named reserpine and tested for physiological actions using different animal test models. A leading American psychiatrist, Nathan Kline, would later test the drugs on human
and Joseph von Mering as the first new psychotropic drugs of the twentieth century. These new sets of drugs could be easily administered and studied over time for their proposed mind- altering properties. As with the early drugs, barbiturates were considered useful but not exactly therapeutic or capable of treating “diseases of the mind.” In essence, the discovery of barbiturates and their subsequent but slow integration into clinical practices marked the beginning of the modern psychopharmacology era. subjects and present his findings to the New York Academy of Sciences in 1954. The clinical effects of reserpine as described by Kline include a unique ability to calm agitated patients diagnosed with schizophrenia. However, the popularity of reserpine as a psychoactive substance of wide clinical acceptance would eventually wane due to its propensity to cause hypotension in many patients and different cases of rebound depression. However, scientists continuously experimented with reserpine, changing its phenothiazine core molecule in an attempt to modify the side effects, produce a psychoactive salt, or synthesize a new reserpine-derived agent. By 1964, these experiments yielded results with the production of a new line of phenothiazines, including promazine (sold as Sparine), trifluopromazine (sold as Vesprine), Trifluoperazine (sold as Stelazine), fluphenazine (sold as Prolixine), thioridazine (sold as Mellaril), pecazine (sold as Pacatal), and methoxypromazine (sold as Tentone). Tranquilizers, Ataractics, and Neuroleptics In an attempt to better classify and understand the clinical uses of these drugs, psychiatrists of this era used terms such as major tranquilizers, ataractics, and neuroleptics. The term antipsychotics was not routinely used until later eras of psychopharmacology. Major tranquilizers distinguished the new phenothiazines from minor tranquilizers such as meprobamate. In general, psychiatrists in the early 1960s characterized major tranquilizers with the following points: • They produce little, if any, dependency. • The prominent clinical effect includes emotional calmness, controlling the symptoms of acutely and chronically disturbed psychiatry patients and exerting relatively little or no sedation. • In both long-term and short-term use, they produce an irreversible extrapyramidal syndrome—a condition characterized by rigidity, drooling, and tremors. • Other limiting side effects are associated with long-term high-dose use. • In the same vein, the minor tranquilizers were characterized by the following points: • In clinical use, they produce calmness and relaxation in psychiatry patients. However, the quality of drug action in this regard is less than that observed in major tranquilizers. • They produce clinical interactions that are specifically useful in the management of psychoneurotic problems and common nervous tension. • Compared to major tranquilizers, these drugs do not produce irreversible extrapyramidal syndrome. • Side effects associated with long-term use are relatively few and many times constitute no dangerous reactions. • Habituation may occur. The term neuroleptics was introduced in 1955 to further describe the extrapyramidal side effects associated with the long-term use of major tranquilizers. Preliminary investigation linked this syndrome with the same mechanism of action by which chlorpromazine effectively controls agitation and produces a therapeutic calmness in many patients. The term ataractic is derived from the Greek word ataraxy, which means “not disturbed” and was also used to describe chlorpromazine.
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