effects with established antipsychotics. The multicenter study report confirmed that clozapine exerted superior clinical efficacy over chlorpromazine in patients previously unresponsive to other typical antipsychotics. Drawing reference from the incident in 1975, Sandoz also instituted a system to track the integrity of white blood cells in patients administered clozapine. This ensured that therapy was immediately discontinued in patients who showed clinical signs of agranulocytosis. Following the success of the multicenter trials, Sandoz found a new clinical claim for clozapine, and the FDA officially approved the drug for prescription use in 1990. Beyond the story of its development, clozapine had a landmark influence on the development of modern psychopharmacology. Its mechanism of action lends credence to growing skepticism about dopamine blockade as a crucial step for antipsychotic activity. Clozapine, despite showing atypical antipsychotic activity, did not appreciably block D2 receptors. This observation led to a new research interest, with independent researchers and pharmaceutical companies using clozapine as a model for the development of new antipsychotics. In 1984, these researchers birthed the first result, with Janssen Pharmaceuticals announcing the synthesis of risperidone. Janssen subsequently secured FDA approval to market risperidone under the brand name Risperdal. As the second member in the class of atypical antipsychotics, Risperdal’s biological activity was similar to clozapine, and it became the first new antipsychotic to be sold in the U.S. With risperidone, research on the development of clozapine-like compounds received a huge boost. In 1996, Eli Lilly announced that had obtained FDA approval for olanzapine, which was sold under the brand name Zyprexa. In 1997, the FDA approved the prescription use of quetiapine, which was sold under the brand name Seroquel. Since 2000, the FDA has approved the prescription use of eight new atypical antipsychotics. These include the widely prescribed antipsychotics: Aripiprazole in 2002 (Abilify; Otsuka Pharmaceutical and Bristol-Myers Squibb), paliperidone in 2006 (Invega; Janssen), and lurasidone in 2010 (Latuda; Sumitomo Dainippon Pharma). The drug activity and efficacy profile of these drugs were significantly different from the typical (first-generation) antipsychotics developed in the 1950s and 1960s. Some of the atypical drugs also displayed considerable affinity to 5-HT2A receptors, prompting a new line of research exploring the influence of these receptors in mental disorders. From the late 1990s to the early 2000s, pharmaceutical companies rigorously promoted atypical antipsychotics as safer and more effective alternatives to typical antipsychotics in the management of mental disorders characterized by
social withdrawal, suicidal ideation, cognitive definite, and schizophrenia. However, the severe metabolic disturbances associated with these drugs have limited their use in clinical settings. Clozapine, as the flagship member, is considered the only atypical antipsychotic free from these side effects. Fluoxetine and the SSRIs Following the mandatory adoption of the RCT amendments, research in psychopharmacology became more refined with a focus on disease specificity. Mental conditions highlighted by depression are distinctly described and separated from those highlighted by psychoses. This allowed researchers to focus separately on different mental diseases. The interest in the development of effective antidepressants was championed by discoveries about the role of serotonin in mental disorders. In 1954, John Gaddum was reported to have accidentally ingested LSD, a compound known for its serotonin-blocking effect. In his report, Gaddum noted that the compound induced an “out of the mind” experience that lasted for about two days. However, years later, Gaddum’s report was questioned when Julius Axelrod demonstrated that Imipramine—an established MAOI—inhibited the reuptake of only norepinephrine, not serotonin. In contrast to Gaddum’s report, the new evidence downplayed the role of serotonin in depressive states. However, research on the clinical correlation between serotonin and depression continued. In 1974, researchers at El Lily announced the development of a molecule that selectively blocks the reuptake of serotonin (Tian et al., 2022). The compound, later named fluoxetine, received FDA approval in 1987 to be sold under the brand name Prozac as an antidepressant. The development of fluoxetine heralded the era of a new line of antidepressants known today as the selective serotonin reuptake inhibitors (SSRIs). Other compounds with a chemical profile similar to fluoxetine were subsequently developed. In 1991, Pfizer secured approval for sertraline, which was sold under the brand name Zoloft. A year later, GlaxoSmithKline secured approval for paroxetine, which was sold under the trade name Paxil. In 1998, Allergan secured approval for citalopram, which was sold under the brand name Celexa. Compared to the older drugs, fluoxetine and other members of this class displayed a better side effect profile. They are also easy to administer and monitor, creating a good fit for the management of mild depression in primary care settings. The increased use of SSRIs in depression led to the discovery of some side effects that were not noticed during development. Following multiple reports, in 2003, the FDA issued advisory warning to clinicians and users of an increased risk of SSRI- associated suicidal behavior in both children and adults. has demonstrated that the number of psychotropic prescriptions for children steadily increased between 2000 and 2002 in all these countries. The UK reportedly had the highest percentage increase (68%), with the rate lowest in Germany (13%). In the context of this course, understanding how global rates have changed consistently over the years will create a better argument for the important roles of psychopharmacology in modern medicine. In a 2021 issue published by The Lancet: Psychiatry, researchers presented more comprehensive details on psychotropic use trends globally. This research leveraged the World Health Organization’s (WHO’s) Comprehensive Mental Action Plan, 2013–2030, a plan that encouraged the routine collection and reporting of essential mental health indicators, including the availability of psychotropics in different countries (Mehra et al., 2022). Using pharmaceutical sales data from the IQVIA-Multinational Integrated Data Analysis System (IQVIA- MIDAS), this research compared the global trend of psychotropic medicine distribution in 65 countries between 2008 and 2019. For easy comparison, the classes of psychotropic medications were limited to mood stabilizers, antipsychotics, tranquilizers, hypnotics, sedatives, and antidepressants.
Global Trends in Prescription and Use of Psychotropic Drugs Globally, psychotropics are considered to be the cornerstone of therapy for the treatment of mental disorders in the adolescents and adults. The prevalence rate of mental disorders is distinctly different in different countries; however, data findings suggest increased trends of psychotropic prescription and use globally (Zhang et al., 2022). It appears the prevalence rate, which subsequently affects the trend in psychotropic use, depends on multiple factors. Depending on geographic location, the trend of mental health disorders may primarily or secondarily be influenced by cultural practices, social and environmental stressors, rate of stimulant use, dominant regulations on prohibited substance distribution, and contagion imitation in the cases of suicidal ideation and behavior. Epidemiologists have conducted multiple cross-country comparisons in this regard. Most importantly, trends in psychotropic prescriptions in children and adults have been compared in the UK and three other European counties with the largest market for psychotropics (Spain, France, and Germany). UK rates have also been compared to three South American countries with the largest psychotropic market (Mexico, Argentina, and Brazil) and two North American countries with the same metric (Canada and the United States). Data analysis
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