Similar to the dopamine hypothesis, the monoamine hypothesis of depression is based on research suggesting how antidepressants work. As summarized by J. J. Schildkraut:
• Amphetamine releases norepinephrine from neurons and blocks inactivation. • Acute administration of amphetamine causes rebound depression, presumably from the depletion of norepinephrine. • Imipramine, desipramine, and amitriptyline inhibit the reuptake of norepinephrine into neurons. In summary, the discovery of more psychotropic drugs and subsequent research inquiries explaining their possible mechanisms of action in animal models and human subjects was considered a legitimate intervention of psychopharmacology in modern medicine. The hypothesis explaining how these drugs relate to the central nervous system and the brain neuronal circuitry formed the foundational knowledge of neuroscience and psychotherapy. with RCT. In 1954, the first RCT comparing lithium with a placebo for efficacy measurement in the management of mania using a crossover design was published. That same year, a similar study also administered chlorpromazine to 27 patients drawn from the hospital at the University of Birmingham, United Kingdom. In a closing remark on patients’ participation, the researchers noted: “The combination of the “blind” nature of the trial, the fact that the patient was used as his control, and agreement among the different observers, all contributed towards some confidence in a field in which assessment is notoriously difficult.” In another landmark achievement for the new clinical trial method, the FDA subsequently enshrined the RCT as the only acceptable claim of drug action, efficacy, and safety in 1970. In later years, studies focused on optimizing the new amendment perfected the dominance of RCT as the standard of clinical trials globally. This single amendment forced researchers and pharmaceutical companies involved with psychopharmacology to ultimately redefine how new drugs are developed, tested, and marketed. RCT in psychopharmacology radically refashioned how researchers think about mental disorders. It helped categorize the major diseases in psychiatry and shape how safety and efficacy outcomes are discussed in the context of improved symptomatology. In a 1964 RCT conducted in nine centers, Jonathan Cole randomized 463 patients to four different treatments using chlorpromazine, fluphenazine, thioridazine, and placebo. The findings conclusively highlighted the superior clinical efficacy of phenothiazines in psychiatry when compared to a placebo. In a concluding remark, the researcher noted: “The findings of this study support the view that phenothiazine drugs have a generalized antischizophrenic effect and are useful in patients suffering from acute schizophrenia psychoses.” in improving psychotic symptoms in many patients. Although confirmed as a tricyclic compound, clozapine did not produce the motor side effects (Parkinson-like effects) associated with long-term therapy of the then-existing antipsychotics. This observation puzzled researchers, and clozapine was later designated as atypical. Invariably, this compound was the first member of the class of antipsychotics known today as atypical antipsychotics. The new designation limited the promotion of clozapine for use in psychiatry, but research on this new drug never stopped. In a 1975 incident, eight patients reportedly died of agranulocytosis after taking clozapine in a clinical trial. This forced Sandoz—the new parent company of Wander—to halt development efforts on clozapine. Because clozapine was the first tricyclic to show no extrapyramidal side effects, psychopharmacology researchers kept conducting independent trials of clozapine with animal models. In 1984, after considering reports from multiple independent studies, Sandoz resumed interest in clozapine with a multicenter study comparing its
“This hypothesis, which has been designated the “catecholamine hypothesis of affective disorders,”
proposes that some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain.” The research evidence J. J, Schildkraut published in support of this hypothesis (Kobayashi et al., 2022) included: • MAIO drugs increase levels of norepinephrine and serotonin in the brain in animals and are antidepressants in humans. psychopharmacology represented an important milestone in the history of modern medicine. Although ignored many times, the development of a standardized approach for clinical trials is as important as the psychopathology hypothesis and the discovery of multiple psychotropic drugs. In 1962, the FDA issued an amendment mandating that all pharmaceutical companies and independent researchers clinically prove the efficacy and safety of all newly discovered substances with physiologic activity. In context, the new amendment replaced the usual method of proving efficacy with self-tests and individual case studies with tests in large populations of patients and animal models. Most importantly, the RCT amendment emphasized the importance of evaluating for bias, measuring outcomes, and considering confounding factors. Outcomes from this unique method of determining if efficacy is proven should also be reproducible as interventions across patients, clinicians, space, and time. RCT ultimately dethroned the era of psychoanalytic dominance and self-tests, making way for a measurable drug effect in humans and associated disease specificity. Randomized Clinical Trials Randomized clinical trials (RCT) in the third era of Before the advent of RCT, psychopharmacological inventions in the mid-twentieth century were approved and commercially marketed based on results, sometimes biased, from open trials, case-controls, self-tests, and clinical judgments. Formally, the first exemption to this norm in the medical community is traced back to the 1946 clinical trial of the antibiotic by the United Kingdom Medical Research Council. The exact methodologies of this first trial are largely unknown; however, it set the framework for the development of the different principles of RCT in modern medicine. These include controls, placebo, blinding, and randomization. In no time, psychopharmacology researchers adopted the new FDA amendment. In this field, reserpine, lithium, and chlorpromazine were the first drug to be studied Late 1980s to the Present Compared to the period from the late 1950s to the mid-1960s, discoveries and research interest in psychopharmacology slowed considerably in the early 1980s. For more than two decades, no new inventions were made in this field, despite the publication of the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (DSM-III) by the American Psychiatric Association, which offered a more specific definition for the clinical presentation and symptomatology of mental disorders. However, the tide changed suddenly with the rediscovery and characterization of a drug that had been synthesized in the late 1950s. Clozapine and the Atypical Antipsychotics The Swiss company Wander announced the synthesis of a new tricyclic compound in 1958. The new compound reportedly produced no tardive dyskinesia and the extrapyramidal side effects notorious with other antipsychotics in circulation then. The new compound, later named clozapine, produced mixed results when subjected to human trials and different animal models of mental disorders. It reportedly failed to exert antipsychotic properties in many studies and was not effective
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