In 1951, a longer-acting form of mephenesin was synthesized and sold as Miltown, which was marketed for the treatment of anxiety, tension, and mental stress. However, post-market reports and surveillance indicated that meprobamate presents considerable addictive tendencies in many patients, prompting research into other agents with mephenesin’s activity but without the addictive properties. Research exploring the possibilities of developing a mephenesin-like agent birthed chlordiazepoxide as the first commercially available benzodiazepine. Marketed as Librium, chlordiazepoxide was developed by Leo Sternbach at Hoffman–LaRoche. In an attempt to create a novel tranquilizer, he embarked on screening unique molecular entities instead Forging Disease Specificity: 1964–1988 Psychopharmacology in the mid-1960s through the later 1980s was heavily rebranded by the introduction of multiple research standards, drug trial processes, and animal model experimentations. The dominance of psychoanalysis and state hospital systems associated with psychopharmacology in the 1950s steadily gave way to radical changes in this third era. There is also the considerable influence of economic and political forces reshaping the default face of modern medicine and by extension, psychiatry and psychopharmacology. This era primarily championed two important drives in psychiatry: The discovery of more active psychotropic drugs and the standardization of the methods used in evaluating these drugs. New psychotropics established the idea of disease specificity and opened the way for the development of the fundamental practices of neurosciences. On the other hand, new methods for drug evaluation birthed randomized controlled trials (RCT). A New Field: Neuroscience The field of neuroscience was championed by the research discoveries of psychopharmacology related to the understanding of neuronal connections and brain circuitry. Since neuronal connections were considered central to the pathologies of the central nervous system, a sizable bulk of the research before 1950 was centered on understanding this phenomenon. Neurochemical transmission with neurotransmitters was first described by Henry Dale in 1933. Dale’s submission on this topic established how adjacent neurons communicate by transporting chemical messengers between synapses in the neuromuscular junctions and the peripheral nervous system. Although the exact mechanism of this communication was unknown, Dale’s work corrected an earlier belief that neuronal communication in the central nervous systems was through electrical impulses. By linking the discovery with the mechanism of action of the early psychotropic agents, researchers kickstarted an important movement in the third era of psychopharmacology. In the later part of the 1950s, Arvid Carlsson submitted research evidence detailing the central role of dopamine in the phenothiazines' mechanism of action. This submission would later form the framework for the dopamine hypothesis of schizophrenia. In 1948, another neurotransmitter was isolated from platelets, studied, and named serotonin. Initial studies confirmed the vasoconstrictive properties of serotonin and its origin in the serum. Curious about its role in psychopathology, researchers explored the effect of serotonin on animal models and organ tissues in large animals. In 1952, serotonin was identified in mammalian brains, reinforcing early suspicions of its major role in neuronal communications of the central nervous system. A breakthrough moment in serotonin was recorded a year later when John Gaddum discovered that lysergic acid diethylamide LSD antagonizes the physiological effects of serotonin in animal models. LSD has been used in animal models to induce psychotic symptoms linked with depression and schizophrenia. Since LSD antagonizes serotonin activity in animal models, researchers theorized that serotonin is critical to sanity and normal central nervous system functionality in humans.
of developing a salt or a chemical derivative of mephenesin. Benzheptoxdiazines were the first class chosen based on available research submissions indicating their possible psychoactive properties. However, a compound designated as Ro 5-0690 proved to be an effective muscle relaxant in animal models with no accompanying excess sedative effect. In comparison to meprobamate, the new compound appeared to be safer, less sedative, and less addictive. Ro 5-0690 later proved to be the first synthesized member of the benzodiazepines, a novel class of biologically active molecules. Sternbach would go on to synthesize other members of this new class, including flurazepam (Dalmane), clonazepam (Klonopin), and Diazepam (Valium). This hypothesis would later form the basis for the serotonin model of schizophrenia. Proposed in 1953 by Dilworth Wooley and Elliot Shaw, the serotonin model of schizophrenia maintained: “The suppression of serotonin action results in mental disorder. In other words, it is the lack of serotonin that is the cause of the disorder.” Further studies on the physiological effects of serotonin completed in 1957 proposed that reserpine depleted serotonin from neuronal storage sites in an action that influences behavioral observation in many patients. Reserpine also depleted the neuronal storage sites of dopamine and the catecholamines—epinephrine and norepinephrine. Arvid Carlsson also showed that the effects of reserpine in animal models, including the depletion of serotonin storage sites, could be reversed by the administration of a metabolic precursor of dopamine (L-dopa) and not by a metabolic precursor of serotonin. In part, this observation suggested that dopamine is more important to serotonin in neuronal communication and the pathology of mental disorders. Although only a few scientists regarded Carlsson’s submission as the function of dopamine in the central nervous system was still largely unknown. However, in the early 1960s, research conducted to understand the mechanism of action of antipsychotics suggested an important discovery. Dopamine was found to be depleted in the autopsied brains of people with Parkinson’s disease, and the administration of L-dopa as proposed by Carlsson alleviated some of the motor symptoms of the disease. Another landmark discovery made during this era indicated a possible link between dopamine and antipsychotic drugs. In an action that directly measures the antipsychotic potency of different drugs, researchers showed that antipsychotic drugs increased the concentration of dopamine brain metabolites. This link was later confirmed in the 1970s when researchers demonstrated the extent of the dopaminergic receptor blockade by directly measuring binding affinity. These works formed the theoretical basis for the dopamine hypothesis of schizophrenia as one of the widely accepted etiological theories of modern psychiatry. The American Journal of Psychiatry’s review of this hypothesis stated: “Schizophrenia may be related to a relative excess of DA [dopamine]-dependent neural activity. It is derived from pharmacological evidence that drugs that decrease DA activity (e.g., the phenothiazines) may be antipsychotic and drugs that promote DA activity (e.g., amphetamine) may be psychotomimetic. The particular means by which “too much dopamine” is produced in schizophrenia is not yet known.” This hypothesis survived scrutiny as researchers tested it against the mechanism of action of new antipsychotic drugs discovered. The catecholamine hypothesis of depression also offered a renewed understanding of the mechanism of action of antipsychotics, with the additional bonus of firmly establishing the place of psychopharmacology in modern medicine.
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