One area in the pharmacological industry that was not developed until the middle of the twentieth century was the creation of drugs that were intended to affect the mind. Alcohol and cocaine were mind altering substances that were offered for consumer use, but these substances were provided by a variety of sources and were not necessarily synthesized by pharmaceutical manufacturers (Klass, 1975). It was not until the late 1940s that psychotropic medications were produced by the pharmaceutical industry. These drugs were actually a by-product of pharmaceutical research in other areas. Only very recently have pharmaceutical manufacturers designed medications based on the expected effects of their physical and chemical structure (Kramer, 1993).
In 1946, William Bradly was experimenting on mice in search of new antibiotics. In trials with the drug mephenesin, Bradly found that high doses caused paralysis of limbs and lower doses produced a quieting effect on the demeanor of the animals. Bradly described this effect as "tranqilization" (Sneader, 1985, p. 182). Mephenesin also produced a relaxed feeling in patients. The term "tranquilizer" was first used by F. F. Yonkman in 1953 when he described the effects of reserpine. Reserpine is the substance in the snake root plant (Rauwolfia serpentina) that produces sedative effects. The calming effect of the snake root plant had been known for thousands of years (Sneader, 1985).
Henri Labroit was performing research with anti-histamines in order to prevent surgical shock. Labroit developed phenothiazine tranquilizers in 1949. When given to patients in the normally stressful pre-operative period before surgery, the drugs caused the patients to seem relaxed and unconcerned with what was happening to them. Labroit persuaded his psychiatric colleagues to try the drug on psychotic patients. After injection with the drug, a previously agitated manic patient became calm for several hours. This same drug later caused thousands of psychotics to be released from mental institutions. The drug was given the name Thorazine when sold in the United States (Sneader, 1985).
Until the 1950's, there was no known physical basis for disorders such as schizophrenia and bipolar disorder. It was not until 1950 when Pierre Deniker recorded the synthesis of chlorpromazine that the connection was realized. Two years later, French journals reported that chlorpromazine produced a remarkable state of inactivity or indifference in excited or agitated patients (Weatherall, 1990). A few years later, the Australian psychiatrist J. F. Cade discovered that lithium had a quieting effect on manic patients. (Heston, 1992). As more discoveries were made, the use of psychotropic agents became widespread. Meprobamate was heavily advertized as Miltown or Equanil and was more than any other drug responsible for the concept that anxiety could be banished with pills. Large numbers of new drugs were introduced, however no large scale studies of their effectiveness in the relief of the symptoms of mental illness were adequately made (Weatherall, 1990). The testing of therapies in a controlled way is a relatively recent medical practice (Kopelman, 1989).
The discovery of the early psychopharmaceuticals was accidental. For instance, Cade was looking for the over or under production of a hormone by examining the toxicity of urine. Solutions of the highly insoluble uric acid were difficult to prepare, and Cade found that the most soluble salt was Lithium urate. It was this coincidence that led Cade to use injections of Lithium Carbonate in his experiments (Sneader, 1985). The popular anti-streptococcal agent Prontosil was originally a brick-red sulfonamide dye. Librium, the drug of great commercial success synthesized by Leo Sternback in 1954 had been made twenty years previously as a dye (Sneader, 1985).
The number of pharmaceuticals currently available is tremendous. There are many different types of drugs for psychiatric uses alone. These function in a variety of ways, based on theories of brain dysfunction. Drug therapy is derived from the belief that disorders such as depression have a biological component that can be influenced by chemical interventions. These interventions affect the level of the neurotransmitters that are operating in the brain. An imbalance of these neurotransmitters, either too much or too little, is believed to be related to the symptoms of various disorders.
The first pharmaceuticals prescribed for depression included monoamine oxidase inhibitors and tricyclics. Monoamine oxidase inhibitors block the enzyme monoamine oxidase, the agent that renders serotonin and catecholamines into inactive forms. These drugs had their origins in antituberculous drug research. The drugs iproniazid and isoniazid were found to make patients more cheerful, these patients also gained weight and showed a general increase in well being. Iproniazid also produced some psychotic episodes, which aroused the interest of psychiatrists (Heston, 1992).
Tricyclics prevent the presynaptic neuron from reabsorbing catecholamines and serotonin after it releases them. Thus the neurotransmitters remain longer at the synapse and continue the stimulation of the post-synaptic cell.
One negative point of neuroleptic drugs (and all drugs) is the problem of side effects. The term "side effect" may be in itself misleading because it makes those effects seem irregular in appearance and relatively insignificant (Weatherall, 1990).
Unfortunately, the side effects caused by the monamine oxidase inhibitors are sometimes great enough that treatment must be discontinued or lowered below therapeutic doses. There is also a need for a specific diet while taken monamine oxidase inhibitors, foods rich in amines would raise blood pressure enough to precipitate strokes and heart failure (Weatherall, 1990).
Fluoxetine was created with the intention of providing a neuroleptic that would be effective as an antidepressant and also would have a decreased incidence of adverse effects. It was theorized that the specificity to serotonin would make this possible (Arky, 1994). Fluoxetine is reported to have a side effect profile favorable to the previous tricyclic and MAO inhibitor antidepressants (Wernicke, 1985).
The side effect most commonly cited for neuroleptics is tardive dyskinesia. This literally means "late developing abnormal movement." It consists of twitches, spasms and writhing movements of the voluntary muscles. There is no known treatment for tardive dyskinesia, and while most cases are mild they also tend to be permanent, not ending with the discontinuation of medication (Breggin, 1991).
A similar side effect is tardive akathsia, which is anxiety or nervousness and an uncontrollable drive to move the body. There have been cases of akathsia reported to be induced by Fluoxetine that is indistinguishable from akathsia produced by neuroleptics. Some believe that Fluoxetine causes this akathsia by indirectly suppressing dopamine, leading up to dopamine hyperactivity or supersensitivity (Breggin, 1991). If it is true that Fluoxetine causes this disorder by the indirect suppression of dopamine, then its status as a Selective Serotonin Reuptake Inhibitor is called into question. The chemical reactions of Fluoxetine with the body may not inhibit dopamine. It is possible that the brain responds to the reuptake inhibition of serotonin by suppression of dopamine. This would prove to be a tricky situation, that the brain has several different responses to even on specific action of a drug. Much research would be necessary to determine if a drug or combination of drugs could be made that would effect one and only one system of neurotransmission.
These drugs also may produce side effects such as dizziness, drowsiness, blurred vision, rapid heartbeat, dry mouth and excessive sweating (Kalat, 1993). Symptoms such as faintness, tremor of extremities, blurred vision and impotence are fairly common for the first two weeks of use, and then decrease. Dry mouth and weight gain are symptoms that do not decrease with continued use (Heston, 1992).
The advent of fluoxetine is an advance in the selectivity of re-uptake. "Dirty" drugs such as the tricyclics have more than one biological effect. Fluoxetine is "clean" because it specifically prevents the re-uptake of serotonin. It is believed that a clean drug will have fewer side effects. A reduction compared to the side effects of tricyclics would be a notable advance, and was the goal of the design of fluoxetine (Sleek, 1995., Kramer, 1993). Fluoxetine is proving to be an effective medication for some depressed persons. It has been the impetus for intensive psychopharmacologic research yielding other new products (Heston, 1992). Fieve (1994) considers fluoxetine to have an exceptionally low incidence of adverse effects. The most common patient complaint is drowsiness (12%) this is half the rate produced by tricyclics (24%). Four percent report a feeling of weakness and less than two percent cite sedation (Fieve, 1994).