Psychiatry, Pharmaceutical Treatment

Psychiatry, the medical specialty that deals with emotional and behavioral disorders, underwent a profound transformation in the mid-twentieth century with the development of psychopharmacology, the use of drug therapy to treat specific mental illnesses ranging from schizophrenia to depression and anxiety.

Following the serendipitous discovery of drugs such as chlorpromazine in 1952, researchers examined the specific effects of these drugs, in turn spawning a revolution in the scientific understanding of the brain and the role of neurotransmitters in the expression of mood and behavior.

Prior to the twentieth century, private practice and asylum physicians used a combination of drugs such as opiates, barbiturates, bromides, chloral hydrate and hyoscine to treat the mentally ill. These nonspecific drugs were used to sedate agitated patients or elevate the mood of the melancholic. Although these attacked the symptoms of the illness, they were adjunct to other treatments that were seen as curative.

During the first half of the twentieth century, psychiatric treatments incorporated drug regimens to alleviate the symptoms of ailments classified as either psychosis or neurosis. One such regimen was sleep therapy, or prolonged sleep, popularized by Jacob Klaesi in 1920. Using various bromides or barbiturates, Klaesi put patients to sleep for days at a time and found that prolonged sleep decreased the symptoms of the illness but did not cure patients. In their search for a cure some psychiatrists turned to shock or convulsive therapies.

Based on the notion that epileptic patients were immune to schizophrenia, psychiatrists tried a host of convulsive agents to cure that schizophrenia. Beginning in the 1930s Ladislas Meduna pioneered the use of the chemical agent pentylenetetrazol, also known as Metrazol or Cardiazol, to cause patients to convulse. Similarly, Manfred Sakel developed insulin therapy, another shock or convulsive therapy.

In this treatment, popular from the 1930s to the mid-1950s, synthetically produced insulin was employed over the course of hours to induce comas and convulsions that seemed to alleviate the symptoms of schizophrenia. The development of electroconvulsive therapy (ECT) and psychopharmacology made Metrazol and insulin therapy obsolete after 1950.

Drug therapies appeared as a byproduct of research in the chemical and pharmaceutical industry. Chlorpromazine (CPZ), better known by the trade name Thorazine, had been explored for its properties as a dye in the late nineteenth century and for its antihistamine properties in the first half of the twentieth century. Its sedative properties were noted and several clinicians including French surgeon Henry Laborit, as well as Jean Delay and Pierre Denker, were to independently confirm its ability to calm agitated mental patients and alleviate the symptoms of schizophrenia.

Thus was born a new class of drugs known as neuroleptics in Europe and antipsychotics in North America. Chlorpromazine set the pattern for the psychopharmacological revolution and followed the life-cycle taken by almost every other pharmaceutical innovation: drugs were introduced with high expectations and enthusiasm, but after the emergence of side effects they were derided and in some cases abandoned.

After its introduction in North America by SmithKline & French in 1953 and its approval for use in the U.S. by the Food and Drug Administration (FDA) in 1954, CPZ became a standard therapy in the state mental institutions leading to the dramatic decline of inmates from 500,000 to 150,000 within a short period of time. However, within a decade severe side effects that created a Parkinson-like disorder known as tardive dsykinesia were discovered and alternative drugs were sought.

The initial success of CPZ led to further research on histamine blockers and in 1957, Roland Kuhn would slightly alter the chemistry of CPZ and create imipramine hydrochloride, (Tofranil), a drug found to be useful in the treatment of depression. Imipramine was the first of the tricyclic antidepressants, so called because of their threering chemical bond, but others followed including amitriptyline (Elavil) in 1961. On this medication, depressed patients became more vivacious, had restored interest in their favorite activities, and experienced restful sleep and healthier appetites.

A third class of drugs known as the monoamine oxidase inhibitors (MAO-I) was developed in pharmaceutical laboratories. Nathan Kline pioneered phenelzine sulfate, marketed by such names as Nardil and Marplan. Its effectiveness was similar to other antidepressants but severe side effects were noted when patients took the medication in conjunction with foods containing tyamine, such as cheese, wine, and pickled foods.

The drug lithium, used during World War II as a substitute for table salt, was discovered to have antipsychotic properties by John Cade who worked in Australia. Although not approved by the FDA in the U.S. until the 1970s, it quickly became a standard treatment for bipolar disorder, or manic depression.

In the 1950s the first antianxiety drugs or minor tranquilizers were developed, the diphenylemythanes such as meprobamate (marketed under the trade name Miltown) was introduced in 1954. Later the benzodiazepine tranquilizers such as Librium or Valium were produced. These seemed to eliminate anxiety with few side effects, however the addictive properties of these drugs would receive a great deal of scrutiny in Congressional hearings and the popular press in the 1970s. In response, pharmaceutical companies sought less addictive versions of these drugs and produced Xanax in 1981, which was found to be effective for the newly named disorder panic attacks.

All of these drugs inspired interest in the neurotransmitters. First identified in 1920 by Otto Loewi, neurotransmitters are found in the synaptic gaps between the neurons of the brain. Although there are hundreds of them in the brain, research focused on two that seemed to be particularly important in both mood and behavior: dopamine and serotonin. Depressed patients were found to have less serotonin available than those who were not depressed.

This led to the now prevalent belief that depression was caused not by environment but by changes in the brain chemistry such as a lack of free serotonin. Depression was therefore assumed to be as treatable as a biological disorder rather than to a psychological one. Researchers at Eli Lilly focused on creating a drug that would block the reuptake of serotonin into the neuron, thus was created an entirely new class of drugs—the selective serotonin reuptake inhibators (SSRIs).

Lilly developed fluoxetine hydrochloride in 1974, but the drug was not approved by the FDA until 1987 when it was marketed under the name Prozac and became the established industry standard, perhaps the most well-known psychiatric drug of all time.

The psychopharmacological revolution that began with the accidental discovery of the clinical possibilities of a variety of drugs generated an interest in the specific effects of those drugs on brain chemistry, leading to the discovery of more specific treatment agents such as the SSRIs. For some this confirmed their belief that mental illness is biological rather than psychological.