Robert Wallace Wilkins and Nathan S. Kline revolutionized psychiatry when they recognized that reserpine had properties as an antipsychotic substance. Reserpine holds a unique place in pharmacology and psychiatry because its discovery established that psychosis could be treated with drugs.
Reserpine is an alkaloid (a nitrogen-containing organic chemical) extracted from the roots of Rauwolfia serpentina, a plant used in India for hundreds of years to treat numerous ailments. Although Rauwolfia serpentina was recognized to have medicinal properties as early as the 1560’s in Europe, disbelief about its true efficacies prevented meaningful acceptance of the plant’s medicinal value in Western medicine until the isolation of reserpine in the mid-twentieth century.
Reserpine’s medicinal importance must be viewed in the context of the longstanding need for effective treatments of mental illnesses such as schizophrenia, a collection of disorders focused around problems with thinking patterns and unstable emotions. Primitive peoples primarily viewed the unusual behaviors that are now recognized as mental disorders in the context of mysticism. Attempts at early therapy included appeals to a higher order, exorcism, and trephining (the practice of opening holes in the skull to release evil spirits or fluids).
As is nearly always the case, when a plant such as Rauwolfia serpentina (or Rauwolfia) has been in use since ancient times, there is uncertainty regarding its exact entry into common use. There is considerable evidence to suggest that Rauwolfia has been an important medicinal natural product for hundreds if not thousands of years in India. By the 1930’s, Rauwolfia had been mentioned in modern Indian medical literature. The list of putative medicinal properties for Rauwolfia is rather long: Cardiovascular effects, use against snake bite, and references to various mental effects compose a condensed listing. The early 1940’s produced a series of reports from India suggesting the medical usefulness of the plant. Robert Wallace Wilkins took note of these hints, particularly the work of Indian physician J. C. Gupta, who mentioned mental effects such as sedation, as well as blood-pressure-lowering properties.
Wilkins, who headed the Massachusetts Memorial Hospital’s Hypertension Clinic, initiated clinical trials in 1950 with crude Rauwolfia to determine its effects in hypertension, or high blood pressure. Early observations included the lowering of blood pressure, decrease in heart rate, and sedation. In addition, the drug is slow-acting. Indeed, the blood-pressure-lowering effects may take weeks or even months. The slow onset of action made things difficult for researchers and played a key role in resistance to accepting the drug’s benefits. Often, investigators gave up before enough time had elapsed to see significant effects.
Nevertheless, by 1952, Wilkins and his collaborator, Walter E. Judson, were convinced that Rauwolfia was useful in treating hypertension
Wilkins repeatedly stressed the central role that changes in nervous system activity appeared to play in the blood-pressure-lowering effect. In an April 30, 1954, article in the Annals of the New York Academy of Sciences, Wilkins stated, “Symptomatic improvement has been so marked in some patients as to be almost embarrassing to the physician. Many patients have become positively lyrical about their sense of well-being on the drugs. . . .” Wilkins went on to say, “I have told many psychiatrists and others interested in psychotherapy that ’Rauwolfia is good psychotherapy in pill form.’” He also concluded that the sedative effects of Rauwolfia were not typical calming effects: As the dose was increased, people did not typically become sleepy. They were perfectly able to participate in activities that interested them. This provided the seeds of revolution for reserpine’s use in psychiatry. As is now known, antipsychotic drugs produce a state of tranquilization that is qualitatively different from sedation. Central nervous system depressants such as phenobarbital or Valium (diazepam) produce sedation and hypnosis (sleep) at higher doses, but are relatively ineffective in countering the psychotic processes of schizophrenia.
Impressed by these reports and those of Indian workers, Nathan S. Kline of Columbia University began testing reserpine’s effectiveness as a psychiatric drug. Using a test population of about seven hundred people at New York’s Rockland State Hospital, Kline analyzed reserpine’s actions as measured by a battery of physiological and behavioral parameters. While verifying the conclusions that others had reached about blood pressure and heart-rate lowering and minor side effects, Kline also observed marked anxiety reduction, relief of situational depression, a tranquilizing effect with accompanying decreased motor activity, and decreased need for shock therapy, such as that induced by insulin overdose in severely psychotic patients. He concluded, however, that reserpine did not seem to cure the underlying psychosis itself. Rather, it changed certain symptomology associated with the psychosis.
Research results since the 1950’s help one to understand the effects of reserpine, as reported by Wilkins, Kline, and others. Reserpine acts in nerve endings that contain monoamines as neurotransmitters. Monoamines are substances like norepinephrine, dopamine, and serotonin, which are released from one nerve cell to contact an adjacent nerve cell in the process that moves information between cells. Reserpine depletes nerve endings of the neurotransmitter, decreasing the nerve’s capacity to signal other cells. Monoamines are found in a part of the peripheral nervous system known as the sympathetic nervous system and at various locales throughout the brain. Reserpine’s known actions in the cardiovascular system, gastrointestinal system, and nervous systems can be explained by this molecular mechanism.
Reserpine has not become a particularly significant clinical drug. This is especially so regarding its tranquilizing effects. In the early 1950’s, a separate but parallel series of developments occurred with a group of synthetic drugs known as the phenothiazines
Reserpine holds a unique place in pharmacology and psychiatry, because its discovery established that psychosis could be treated in a relatively specific fashion with drugs. Its introduction broke a long string of failure and frustration to find effective treatment, drug or otherwise. The revolution that ensued is one of the more remarkable in modern medicine. Almost every introduction to modern psychology and pharmacology illustrates the precipitous out-migration from mental institutions in the late 1950’s. This occurred because many psychiatric patients who previously could not cope with the outside world were able to function in the noninstitutional world with the help of antipsychotic drugs and occasional medical consultation. The out-migration not only relieved the terrible strain on resources at institutions by reducing patient loads but also improved the entire institutional environment as patients who could not leave hospitals were changed by using the drugs to reduce their psychotic behavior. Although controversies continue regarding societal consequences of the outpatient movement, about the “mind control” potential of antipsychotic drugs, and unusually high occurrences of some side effects, most observers believe that the overall cost-benefit analysis associated with use of antipsychotic drugs is heavily weighted toward benefits, for individuals and society.
Antipsychotic drugs such as reserpine have contributed substantially to an understanding of the brain mechanisms that are out of balance in schizophrenias. A recurring theme in the history of pharmacology is that clinically useful drugs also become tools in deciphering the nature of diseases. Reserpine’s lasting legacy—perhaps even beyond its germinal role in the revolution of psychiatrically useful drugs—is its productivity as a pharmacological tool. It remains an important probe in studies of nerve cell function, both in the peripheral and central nervous systems. Drugs derived from the natural products may or may not become long-term players in therapeutics, but even if they do not, their uses as models for better drugs and as experimental tools are invaluable.
-
Evans, William Charles, George Edward Trease, and Daphne Evans. Trease and Evans Pharmacognosy. 15th ed. New York: W. B. Saunders, 2002. Contains not only the standard characterization of natural products such as reserpine and related alkaloids but also the broadest spectrum available of drugs derived from nonsynthetic sources. -
Gilman, Alfred G., et al., eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Edited by Laurence L. Brunton et al. 11th ed. New York: McGraw-Hill, 2006. No book in the history of pharmacological study has made the impact of this tome, written and updated for years by Gilman’s father and the renowned Louis Goodman. Reserpine’s basic actions and its clinical use in cardiovascular disease and psychiatry, in addition to parallel coverage of all other well-known drugs, are presented in exemplary fashion. -
Katzung, Bertram G., ed. Basic and Clinical Pharmacology. 9th ed. New York: Lange Medical Books/McGraw-Hill, 2004. This widely used general pharmacology book details reserpine’s actions, both positive and negative, and describes its uses in the peripheral and central nervous systems. The broader context of drugs used to treat mental disorders is well described in both the historical context and in modern use. -
Kline, Nathan S. “Use of Rauwolfia serpentina Benth in Neuropsychiatric Conditions.” Annals of the New York Academy of Sciences 59 (1954): 107-132. Kline’s article on the use of reserpine as an antipsychotic. Provides the rationale for using the drug in mental illness and documents carefully the use of Rauwolfia in India prior to its introduction in the United States. -
Lickey, Marvin E., and Barbara Gordon. Drugs for Mental Illness: A Revolution in Psychiatry. New York: W. H. Freeman, 1983. Cogently describes the major changes in psychiatry flowing from the introduction of antipsychotic drugs in the 1950’s. Outlines the nature and diagnosis of mental illness while discussing the types of drugs used to treat common psychoses. -
Robbers, James E., Marilyn K. Speedie, and Varro E. Tyler. Pharmacognosy and Pharmacobiotechnology. Rev. ed. Baltimore: Williams & Wilkins, 1996. This book is one of the classics of pharmacognosy, the science that studies drugs derived from natural products. Contains an extensive section on reserpine’s parent plant, Rauwolfia serpentina. Also provides much information on many other natural drugs that are significant historically and in modern medicine. -
Shershow, John C., ed. Schizophrenia: Science and Practice. Cambridge, Mass.: Harvard University Press, 1978. Using a group of influential contributors, this book discusses the main psychotic disorders in their historical, cultural, and scientific contexts. Provides exceptional analysis of the similarities and differences between different ways of viewing schizophrenia. -
Wilkins, Robert W. “Clinical Usage of Rauwolfia Alkaloids, Including Reserpine (Serpasil).” Annals of the New York Academy of Sciences 59 (1954): 36-44. A primary account of Wilkins’s move into research with reserpine with special emphasis on its cardiovascular effects. Also contains assertions that led to its use in psychiatric medicine. Includes an interesting segment crediting the early use of Rauwolfia in India.
Aversion Drug Found for the Treatment of Alcoholism
Wilkins Introduces Reserpine for the Treatment of High Blood Pressure
Federal Law Requires Cigarette Warning Labels