The chlorpromazine enigma.

Two revolutionary drugs were introduced into psychiatry in the early 1950s for the treatment of agitated mental patients - reserpine and chlorpromazine. These drugs initiated the modern era of drug treatment for schizophrenia and other psychoses. Early research revealed that, although the pharmacological profiles of the two drugs overlapped considerably, they had different mechanisms of action. The mechanism of action of reserpine was determined first: it depletes monoamines from the brain and other tissues. By contrast, chlorpromazine has little or no effect on brain monoamine concentrations. The mystery created by two drugs that have similar pharmacological profiles but different mechanisms of action is the chlorpromazine enigma. For about eight years after the mechanism of action of reserpine was determined, researchers followed several false leads about the mechanism of action of chlorpromazine. Then, in 1963, Arvid Carlsson and Margit Lindqvist proposed that chlorpromazine (and haloperidol) work by blocking "monoaminergic" receptors. It was quickly determined that dopamine receptor blockade was the most important action. Although the idea of chemical communication between central neurons had yet to gain wide acceptance, this idea was central to resolving the chlorpromazine enigma.

[Milestones of cardiovascular therapy. IV. Reserpine]. / Milníky kardiovaskulární terapie. IV. Reserpin.

Reserpine, the purified alkaloid of Rauwolfia serpentina, was the first potent drug widely used in the long-term treatment of hypertension. Rauwolfia serpentina is a tropical woody plant of the Apocyanaceae family ingenious to Asia, South America and Africa. Extracts of its different parts and of plants resembling to rauwolfia were used in Hindu medicine for snakebite, insomnia, insanity and many other diseases and complaints. In Europe, Georg Eberhard Rumpf first reported about rauwolfia in his Herbarium amboinense, 1755. The first modern paper about therapeutic applications of the whole root of rauwolfia was published in 1931 in the Indian Medical Journal by Sen and Bose, and many papers dealing with botanics, chemistry and pharmacology then appeared in Indian and European periodics. In 1949, Vakil published the first report of the antihypertensive effect of rauwolfia in the British Heart Journal. In the Ciba laboratories in Basel, Switzerland, Mueller, Schlittler and Bein analysed various rauwolfia alkaloids and published in 1952 the first complete report about their chemistry and pharmacology. In the same year, reserpine was introduced under the name Serpasil in the treatment of hypertension, tachycardia and thyreotoxicosis. The combination of reserpine, dihydroergocristine and a diuretic is still on the market (Brinerdin, Crystepin). In psychiatry, reserpine was prescribed as a tranqulizing agent until modem synthetic antidepressant and antipsychotic drugs were introduced. The author also briefly summarizes the chemistry, pharmacology and clinical use of reserpine.

Psicofarmacología: una aproximación histórica / Psychopharmacology: a historical approach

La psicofarmacología puede definirse como una disciplina cien-tífica centrada en el estudio de los fármacos que modifican el comportamiento y la función mental a través de su acción sobre el sistema neuroendocrino. Se trata de un campo del saber que tiene un marcado carácter multidisciplinario, al agrupar el interés que comparten farmacólogos, bioquímicos, psiquiatras y psicólogos por el análisis de las sustancias que actúan modificando las funciones del sistema nervioso que se manifiestan en la conducta de los individuos. A lo largo de esta revisión teórica se realiza un análisis conceptual de la psicofarmacología y se revisan los principales acontecimientos históricos que han marcado el curso de la disciplina, destacando los descubrimientos más relevantes que se han sucedido en ámbitos como la práctica clínica psiquiátrica, la investigación farmacológica de laboratorio, y los estudios conductuales realizados con animales y seres humanos

Psychopharmacology can be defined as a scientific discipline that studies drugs able to modify the behaviour and the mental function through its action on the neuroendocrine system. Pharmacology, biochemistry, psychiatry and psychology share their interest for this multidisciplinary field of knowledge, devoted to the analysis of the substances that alter those functions of the nervous system that are shown on the organism’s behaviour. This paper reviews the theoretical concept of psychopharmacology, and the main historical events that occurred in clinical psychiatry, laboratory pharmacological research, and behavioural studies conducted in both animals and human beings

[Historical approach to reserpine discovery and its introduction in psychiatry]. / Aproximación histórica al descubrimiento de la reserpina y su introducción en la clínica psiquiátrica.

Reserpine, an alkaloid of the Rauwolfia serpentina plant isolated during the middle of the 20th Century, represented a highly important clinical advance in the treatment of schizophrenia whose pharmacological tools were limited to chlorpromazine that was introduced in the clinical area two years before. Both agents would come into the history as the drugs that made possible the beginning of the psychopharmacological era. In the present article, a revision is made of the complicated process leading to the isolation and synthesis of reserpine, by the Swiss pharmaceutical company Ciba (Schlittler and Müller) and how its pharmacological properties (Bein) were discovered and studied, in the animals laboratory, mainly, the "tranquillizers". The introduction of this antipsychotic in psychiatry, which was initiated in 1954 (half a century ago), and the results obtained in the first clinical studies, as well as the role played by researchers such as Kline, Delay, Noce, Hollister, Altschule, etc. are then described. In addition, and from a historical perspective, the discovery of the adverse effects of this drug, especially those of extrapyramidal nature (dyskinesia and akathisia), are studied, concluding with the reasons that produced its rapid clinical decline, among which the genesis of depressive pictures (phenomenon presently questioned) may be emphasized. Finally, the conclusion reached was that, although the clinical relevance of reserpine was not as evident and long lasting as chlorpromazine, its initial contribution to the treatment of schizophrenic patients was of maximum importance.

The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis.

For five decades it has been generally accepted that reserpine, an antihypertensive and antipsychotic drug, causes depression. The discovery that reserpine depletes brain monoamines was an important factor in the development of the monoamine hypothesis of depression, and it continues to be widely cited in support of this hypothesis. The present paper argues that, contrary to prevailing belief, reserpine is not depressogenic. The reason for perpetuation of this myth is reluctance to discard the monoamine hypothesis. This hypothesis ushered the modern biochemical paradigm into psychiatry and is still of great importance. It serves as a heuristic to guide research, it enhances psychiatry's prestige, and it helps to validate and promote drug therapy for depression and other mental disorders.

Historical development of the dopamine hypothesis of schizophrenia.

This review examines the history of discoveries that contributed to development of the dopamine hypothesis of schizophrenia. The origin of the hypothesis is traced to the recognition that neuroleptic drugs interfere with brain dopamine function. This insight was derived from two distinct lines of research. The first line originated from the discovery in 1956 that reserpine depletes brain serotonin. This finding resulted in a sequence of studies that led to the discovery that brain dopamine is involved in neuroleptic-induced extrapyramidal motor disturbances. The second line of research was aimed at determining the mechanism of action of psychomotor stimulants. This research produced evidence that stimulants directly or indirectly activate brain dopamine receptors. Because nonreserpine neuroleptics such as chlorpromazine block stimulant-induced movement, these findings suggested that neuroleptics were dopamine antagonists. Most previous accounts of the development of the dopamine hypothesis of schizophrenia emphasize the first line of research and ignore the second.

[Short history of L-Dopa]. / Breve historia de la L-Dopa.

The introduction of L-Dopa has been a landmark in Neuroscience. Before the use of L-Dopa, Parkinson's disease (PD) was considered a disabling disease with no effective treatment. The development of L-Dopa followed a rationale approach: first, the discovery of dopamine deficiency in the striatum of patients with PD; and then the use of precursor of dopamine. Overall, the whole process took less than 12 years; this is a remarkable short time taking into account that the development of a similar crucial drug such as insulin took 50 years. In addition, the success of L-Dopa stimulated the neurochemistry research for all neurodegenerative diseases.

The new drugs (chlorpromazine & reserpine): administrative aspects. 1956.

The article on the new drugs reprinted below appeared in the February 1956 issue of Mental Hospitals. It is based on a discussion held during the Seventh Mental Hospital Institute in October 1955 in Washington, D.C. Chlorpromazine and reserpine had been available in the United States less than two years when the institute participants met to discuss how their hospitals were coping with the demands of the new treatments. In a commentary and analysis beginning on page 333, Robert Cancro, M.D., considers the broader impact of the introduction of neuroleptics and examines the concerns of the 1956 institute participants in the context of today.

The introduction of neuroleptics: a psychiatric revolution.

In the commentary below, Robert Cancro, M.D., discusses the article on page 327, reprinted from the February 1956 issue of Mental Hospitals, describing how hospitals were dealing with clinical and administrative issues surrounding the use of neuroleptic drugs. Although Dr. Cancro considers the introduction of neuroleptics one of the great psychiatric revolutions of the 20th century, he believes that the changes in patient care and treatment following their introduction have not always been positive.

Rat AA-26: behavioral pharmacology science pioneer.

Rat AA-26, despite 1950s "state of the art," nonetheless generated the first set of behavioral pharmacology cumulative records to appear in the weekly journal Science, the century-old publication of the American Association for the Advancement of Science. The laboratory exploits of this dedicated animal called early attention to the methodological fruits of a marriage between pharmacology and the experimental analysis of behavior.

Prejudices in pharmacology and pharmacotherapy: reserpine as a model for experimental research in depression.

The choice of reserpine as practically the sole model substance used in research in depression over two decades was not dictated by rational considerations alone: hypothetical notions, prospects of the rapid realization of experimental research aims and the fascination of the exotic origin of this "natural" drug made a significant contribution.