Editorial Reviews
From The New England Journal of Medicine, March 23, 2000
As the new millennium begins, the identification of cardinal historical events has become standard. In the field of psychiatry, a good case can be made for choosing the development of psychotherapeutic drugs as the key advance of the past century. What many do not appreciate is that the principal classes of antipsychotic, antidepressant, antianxiety, and antimanic drugs were all discovered and introduced into clinical use between 1949 and 1960. Hence, this book's title, Ten Years That Changed the Face of Mental Illness, is altogether appropriate. The author is uniquely suited to tell this remarkable tale, since Thuillier was a house physician of the great Parisian psychiatrist Pierre Deniker. Thuillier and Deniker worked together during the crucial clinical studies that established the antipsychotic actions of chlorpromazine, the drug that most people will agree initiated the era of modern psychopharmacology.

The development of chlorpromazine and the other major drugs used in psychiatry stemmed more from serendipity than from rigorous science. Chlorpromazine comes from the chemical class of the phenothiazines. One of the first phenothiazines that was widely used was promethazine, a drug that is still largely used as an antihistamine but that has substantial sedative effects. The French surgeon Henri Laborit and his colleague anesthesiologist Pierre Huguenard had been trying to develop an anesthetic cocktail to diminish operative and anesthetic shock and to calm patients. A combination of promethazines and the opiate meperidine had been effective. Laborit and Huguenard requested stronger phenothiazines from Rhone-Poulenc and in 1949 were provided with the recently synthesized chlorpromazine, which differs from promethazine only in the addition of a chlorine substituent on one of the three rings. They were greatly impressed with chlorpromazine's calming effect as well as with its antinausea and analgesic actions and recommended the drug to their colleagues in psychiatry.

Although Deniker had never met Laborit or Huguenard, he had heard of their work and obtained samples of chlorpromazine directly from Rhone-Poulenc. Whereas Laborit and his colleagues had used small, 50-mg doses, Deniker and his chief of service, Jean Delay, administered doses of up to 600 mg to agitated manic and schizophrenic patients, which brought about dramatic relief of symptoms. In the spring of 1952, Delay and Deniker presented a series of papers showing that chlorpromazine exerted a selective antipsychotic action; patients were calmed and their thinking processes were cleared, yet the drugs did not have a sedating "chemical-straightjacket" action. Within a year, the pharmaceutical industry was galvanized into developing dozens of antipsychotic agents that were met with rapid, widespread acceptance.

The acceptance of lithium for the treatment of mania and depression took far longer. In 1949, the Australian psychiatrist John Cade administered lithium to manic patients on the basis of chance observations that guinea pigs appeared to be calmed when given lithium urate to reduce the toxic effects of urea. The results in these patients were impressive. Cade's paper, published in an obscure Australian journal, received little notice. Mogens Schou, a Danish psychiatrist, confirmed the therapeutic benefits of lithium and became its obstinately persistent champion, despite disregard or derogation on the part of his colleagues. The marketing of lithium was delayed for more than 20 years after its discovery, perhaps in part because a patent to provide proprietary protection was difficult to obtain for a widely available metal salt.

Thuillier recounts the remarkable career of the American psychiatrist Nathan Kline, who pioneered the development of key antipsychotic and antidepressant agents. Attempting to determine whether the depression that occurs in patients with hypertension who are receiving reserpine was a true effect of the drug, he administered reserpine to a group of agitated patients with a variety of conditions, including some with schizophrenia. He discovered antipsychotic actions of reserpine that were similar to those of chlorpromazine and reported his findings in 1954, two years after the introduction of chlorpromazine. Only later was it learned that both chlorpromazine and reserpine act by diminishing the synaptic effects of dopamine: chlorpromazine blocks dopamine receptors, and reserpine depletes the brain's content of dopamine.

In 1956, Kline developed the first monoamine-oxidase-inhibitor antidepressant by linking disparate observations in animals and humans. Investigators at the National Institutes of Health had discovered that iproniazid, an antituberculosis drug that also inhibited monoamine oxidase, transformed reserpine-induced sedation in rats into hyperactivity. Meanwhile, clinicians had observed euphoria and elation in patients treated for tuberculosis with iproniazid. Kline began clinical trials of iproniazid in depression, and by 1957 the drug was marketed, a year before the initial marketing of imipramine, the first tricyclic antidepressant. Interestingly, the two classes of antidepressants both potentiate monoamines, such as serotonin and norepinephrine. Monoamine oxidase inhibitors block the degradation of monoamines, whereas the tricyclic antidepressants prevent their inactivation, which normally involves transport into the nerve endings that had released them.

Thuillier recounts these and other episodes with a literary verve that is rare in medical and scientific books and draws on numerous anecdotes from his personal relationships with the pioneers. The eminently lucid presentation is retained in this excellent English translation. Thuillier's literary skills are easy to appreciate: besides his major contributions as a psychiatrist and pharmacologist, he has published several novels and books of poetry, as well as books of medical history.

A number of published accounts have detailed the discovery of chlorpromazine and other psychopharmacologic agents. Thuillier's contribution is by far the most authentic account and the only one that makes for easy bedtime reading. It is a must for anyone interested in the genesis of modern psychiatry.

Reviewed by Solomon H. Snyder, M.D.
Copyright 2000 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.

Book Info
(Martin Dunitz) Translation of the memoirs of Jean Thuillier during the 1950s. Concentrates on the author's personal experiences during an unprecendented series of discoveries of the basic classes of psychotropic drugs in 1949-1960. The end of the book provides a look at potential psychopharmacology beyond the year 2000. For clinicians, researchers and historians. Softcover.