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April 10, 2002

Chlorpromazine and the Psychopharmacologic Revolution

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JAMA. 2002;287(14):1860-1861. doi:10.1001/jama.287.14.1860-JMS0410-6-1

Before 1955, psychiatry was still heavily influenced by the psychoanalytic method and had yet to come up with a reliable treatment for schizophrenia that went beyond the usual methods of institutionalization, restraint, sedation, and psychosocial intervention1 Chlorpromazine was not only the first pharmacologic agent that relieved many of the symptoms associated with schizophrenia but also represented the first step toward understanding mental illness in terms of receptors and neurotransmitters.

Treatment for schizophrenia in the pre-chlorpromazine era was empirical and based on hypotheses that were popular at the time. In the 1930s, psychiatrists believed a "biological antagonism" existed between schizophrenia and epilepsy, and hence induced convulsions in patients both chemically and electrically.2 Despite some success in relieving psychotic symptoms, these methods were traumatic and ultimately unhelpful.1 The chemical convulsants induced cyanosis and muscle pain, and were dreaded by patients. A director of a Swiss public asylum during this period described the experience in the following manner: "The sight of the artificially produced attack of epilepsy, especially of the contorted blue faces, was so awful to me that I sought to get away from the room whenever I could."3 Electroconvulsive therapy (ECT) was also used to treat schizophrenia along with other mental disorders; however, the convulsions put the patient at risk for broken limbs and fractured vertebra.

Manfred Sakel, a physician from Vienna, believed that schizophrenia resulted from the influence of abnormal brain cells on behavior.2 Thus, contemporary psychiatrists attempted to selectively destroy these weaker cells by inducing insulin comas in patients.2 Although the procedure worked for at least the short-term, the induction of an insulin coma brought patients dangerously close to hypoglycemic death and consequently was associated with a 10% mortality.3

Treatments in the 1940s were equally unpleasant. Influenced by the work of the Portuguese neurologist Egas Moniz, Walter Freeman pioneered the transorbital leucotomy whereby a blunt surgical knife was used to destroy the frontal cortex. Although the procedure was initially used only on patients with severe mental disease, it was later expanded to include patients with a wide range of diagnoses.2 Unfortunately, prefrontal leucotomy was also a mutilating procedure that was irreversible and associated with a high mortality rate.2

Although these treatments for schizophrenia sometimes improved psychotic symptoms, their efficacy was unreliable and the side effects often negated their overall benefit to patients. In 1951, Henri Laborit, a surgeon in the French navy, began experimenting with chlorpromazine, which was originally intended to be used as a surgical anesthetic.3 Soon psychiatrists throughout France, including Jean Delay and Pierre Deniker who pioneered the use of the drug for schizophrenia, began using chlorpromazine to treat patients with symptoms of mania and psychosis.3 After Smith Kline & French started marketing chlorpromazine as Thorazine, psychiatrists were able to treat this disease with a specific drug, thus making their therapeutic approach more similar to the rest of the medical profession.3 In addition, the use of chlorpromazine for schizophrenia marked one of the first instances in which this disease was treated by an orally administered agent rather than by a medically supervised, physically invasive procedure.

Within 8 months of the introduction of chlorpromazine, approximately 2 million patients had received the drug.4 Chlorpromazine was 70% effective in relieving the hallucinations, delusions, and disorganized thought associated with schizophrenia.1 Unlike previous therapies, chlorpromazine made uncontrollable patients more manageable without rendering them unconscious.5 It suddenly seemed possible that schizophrenia could be a more treatable disease, and patients who had once been confined to living in an institutionalized environment could now visit art museums, meet relatives for dinner, and shop at stores with or without an attendant.3 One report describes a 29-year-old woman whose pre-chlorpromazine conduct was characterized by "self-inflicted injuries, temper tantrums, sullenness, and antagonistic behavior" toward staff and other patients. After the administration of the drug, her physician described her as "pleasant, cooperative, capable."6

The effects of the drug seemed miraculous to physicians who had previously worked with patients with schizophrenia. Robert Cancro states, "It is difficult to communicate to younger colleagues the miracle that 150 to 300 mg of chlorpromazine a day appeared to be to the house officers of 1956."7 Heinz Lehmann, who introduced chlorpromazine to North America, was astonished by the results of this new agent: "Two or three of the acute schizophrenics became symptom-free. Now I had never seen that before. I thought it was a fluke—something that would never happen again but anyway there they were. At the end of four or five weeks, there were a lot of symptom-free patients. By this, I mean that a lot of hallucinations, delusions, and thought disorder had disappeared. In 1953, there just wasn't anything that ever produced something like this—remission from schizophrenia in weeks."3

Eventually, the widespread use of chlorpromazine resulted in an the deinstitutionalization of large numbers of patients with schizophrenia. Although the behavior of schizophrenic patients was once considered to be incompatible with independent functioning in society, the drug enabled thousands to lead lives outside psychiatric institutions. In 1953, the highest point of population in mental hospitals was 560 000, and by 1975 this number had dropped by two thirds to 193 000.8

At the same time, some psychiatrists viewed chlorpromazine as an inadequate replacement for institutionalized care. Previously, patients diagnosed with schizophrenia may have been hospitalized for their entire lives; now many of these individuals who still manifested psychotic symptoms were left to wander the streets, often unable to care for themselves.5 In addition, the deinstitutionalization movement was driven as much by the federal and state governments' desires to reduce the costs of caring for mental illness as much as by the success of chlorpromazine.5

Despite the controversy surrounding it, chlorpromazine began a novel trend in psychiatry: treatment of mental diseases with pharmacologic agents. Like the cardiologists, who had digitalis and α-blockers, psychiatrists now had their phenothiazines and tricyclic antidepressants. After the introduction of chlorpromazine, drugs were developed for schizophrenia as well as other Axis I disorders that were previously deemed incurable. In 1956, imipramine, a tricyclic antidepressant, and iproniazid, a monoamine oxidase inhibitor, were found to introduce "euphoria" in depressed patients.9 Eventually, categories and subcategories of drugs for specific mental illnesses were established. For instance, the anxiolytics (meprobamate, lorazepam) and hypnotic-sedatives (phenobarbital, propofol) were used for anxiety disorders.9 For the treatment of depression, a psychiatrist can now choose from a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a norepinephrine/dopamine reuptake inhibitor, a serotonin/norepinephrine reuptake inhibitor, and a serotonin type 2A receptor antagonist.9 Patients who prior to the pharmacologic revolution may have been treated with lobotomy and ECT for an "incurable" mental disease were finally receiving treatment that made their illnesses manageable.

The psychopharmacologic revolution also influenced the attitudes of psychiatrists. During the pre-chlorpromazine era, psychiatry had alienated itself from the rest of medicine, whereas afterwards a new generation of psychiatrists emerged who identified themselves more as medical physicians than as psychoanalysts. In a 1987 study, psychiatric residents who completed their training in the late 1970s and early 1980s expressed less antagonism toward the medical model, endorsed medical education in larger numbers, experienced more hours in neurology training, and felt that the internship was an essential aspect of psychiatric education.10

Although chlorpromazine may have been responsible for several significant changes in psychiatry, the drug did not necessarily correct all the problems associated with earlier schizophrenia treatment. First, chlorpromazine's mechanism of action remained a mystery until the dopamine receptor binding studies conducted in the 1960s and 1970s, and even in modern times, psychiatrists do not have a clear understanding of the molecular basis of many psychopharmacologic agents. In 1984, decades after the introduction of chlorpromazine, one of the major complaints among medical students about psychiatry was the ambiguity of treatment.11 Second, chlorpromazine had a variety of adverse effects that included postural hypotension, tardive dyskinesia, a permanent condition characterized by abnormal choreoatheroid movements, and confusion. Heinz Lehmann went as far as to describe the drug as acting like a "chemical lobotomy."3 Finally, chlorpromazine made schizophrenia manageable rather than curable, and thus the benefit came with a degree of risk.

However, chlorpromazine marked the first step in the direction of chronically managing schizophrenia, and it stimulated a series of investigations that began to provide psychiatry the biological explanations that it had always lacked. The main target of the drug was found to be the D2 dopamine receptor, and this information was correlated with the fact that chlorpromazine only relieved positive symptoms. Furthermore, the identification of receptor subtypes during the 1980s helped researchers understand the affinities of neuroleptics for the dopamine-D2 and serotonin 5-HT2A receptors.9 Consequently, this understanding of schizophrenia has continued to lead to the development of more specific neuroleptic agents with fewer adverse effects and more specific actions.

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