Work record
Founding Papers of Psychopharmacology: Cade on Lithium (1949), Delay, Deniker and Harl on Chlorpromazine (1952), Kuhn on Imipramine (1957)
John Cade; Jean Delay, Pierre Deniker and J.-M. Harl; Roland KuhnJohn Cade; Jean Delay, Pierre Deniker and J.-M. Harl; Roland Kuhn; John Cade; Jean Delay, Pierre Deniker and J -M Harl; Roland Kuhn; John Cade; Jean Delay, Pierre Deniker and J. -M Harl; Roland Kuhn; JohnCade;JeanDelay,PierreDenikerandJ-MHarl;RolandKuhnFounding Papers of Psychopharmacology: Cade on Lithium (1949), Delay, Deniker and Harl on Chlorpromazine (1952), Kuhn on Imipramine (1957) by John Cade; Jean Delay, Pierre Deniker and J.-M. Harl; Roland Kuhn (1949–1957)This record brings together three short clinical papers that began the modern era of drug treatment in psychiatry.1949–1957 · Postwar Contemporary · Essays · English, French and German
Abstract
Context. In the late 1940s mental hospitals were crowded with long-stay patients and the main physical treatments, such as induced comas and shock therapy, were crude.
Lithium. A Melbourne psychiatrist seeking a toxin in manic patients' urine saw that a lithium compound made laboratory animals placid; given to ten manic patients, it calmed several so much that they went home. Toxicity concerns slowed its adoption for two decades.
Chlorpromazine. Paris clinicians gave a new drug, first used by a surgeon to calm patients before operations, alone and in steady doses to agitated psychotic patients, who became calmer and less deluded without being sedated into sleep.
Imipramine. A Swiss asylum doctor testing a company compound meant for psychosis found it did little for that purpose but noticed that it lifted severe, melancholic depression in many patients, who regained energy, appetite and hope within weeks.
Method. All three rested on small groups of carefully watched patients described one by one, rather than on the controlled, randomized trials that later became the standard for testing new medicines.
Consequences. Within a decade the drugs had transformed mental hospitals and launched research into the chemistry of the brain, while raising lasting questions about side effects and long-term use.
Key figures
- John Cade: Australian psychiatrist
- Jean Delay: Professor of psychiatry, Sainte-Anne Hospital, Paris
- Pierre Deniker: Psychiatrist at Sainte-Anne
- Roland Kuhn: Swiss psychiatrist at Münsterlingen
- Henri Laborit: French surgeon who first used chlorpromazine
Summary
This record brings together three short clinical papers that began the modern era of drug treatment in psychiatry. Before them, patients with severe mental illness were often confined for years in crowded hospitals, and the available physical treatments, such as sedation, insulin coma and electroconvulsive therapy, were limited or dangerous. In 'Lithium salts in the treatment of psychotic excitement', published in the Medical Journal of Australia in September 1949, John Cade described giving lithium to patients at a repatriation mental hospital near Melbourne. He had been searching for a toxic substance in the urine of manic patients and noticed that lithium made guinea pigs calm. Several of his ten patients with mania, some ill for years, improved strikingly and were able to leave hospital. Fears about lithium's toxicity delayed its acceptance until the Danish psychiatrist Mogens Schou and others tested it rigorously in the 1950s and 1960s. In 1952 Jean Delay, Pierre Deniker and J.-M. Harl of the Sainte-Anne Hospital in Paris reported in the Annales Médico-Psychologiques on the use of a new phenothiazine compound, numbered 4560 RP and later called chlorpromazine. The drug had been made by the Rhône-Poulenc company and used by the surgeon Henri Laborit to calm patients before operations. Given alone in steady doses, it quieted agitation and reduced hallucinations and delusions in psychotic patients without putting them to sleep. Within a few years chlorpromazine was used around the world, and hospital populations began to fall. In 1957 Roland Kuhn reported in the Schweizerische Medizinische Wochenschrift that an iminodibenzyl compound, G 22355, later named imipramine, relieved depression in many of his patients at Münsterlingen. The Geigy company had developed it as a possible treatment for psychosis; Kuhn, observing his patients closely, noticed its effect on depressed mood. Imipramine became the first tricyclic antidepressant. All three discoveries came from careful clinical observation rather than from theory, and each raised new questions about the brain and about the risks and limits of medication.
Plot or Argument
- Cade, 1949: lithium
Lithium salts calm patients with mania; several long-term patients recover enough to leave hospital.
- Delay, Deniker and Harl, 1952: chlorpromazine
A new phenothiazine given alone in continuous doses calms agitation and reduces psychotic symptoms.
- Kuhn, 1957: imipramine
An iminodibenzyl compound relieves depression, especially of the severe, melancholic kind.
- Common features
Each began with a chance or unexpected observation, tested by close clinical study of a small group of patients.
Lessons
Observation in the clinic
All three discoveries came from physicians watching their patients closely. Careful attention to individual patients remains essential in medicine.
- What did each author observe that others had missed?
- Why is clinical observation still important when we have laboratory science?
Benefits and risks
Each drug brought great relief but also side effects and dangers. Medicine always weighs benefits against harms.
- What risks did lithium pose, and why did that delay its use?
- How should doctors and patients decide whether a treatment is worth its risks?
Changing institutions
The new drugs helped many patients leave hospitals, but closing institutions without adequate community care caused new problems.
- How did these medicines change mental hospitals?
- What do societies owe people with severe mental illness?
For the Christian reader
The Gospels show Christ caring for those tormented in mind. Christians can welcome medicines that relieve such suffering while also attending to the whole person, body, mind and soul, and to the community that should surround the sick.
- How can medical treatment and spiritual care work together for people with mental illness?
- What does the Church owe to those with severe mental illness?
Context
In the 1940s psychiatric hospitals in Europe, North America and Australia held hundreds of thousands of patients. Treatments included barbiturates, insulin coma, electroconvulsive therapy and lobotomy.
Composition
Cade's paper appeared in the Medical Journal of Australia on 3 September 1949. Delay, Deniker and Harl's report, in French, appeared in the Annales Médico-Psychologiques in 1952 after presentations to the Société Médico-Psychologique. Kuhn's paper, in German, appeared in the Schweizerische Medizinische Wochenschrift in August 1957, and he presented it at a congress in Zurich that September.
Reception
Chlorpromazine spread fastest, transforming psychiatric wards within a few years. Imipramine opened the age of antidepressants. Lithium was approved in the United States only in 1970 but became a standard treatment for bipolar disorder.
Comparisons
- Medical Inquiries and Observations upon the Diseases of the Mind
Benjamin Rush's 1812 treatise shows how mental illness was treated before modern medicines.
- The Internal Secretion of the Pancreas
Insulin, discovered a generation earlier, was also used in psychiatry in the insulin-coma treatments these drugs replaced.
- The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research
Later research ethics required more rigorous consent and trial design than these early studies.
Quotes
For Students
A reading companion for classical Christian high school students. See the student guide.
Reading Guide
Watch for
- What each author observed.
- The patients each study involved.
- Risks and side effects.
- How chance played a part.
Key terms and names
- Mania
- A state of abnormally elevated mood, energy and activity.
- Psychosis
- A state in which a person loses contact with reality, often with hallucinations or delusions.
- Antidepressant
- A medicine used to treat depression.
- Antipsychotic
- A medicine used to reduce psychotic symptoms.
Seminar Questions
- Comprehension What did Cade notice about lithium in guinea pigs?
- Comprehension For what purpose was chlorpromazine first used?
- Interpretation Why might careful observation of patients have been more important than theory in these discoveries?
- Interpretation How did these drugs change psychiatric hospitals?
- Interpretation How did chance and careful observation each contribute to these discoveries?
- Big Question What are the limits of treating the mind with medicine?
Faith Connections
- Mark 5:15 (Scripture)
The man once tormented is found "clothed, and in his right mind": Christ's compassion for the mentally afflicted.
- 1 Samuel 16:23 (Scripture)
David's music relieves Saul's distress, an early picture of care for a troubled mind.
- Robert Burton, The Anatomy of Melancholy (Great Conversation)
A seventeenth-century survey of depression and its remedies.
Logic and Rhetoric
Central argument: Careful clinical observation showed that specific drugs could relieve mania, psychosis and depression, opening the era of psychopharmacology.
Rhetorical device: case series. Each paper reports a small series of patients described individually.
Debate: Resolved: that the benefits of psychiatric medicines have outweighed their costs.
Writing Prompts
Essay: Explain how these three papers changed the treatment of mental illness.
Comparison with Medical Inquiries and Observations upon the Diseases of the Mind: Compare the treatments of mental illness in Benjamin Rush's day with those introduced in the 1950s.
Medical Lens
The three clinical reports that introduced lithium, the first antipsychotic and the first tricyclic antidepressant.
- Cade (1949)
Lithium salts used to calm mania.
- Delay, Deniker and Harl (1952)
Chlorpromazine given for psychotic agitation.
- Kuhn (1957)
Imipramine found to relieve depression.
Creative Prompts
- Essay
Compare how chance and careful observation each contributed to these three discoveries.
- Classroom
Make a timeline of psychiatric treatment from the asylum era to the 1960s.
- Dialogue
Write a conversation between a nurse in a 1950s mental hospital and a patient newly treated with chlorpromazine.
Further Reading
- A History of Psychiatry, Edward Shorter
- The Creation of Psychopharmacology, David Healy
Verification notes
Abstract only; all three papers are in copyright, so no text or quotations are stored. Publication details follow standard histories of psychiatry (Shorter, Healy). Original languages: Cade in English, Delay, Deniker and Harl in French, Kuhn in German.
- Bibliographic details: Cade, Med J Aust 1949;2:349–352; Delay, Deniker and Harl, Ann Méd-Psychol 1952;110:112–117; Kuhn, Schweiz Med Wochenschr 1957;87:1135–1140. Page numbers follow standard citations and should be checked.