Tuesday, 26.05.2020

Thomas A.Ban, editor. Lithium in Psychiatry in Historical Perspective.

Bernard Carroll Interview by Leo Hollister and Thomas Ban*

                                                             

LH: In knowing the history of Australian neuropsychopharmacology from early on did you ever have occasion to meet the most famous Australian psychopharmacologist, John Cade?

BC:  John Cade was one of my teachers in psychiatry.

LH: Did he teach at the medical school?

BC: He did. I knew him well. His son, David, was in my medical school class and his other son, John, was two years ahead of us in medical school. I knew the Cades and I knew John; in clinical psychiatry we were taught at the Royal Park Psychiatric Hospital, the inner-city State hospital where John Cade was director of. We would go, as medical students, to the auditorium on Saturday mornings where John Cade would teach us psychopathology and his style was very Kraepelinian. He was up on stage with two chairs, one for the patient and one for him.  An assistant would be hovering around and the patients would be lined up off stage. He would signal to stage right for a patient to be brought in and would say, in a very Edwardian authoritarian manner, “Ladies and gentlemen, I’m now going to demonstrate a patient with schizophrenia.” The patient would be brought and John Cade would put the schizophrenic patient through his hoops, send the patient off stage left, signal again to stage right and say, “Ladies and gentlemen, I’m now going to demonstrate a patient with mania so you should pay close attention to the differences between them.” His style was very autocratic and old fashioned, but in many ways, effective.

LH: Better than learning from a textbook.

BC: Much better. Then, in my psychiatry training, I had more encounters with Dr. Cade. I learned he had what can be called a divergent manner of thinking, a cognitive style with lateral and not always linear thinking. He published a paper in the Australian Medical Journal, on his theory of the etiology of schizophrenia. This, is in the late 1950s, was that schizophrenia was a disease that resulted from a deficiency of stone fruit such peaches and plums. An epidemiological study in the State of Victoria found that most acute schizophrenics were admitted to the receiving hospital from the densely populated parts of the city. They had the lowest density of fruit trees. That’s very similar in style to the thinking that led to his discovery of lithium.  He had this weird idea that some toxin in the urine of manic patients was responsible. He thought it was a urate salt. Needing a soluble urate salt, he got onto lithium urate. And his one good scientific question was to ask was it the urate or was it the lithium?  And the rest is history.

LH: When he was teaching you had he already made that discovery?

BC: He had.

LH: Why did it take so long to catch on?  Was it because he had a reputation of being a wild thinker and nobody believed him?

BC: No. Australians are very pragmatic and all through the 1950s, lithium was widely used in Australia and was picked up in England through Mogens Schou in Scandinavia and later in Europe in the 1950s and the 1960s. The resistance to lithium as a clinical agent was centered mostly in the United States.

LH:  That was due to its earlier use as a salt substitute for congestive heart failure and deaths due to toxicity before blood levels were available.

BC: Exactly, and that’s all being written up in Frank Ayd’s book, Discoveries in Biological Psychiatry.  I now have in my possession glossy photograph copies of John Cade’s original case notes of the first patients he treated with lithium and I will donate them to the ACNP Archives.  They are very, very interesting.

LH: How was he lucky enough to pick the right dose?

BC: The dose was known, because lithium had been used for epilepsy and gout, so people knew t lithium was safe. John’s description of his IND process, shall I say, was that after he’d completed his guinea pig experiments he did a Phase 1 clinical trial on himself and the determining factor, when he treated himself with lithium for two weeks, was whether his wife, the long suffering Mrs. Cade, noted any difference. She did not notice, so he proceeded to treat a group of patients who were essentially chronic residents of the hospital.  Today, we would call those patients, looking at the case notes, rapid cycling bipolar. They were in and out of manic and depressive phases of bipolar illness and to everybody’s astonishment, they were all discharged within about four months of starting on lithium, so they truly were stabilized. John had complete freedom to do whatever he wanted in those days. There was no drug regulatory agency.

LH:  He was the superintendent of the hospital.

BC: He lived on the hospital grounds.  I remember going to his house to visit with his sons, who were in medical school with me, going in by the back gate from the hospital grounds to the superintendent’s house. There was a basket on the gate that was replenished every day with vegetables from the patients’ garden for the consumption of the superintendent and his family.

LH: This is really old style, isn’t it?

BC:  He was a beloved figure in the hospital and a very conscientious clinician.

LH:  That’s a new element to your Australian training.

TB: So, you were in medical school about ten years after his publication on lithium, in the late 1950s?

BC: I entered medical school in 1958.

TB: Just ten years after.

BC: That’s correct.

TB:  Some clinicians had already picked up lithium?

BC: Sam Gershon was using lithium in Australia and in the pharmacology department in Melbourne a number of basic studies of lithium kinetics and distribution were under way and were published during the 1950s. Sam Gershon was already publishing his work on lithium.

LH: I think Gershon came to this country around the early 1960s.

BC: Correct.  I was with him in 1961 and he came to America in 1957-1958, came back in 1959-1961 to Melbourne and in 1962, returned to the United States.

LH: Sam would talk lithium to the sceptics over here. I remember saying, “Lithium, that’s a good thing to kill you,” because I had fresh in my mind toxicity in cardiac patients.

BC: The last time I saw John Cade was at a very important event.  It was the 1979 International Conference on Use of Lithium in New York and John was the featured person at that meeting, along with Schou. I remember being at the hotel, walking across the lobby the day the meeting was getting underway, and I saw John wandering around in a dazed and confused way. I knew immediately what the problem was. He was in his late seventies and terribly jet lagged. I went up to him and I said, “John, how are you? ”  And, he said, “I’m alright, Barney, leave me alone.”  That was his usual style but I went on, “John, you look as though you’re not very well.”  He replied, “All I need is a little sleep.”  I asked, “Where have you been?”  and he said, “I just got off the plane from Australia.” So, I said, “John, do you mean to tell me you didn’t break the journey anywhere between Melbourne and New York?”  He said, “No, I just flew straight here.” I admonished him but he was in a travelers’ delirium with severe jet lag and disorientation. So, we got him to his room and he slept that off was back to his happy self for the rest of the meeting.  I take credit for helping to get John settled down in time for his public appearance.

LH: Well, that’s an interesting side light on an aspect of major importance in the history of psychopharmacology.  Thank you, then.

BC: Thank you.

LH: I’m glad we caught that.

*Extracted from the interview of Bernard J. Carroll by Leo E. Hollister and Thomas A. Ban conducted for the Oral History series in Las Croabas, Puerto Rico, at the Annual Meeting of the American College of Neuropsychopharmacology on December 17, 1998. The edited interview was first published in Samuel Gershon, editor. Neuropsychopharmacology, in Thomas A. Ban, series editor: An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume 5. Brentwoood: American College of Neurosychopharmacology; 2011, pp. 85 -101.

            

April 2, 2020