Turan m. Itil interviewed by Thomas A. Ban San Juan, Puerto Rico, December 11, 2002

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Interviewed by Thomas A. Ban

San Juan, Puerto Rico, December 11, 2002
TB: This will be an interview with Dr. Turan Itil for the Archives of the American College of Neuropsychopharmacology. I am Thomas Ban. We are at the Annual Meeting of the College in San Juan, Puerto Rico. It is December 11, 2002. Let’s start from the very beginning. Where and when were you born? Tell us something about your education.

TI: I was born in Bursa, Turkey in 1924. Bursa is the old capital of the Ottoman Empire. My family moved to Eskisehir and then to Istanbul. I finished my high school at the Istanbul High School, and subsequently went to medical school and finished at the University of Istanbul, Medical School. And, after that, I went to military service for one year.

TB: Did you want to become a medical doctor all the time?

TI: Actually, I wanted to be an engineer, but I couldn’t get into the engineering school. With my awards from the high school I was ultimately admitted to medical school. At that time, in Turkey, it was easier to get admitted to medical school than engineering. After I finished my military service, I went to Germany, where I was told that one of the most famous doctors alive was a professor at the University of Tübingen. His name was Ernst Kretschmer. Kretschmer, as you may know, wrote several books. He was one of the first biological psychiatrists of the century. I stayed at the Tübingen Clinic and finished my education in neurology and psychiatry there to become a neuropsychiatrist. When I joined the University in Tübingen, we were treating patients with phantom pain. These patients lost their arms or legs in the war and felt excruciating pain in their lost limb.

TB: Are we in the late 1940's?

TI: That is the beginning of the 1950s.

TB: When did you get to Tübingen?

TI: Just the beginning of the ’50s. At that time, several of my professors told me that in a new article published by French people it was reported that promethazine, called Atosil, had a significant effect on relieving phantom pain. I was told to get the information and check out whether we should give it to our patients. So, I did that. According to the French publication Atosil was effective in phantom pain but not in all patients. So we started to give it to our patients. I found it unusual that some patients responded whereas others did not. So I asked my professors, “how can I predict which patient will show a response and which will not?” Several of them said, “There is no way to know in advance.” Then another said, “why don’t you read this publication from Dr. Berger? He claims that electroencephalography (EEG) would show the effects of the derivatives of opiates and barbiturates, as well as of mescaline, on the brain.”

The next day I went to Fritz Flügel, and asked whether he thought I should learn EEG in order to see the effect of promethazine/Atosil on the brain. The obvious question was whether promethazine penetrates the blood-brain barrier in every patient. The EEG might show in which patient promethazine penetrated the blood-brain barrier and had an effect on the brain. He did not believe in Dr. Berger’s findings and told me that I shouldn’t bother to learn EEG. Then, I went to my neurology professor. His name was Ishman. I asked the same question, and he said, “That’s not a bad idea. Why don’t you go and learn it?” Over the next six months I started to learn about the EEG. It was at that time the first papers on the effectiveness of chlorpromazine in some psychotic patients were published by Deniker and Delay.

TB: Could you tell us something about Fritz Flügel?

TI: Flügel was a guest doctor like me, without pay, in Tűbingen, and became chairman of one of the largest neuropsychiatry department in Germany, at Erlangen. Professor Flügel invited Bente first and then me to join him in his department, and one day he said to me, “We have a machine, but nobody’s using it. Why don’t you come and start to use it?” At the time, I was working with Dr. Dieter Bente who was one or two years older than me. He was also interested in EEG, but was always busy. It was just about that time that a meeting took place in Paris on chlorpromazine which Professor Flügel attended. When he returned from Paris, he was very enthusiastic and said that he wanted to talk to the Bayer people in Germany to get chlorpromazine. And indeed, a few weeks later, we got chlorpromazine and Professor Flügel said, “let us see whether chlorpromazine has any effect on the brain.”

TB: Was this in 1955?

TI: The meeting took place in 1954, and we started to give chlorpromazine to all kinds of patients. To our surprise, we saw some effect. The findings became my first publication on a psychotropic drug. Our paper with Bente was published in 1954 with the title, “The Effect of Chlorpromazine on Human Brain.”

TB: Was this the first publication on the effect of chlorpromazine on the human brain?

TI: Yes. There was an Italian publication before ours of the effect on the brains of animals; ours was the first publication on the human brain. We showed that chlorpromazine produced sleep-like effects. But the effects appeared to me more than just an effect that produces sleep. And after we published our paper, we also presented our findings at several meetings in Germany. There was no interest on the effect of the drug on the EEG; all people were interested in was that it induced sleep. To show that chlorpromazine-induced sleep was different from normal sleep we did a study in which we recorded sleep in a group of people after sleep deprivation and in another group after chlorpromazine administration. We found a significant difference between physiological and chlorpromazine-induced sleep. And, we published these findings as well. We also found that chlorpromazine had an effect in some people but not in others, something similar to what we saw with promethazine. We compared the effects of chlorpromazine and promethazine on the EEG, and found that even though both induced sleep, the brain sleep of patients was different with the two drugs. With chlorpromazine we saw slow-wave synchronized activities, and with promethazine, we saw fast activity.

TB: So, adding one methyl group to the side chain made a difference on the effect of the drug on the EEG.

TI: Exactly. In the meantime, there were important meetings taking place. First, the one in Milan, on Psychotropic Drugs, then the founding of the CINP in Zurich, and finally, the first CINP meeting in Rome.

TB: How did the psychiatric community respond to your findings?

TI: There was no response. At the time the German psychiatric society considered pharmacological treatment a gimmick of the drug companies. There were nineteen departmental chairmen in Germany, and only one, Professor Flügel, was involved with chemicals. They called him jokingly, the “chemical doctor,” and he was not taken seriously. The first time that he was taken seriously was when he was invited to Switzerland to meet Professor Binswanger whose daughter had schizophrenia with hallucinations. She was treated unsuccessfully with psychotherapy, and he wanted to see whether the drug Flügel described to him would help his daughter. It did, and Binswanger was very impressed.

TB: So, Binswanger was impressed with the effects of chlorpromazine?

TI: He was very, very impressed. And of course, he was telling the other doctors and professors, so Professor Flügel started to have a reputation. Before that it was based on introducing occipital (cysternal) pneumoencephalography. Prior to that, pneumeoencephalography was always done by lumbar puncture. He used occipital puncture because prior to becoming a neuropsychiatrist he was a neurosurgeon.

TB: So, it was Flügel who introduced cysternal puncture. Was cysternal puncture, rather than lumbar puncture, used at the clinic?

TI: Yes, it was routine in our clinic, but not in every clinic in Germany. Lumbar puncture is still used a lot, because cysternal puncture has some dangers.

TB: It’s very simple to do.

TI: Yes, and much less painful for the patient.

TB: There are much less after-effects.

TI: The after-effect is little because you need to inject much less air.

TB: Am I correct that you did your EEG studies with chlorpromazine in collaboration with Bente?

TI: Yes. In 1957 there was a meeting in Milan and Flügel took me along. It was the meeting where it was decided to found a society that was to become the CINP. It took place in a small room at the university.

TB: So you are one of the few people who attended the meeting at the Milan symposium that led to the founding of the CINP?

TI: There were no more than 20 people there.

TB: Can you recall the names of the people?

TI: No, I can’t.

TB: I’m sure Trabucchi, who was president of the Milan symposium was there, and also that Garattini, who organized the symposium, was there.

TI: I remember that there was a long discussion about whether it should be a society of brain pharmacology, neuropharmacology, neuropsychiatry, or psychopharmacology. I think my boss and me were the only ones from Germany there, but I am not sure. The majority of the people were from Italy and Switzerland. There were also a couple of people from France and the United States. We really didn’t understand what was going on. As a matter of fact, we were there accidentally. We were walking somewhere with my boss, when somebody said, “Oh, we have a meeting to form an organization.” My boss shook his head and asked, “What organization?”

TB: This was in the spring of 1957.

TI: Yes. And then, we heard that in 1958, there would be a meeting in Rome. And the Rome meeting was probably one of the most important meetings in my life, because it was at that meeting that I presented on the differences in the effect of chlorpromazine and promethazine on the EEG. And just before I presented, Dr. Max Fink presented his findings. He described the effects of chlorpromazine on the brain, and that the effect of chlorpromazine is different from the effect of anticholinergic drugs. I presented my findings with chlorpromazine after him, and our findings were identical. We both got excited that the effects of chlorpromazine were different from both anticholinergic and antihistaminic drugs. We were also excited that we could almost use each other’s slides to show the effects of chlorpromazine. So, we became the best of friends, and since we were the only people in the field of EEG in psychopharmacology, we began to correspond with each other to exchange information. As you know, at that time there was no e-mail or fax. As a result of my frustration in Germany, I started to have the idea of going to the United States to do my research in a more sophisticated setting.

In 1959 or 1960 I traveled around in Germany to show my slides to professors of physiology at universities; those famous professors looked at me, and said, “ you might be right, but prove it.” So I started to ask people, “How can I prove it?” And they replied, “you have to quantify your findings and apply statistics, to show that the effect is not by chance, but real. That’s science.” We never learned science in medical school, nor after medical school, and certainly not in our training in neuropsychiatry. In Erlangen, we were working very closely with Bayer. As a Turkish citizen in a German university, you could neither get an appointment nor be paid. So I was studying Bayer drugs at the University in Erlangen. At that time, everybody was looking for something better than chlorpromazine and for better methodology to study these drugs. We were, scientifically, absolutely like lay people. One of the scientists at Bayer, named Friedrich Hoffmeister, was a corresponding member of the American College of Neuropsychopharmacology; he was one of the top researchers at Bayer. He started to teach me about scientific methodology. At the time Bayer was interested in studying piperazine phenothazines.

TB: Could you tell us about the piperazine phenothiazines you worked with?

TI: One of them was Stelazine.

TB: We are in the late 1950s. Correct?

TI: Yes. At the time we thought that more effective drugs would have greater EEG effects. One of these drugs was called butaperazine; it had a greater EEG and behavioral effect. Clinically, it turned out to be a very effective compound.

TB: Butaperazine was studied but not introduced into clinical use in North America. I am wondering why?

TI: Butaperazine came to this country but not sold because, in the meantime, Stelazine was of interest. Butaperazine produced more extrapyramidal side effects than any of the other compounds, but as I said, at the time the idea was one would have better therapeutic effects with compounds which induced more extrapyramidal side effects. With that kind of belief we started to study the effects of reserpine. Reserpine was first introduced in Germany as an antidepressant, but Professor Flügel found it had therapeutic effect in psychotic patients.

TB: Reserpine was given for treating neurotic depression in some countries in those years. Right?

TI: Yes, I think it was given to patients with neurotic depression.

TB: At the same time, it was also reported that it caused depression when used in the treatment of hypertensive patients.

TI: We studied the effect of reserpine in psychotic patients, especially in schizophrenics, and we thought it was more effective than chlorpromazine. We had also seen more extrapyramidal side effects with it. Professor Flügel combined reserpine with chlorpromazine and found that the combination was better than either of the two drugs alone. But it also induced more Parkinsonian effects. We presented and published our findings, but then within six months, seven patients committed suicide while taking reserpine. At first, we couldn’t link reserpine with the suicidal attempts, because many of those patients were receiving other drugs as well. But by giving only reserpine to some patients we observed that not only their suicidal thoughts increased, but also their energy level. So it was not a depressive effect alone, but together with an increase in anxiety and drive that led to suicide.

TB: Was it akathisia you saw with reserpine?

TI: Yes, patients had akathisia, anxiety and restlessness; they could not sit still.

TB: Were you the first to report it?

TI: Yes.

TB: This was in the late 1950s. How did it show up on the EEG?

TI: That was very interesting. When we did EEGs with the reserpine and chlorpromazine combination, what we saw was an increase in synchronization in the frontal area, the kind of effect seen in Parkinson’s disease. In our model, that was supposed to be an indicator of better therapeutic effects. We thought the more we can change brain function, the better the therapeutic effects would be. And the changes we produced were in the direction that chlorpromazine alone had produced. It was about that time I started writing my thesis on the effect of drugs on the EEG as the prerequisite for being appointed as dozent. One area I was especially interested in was the identification of drugs with therapeutic effects using the EEG in schizophrenia. We started to call these drugs neuroleptics to differentiate them from sedative drugs. I completed and published my thesis and became a dozent at the University of Erlangen.

TB: What year was that?

TI: 1962. My thesis was published in the form of a book in Turkey and in Germany, but didn’t have any impact. In the meantime, Max Fink invited me to the United States. When you become a dozent in Germany, you know that in five to six years you will become professor, even if you don’t do anything, so I thought I should go to the United States to learn English and how to quantify the EEG. Max was working at the time with electronic frequency analyzers.

TB: Was Max Fink in St. Louis at the time?

TI: No, Max was in New York, in the Great Neck area. It was just about the time he got the wonderful offer from George Ulett to set up a research institute in St. Louis, Missouri. I was planning to visit Max Fink at Hillside Hospital, but about three months before my visit he told me that he was moving to St. Louis. He was planning to bring famous people, young people, from all around the world. I told him that I’m not so famous, but active, and he said I should come to St. Louis.

For me, of course, New York was a very attractive place; I didn’t have any idea about St. Louis. One day I was sitting at the Rotary lunch in Nuremberg, and next to me was a young man whose father had the biggest brewery in the city. While I was talking to him, he said had just come from Missouri, where he visited the Busch Company, the famous brewery in St. Louis. I said, “I’m going to go to St. Louis.! What kind of a city is it?” He shook his head, “It’s terrible; cold with lots of snow in winter, and hot and humid in summer.” I was shocked, but we had already planned our trip and were ready to leave.

I asked the University for a leave of absence for the year, and they approved my request. Then a very important thing happened. Bavaria did not have any rules that foreign citizens couldn’t become dozents, so as soon you were appointed you automatically became a civil servant with pay. So as it turned out I became not only a dozent, but also an employee of the department and clinic. That was a big thing because I could go on sabbatical for a year. Now, sabbaticals are usually with pay, but because I was not a German citizen as yet they didn’t want to pay me. In the meantime, Max Fink offered me $18,000 a year. I didn’t know how much that was worth, so I wrote to my brother who was living in Toledo, Ohio, and asked him whether I could live on that money with my wife and my son. He wrote back saying, that’s fantastic! He had been in the United States for thirteen or fourteen years and was making only $12,000 a year. So he told me that would be great money, and I should come immediately. So that’s how I decided to come to the United States for one year.

But when I arrived to St. Louis I was shocked. In Erlangen we had 150 beds, and our EEG laboratories were working steadily. This was not the case at the Missouri Institute of Psychiatry. The name was great; the building was great and brand new, but there was nothing else. There were no patients and there were no machines. There was nothing. I said to Max, “What’s going on?” He said, “Wait, I have lots of money. Just tell me what you need.” I said to Max, an “EEG, of course.” He replied, “No problem, just get the information about what kind of machine you want and we’ll get it.” Indeed, there was a lot of money from the state, a lot of space and plenty of patients, because the Missouri Institute of Psychiatry served nine state hospitals. Ulett was Commissioner of Mental Health for Missouri, and made Max Fink Director of the Institute so he could get patients from the state hospital system. Ulett was also professor at Washington University, and had Max appointed professor in the department. The plan was to create the necessary environment for research.

I was anxious, thinking I had only twelve months and that might not be enough to set up a laboratory, learn English and how to quantify the EEG. While Max was recruiting Sam Gershon from Australia and young people from around the world he told me I should write an application for a new grant. I had no idea what a grant was or how to write one. But of course, he helped a lot with writing it. In Germany we had studied treatment-resistant schizophrenics and found that those with enlarged third ventricles and abnormal EEGs did not respond to butaperazine. We published our findings and Max and George Ulett read our reports.

TB: When did you publish those findings?

TI: 1958, 1959. Recently others found similar findings with MRI and CT scans.

TB: Similar to the findings you published in the late 1950s?

TI: After they read the German results they thought it was very interesting and suggested, “You should write a grant application to study schizophrenia and psychopharmacology.” After I wrote the grant Jonathan Cole himself came with a group of people to review our request. It was approved for $70,000 annually, for five years. In addition Max had other grants. We had plenty of money. My time was up by then and I was supposed to go back to Erlangen. I had a very difficult decision to make; whether to go back to Germany or stay in the United States.

I returned to Germany with my wife and told Professor Flügel I was entertaining the thought of staying for one more year in St. Louis. I’ll never forget his expression; he looked at me and said, “You are crazy. You worked like a slave for many years and now that you have become a dozent and will be a professor in two or three years, you want to leave for the United States. A professor in Germany is close to God; what do you want to do in the United States? Forget it.” But his wife was much more understanding. She said, “People say to do research in the United States is much better than here.” My wife who was critical of everything when we arrived in the States, by the end of our year in St.Louis, started to accept the American way of life and suddenly didn’t like her native country. That was crucial, and when we went back to St. Louis we started to look for a house. Our family was growing as were the laboratories at the Institute.

We started our psychopharmacology research in schizophrenia and that turned out to be a major project. Just recently, somebody became interested in writing my biography, and when he asked me what I would consider my greatest achievement I told him it was the quantification of the EEG. Max Fink was heavily involved with computers and we used them to analyze our data.

TN: What other important findings did you have?

TI: We discovered that all drugs that are effective on behavior have an effect on the brain and this effect can be demonstrated by using the quantified EEG. Probably even more important were our findings that drugs which have certain therapeutic effects show similar EEG changes. All antidepressants produce one type of effect; all neuroleptics produce another type of effect; all anxiolytic drugs produce yet another type, and all drugs we call cognitive activators or psychostimulants produce a fourth type of effect. So we published our findings which showed that drugs produce different effects on the quantitative EEG if they have different therapeutic properties.

TB: When did you publish these findings?

TI: In 1965–1966. About the same time, we accidentally discovered Tacrine, that was to become the first anti-Alzheimer’s drug. We were working with schizophrenic patients who had cognitive deficits, and were trying to figure out how to treat patients who seemed also to have – as indicated by their large ventricles and EEG changes – an organic state that interfered with the therapeutic effect of neuroleptics. We gave this kind of schizophrenic Ditran, a potent anticholinergic substance, to make them acutely psychotic and then treat them with neuroleptics. It didn’t work, but when we gave them Tacrine, (tetrahydroacridane), a substance Sam Gershon brought from Australia, it controlled both their psychosis and confusion. It also reversed the EEG changes induced by Ditran. We published our findings is 1965. We wrote that Tacrine had a significant effect on human behavior, and reduced experimentally-induced confusion. We were not smart enough to relate experimentally-induced confusion to dementia. It was several years later that Bart Summers recognized the potential of Tacrine and pharmacologically similar drugs in the treatment of dementia. At the same time we found that schizophrenic patients have different EEG patterns from normal subjects. Then, we looked at psychotic, schizophrenic children and found similar differences between schizophrenic and normal children as we found in adults.

Finally, we took part in a WHO project in Copenhagen, with Sarnoff Mednick and Fini Shulsinger, and found that children at high risk for schizophrenia have significantly different EEG patterns than normal controls. They have more fast activity in their EEG. Since all neuroleptics decrease fast activity and increase alpha activity they correct these EEG changes in schizophrenia. Now, twenty-five years later, we recognized a similar pattern in patients with Alzheimer’s disease where all cognitive enhancers that exist today, including memantine, increase alpha acivity that is proportionately reduced with the severity of dementia. So, as in schizophrenia, in Alzheimer’s demetia one can use EEG to measure therapeutic effects.

TB: How do you predict whether a drug will be therapeutic for a patient, using the EEG?

TI: Using a single test dose, you can predict whether a particular drug will produce the desired therapeutic effect in the central nervous system of a particular patient. You can see whether the drug modifies brain reactivity in the direction of normalizing the EEG. Based on this, we think that one can predict whether a particular drug will be effective in a particular patient. We call this method the test dose procedure of the quantitative pharmaco-EEG. We organized a society, the International Pharmaco-EEG Group (IPEG) and developed databases, like fingerprints, for antidepressants, antipsychotics, anxiolytics and cognitive activators.

TB: When and where did you move from St. Louis?

TI: In 1973 I moved to the New York Medical College, to Al Freedman’s department because Max Fink had left the College and moved to Stony Brook University on Long Island. I set up laboratories at the College and at the VA and we established databases for findings with drugs on the quantitative EEG.

TB: How many drugs did you study and have in your database?

TI: We studied about 250 experimental drugs.

TB: Is your database accessible to everyone?

TI: Naturally. Many of the drug profiles are published.

TB: Would it be correct to say that clinical improvement is reflected in the EEG changes?

TI: That’s right, and I thought the EEG was important in the detection of the psychotropic qualities of drugs. For example we examined hormones and found that mesterolone, a synthetic androgene preparation, in low dose shows an anti-anxiety pattern, and in high dose an antidepressant pattern on the EEG. The antidepressant effect of mianserin was discovered by this type of screening.

TB: We are running out of time. Is there anything important we left out you would like to add?

TI: When we published our findings all the drug companies wanted to have their drugs studied with quantitative EEG. We couldn’t do this because studies with computerized EEG are very expensive. In the 1980's, the new computers completely changed the picture, and this was the time I moved into research and set up studies with Gingko Biloba in Alzheimer’s disease, and also organized a multi-center trial with amitriptyline in a WHO program to show that its therapeutic effectcan be predicted by EEG analyses. In the WHO study, we enrolled 450 patients. In the Alzheimer’s study, we had 310 patients. I hope one day psychiatrists will be able to give a drug and be able to predict, with an automated EEG, whether a patient will respond to a psychotropic drug without waiting several weeks.

TB: Am I correct that you are still active in your research?

TI: I’m very active. I am very much concerned that drug therapy is given without checking the effect of drugs on the brain. So we are setting up memory centers where we can check with our EEG methodology the effect on the brain of the drugs given to patients.

TB: On this note we conclude this interview with Dr. Turan Itil. Thank you, Turan, for sharing this information with us.

TI: Thank you.

 Turan M. Itil was born in Bursa, Turkey in 1924.

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