San Juan, Puerto Rico, December 12, 2004
AT: My name is Dr. Andrea Tone and we are at the ACNP Annual Meeting in San Juan. It is December 2004 and I’m interviewing Dr. Turan Itil. I wanted to start with some basic questions about how you got interested in medicine in Turkey and what the state of the field was at the time you entered the medical profession?
TI: I originally wanted to be an engineer, but I could not pass the entrance examination for the school in spite of being an honor student in high school. I could enter medical school without any examination.
AT: It was easier, at that time in Turkey, to get into medicine?
TI: Exactly. I went to medical school with the understanding I would go back a year later to engineering. But in that year my father died so I stayed in medical school.
AT: What interested you among the different specialties?
TI: I was always much more interested in the scientific aspects of medicine.
AT: Did you know when you entered medical school that you would focus on neurology and psychiatry?
TI: No, when I finished medical school I wanted to be a surgeon. But that was not possible in Turkey.
TI: We didn’t have a neurosurgery department in 1949.
AT: So, you picked psychiatry as a second choice. Why?
TI: I was accepted in neurology and psychiatry at the University of Tűbingen. The professor was Emil Kretschmer whose name I knew. I had read two of his books, one on Medical Psychology, and the other on Body Type and Character, and I liked both very much.
AT: That’s an interesting way to get into the field. What was “in vogue” in psychiatry at the time?
TI: Psychiatry was very much influenced by Freud. Binswanger was also influential. But Kretschmer was the father of biological psychiatry.
AT: Tell me about your first experiences in psychiatry at Tűbingen?
TI: At the time I arrived in Tűbingen the hospital had a big floor with lots of bath tubs, and patients caught up by nets treated by sitting in warm water in the tubs. People were screaming and crying and the best treatment for that was thought to be cold water up to the neck. They were also given barbiturates so they either slept or were awake screaming and yelling. Then, suddenly, chemical treatments arrived and the wards changed; the doors were opened.
AT: You’ve been doing work with electroencephalography for a long time. Tell us how you got interested in that. Did it have anything to do with your desire to be an electrical engineer?
TI: Maybe, but only in part. I moved from the University of Tűbingen to the University of Erlangen in Germany, and we used to gets lots of patients with phantom pain.
AT: Were these amputees from the war?
TI: There were lots of amputees from the war but also others. The French published a paper at the time which suggested that a new drug, promethazine, could relieve phantom pain. My professor, whose name was Flűgel, said we should study this new drug in our patients. In some patients it worked whereas in others it did not, and I couldn’t understand why. One of my professors said it could be because in some patients promethazine didn’t get to the brain. That made sense so I asked how to find out. First I was told you can’t do that but then, the professor’s chief assistant told me, “Somebody in the twenties wrote a publication that the electroencephalogram shows whether a chemical has an effect on the brain or not”. So, I looked and there were lots of publications in German. I was very impressed and could not understand why people didn’t use electroencephalography for that purpose. I went to our EEG department and was told you can’t show whether the drug goes to the brain or not. They didn’t believe in Hans Berger’s findings. So, I learned how to do and evaluate an EEG and saw the effects of the drug myself. I started to do more and more and around 1957, I took all my EEG records and went from one professor to the next, asking for advice how to proceed. I was told that in order to be scientifically acceptable my findings needed to be replicable and to show predictability. Others told me if I quantified the EEG it would render my findings replicable and predictable. So I didn’t know what to do.
AT: I see. What happened next?
TI: In 1958, at the first CINP meeting in Rome, I gave a talk and Max Fink gave a paper in the same symposium. We were both tremendously enthusiastic, because both of us reported the same effects of chlorpromazine on the EEG. This united us and we became friends. He said, “We will start quantitative EEG studies in the United States; come and we will do it together”. Professorship in Europe is not awarded as in America. You have to pass lots of examinations, write a thesis and do all kinds of other things, and I was in the middle of all that. So I said, “I would like to come, but I can’t right now”. It took me five years to get to the United States but once I finished my examinations I came. When I first asked my professor for a one year sabbatical to work with Max he was at Hillside Hospital on Long Island. But, at the beginning of 1962, he wrote to say he’d moved to St. Louis to be in charge of a Research Institute with a computer and all the new technology. So, in 1964, I went to Missouri for one year and that one year extended to many more.
AT: Max is very persuasive!
TI: Very persuasive, but I wanted to go anyhow, that was the goal.
AT: Let me ask you something. There’s a lot of emphasis on MRI scans and how you can look at the brain of someone with schizophrenia and recognize it is completely different from a normal patient. One of Max’s pet peeves is that this kind of brain mapping is being celebrated as brand new but he talks about the work the two of you did and the central importance of the electroencephalogram as a technique that was going on decades earlier. Why has this technology that you pioneered fallen by the wayside while brain imaging via MRI’s seems to be sexy and is being presented as brand new, when what you were doing was revolutionary?
TI: As a Harvard professor put it, some of the new technologies have advantages to the old ones. The electroencephalogram was discovered in 1920, long before computers, by a psychiatrist who didn’t understand technology. You know why he discovered the EEG?
TI: In his biography, he wrote that he had one daughter and one son. The son went from Magdeburg to Duisburg with his friends and a couple of days later his daughter came to see him at the hospital. He thought, that’s very unusual, because his daughter never come to the hospital. She asked, “Did you hear from my brother”? When Berger answered, “No, why”? she said, “Please send this cablegram, something’s happened to him.” So, Berger asked, “What is it”? And she replied, “I have a feeling something happened to him”. The father sent the cablegram and the son responded, “Everything’s alright”. When the son came home he asked his father, “Why did you send this cablegram? It’s unusual”. The father told him, “Because your sister asked me”. The son said, “She was right. I was with friends on a winding road and, suddenly, we heard a horrible noise and saw a big water vehicle with horses and carts coming towards us and we were scared. But how in the world did my sister have this kind of feeling”. Then, Berger writes, “I always thought that the brain may produce some electrical activity, that it has a certain kind of synchronized activity. My daughter and son, because of their love for each other, synchronized their brain activity. Because Berger thought electrical activity travelled through the air he discovered the electroencephalogram. That kind of discovery seems absolutely crazy. What neuroscientist would accept this sort of reasoning?
AT: But so much of the history of science and technology comes about in this way.
TI: Yes, but many of them aren’t accepted. What Dr. Berger wrote, nobody remembers any more; what people do remember is that he found when patients have epileptic seizures, they have atypical brain waves. Even today, we don’t have of any other method to determine this. So the EEG is good for epilepsy. It’s true that the EEG once in a while shows a brain tumor, but it is not a good method for detecting brain tumors. It is a method for detection of physiological changes. What Berger was really interested in was the relationship between the changes in electrical activity and what is going on in the mind. The detection of epileptic activity was a by-product. He didn’t care so much about detection and localization of tumors. He was interested in what goes on in the brain of patients with schizophrenia. He saw the effects of mescaline, barbiturates, and cocaine. His interests were more in relating changes in electrical activity to the soul and not to tumors. Because, at that time, the only tool for neurologists to determine substantial change in brain was the EEG it became a method for tumor detection. And for that it did not fulfill expectations. The angiogram and the pneumoencephalogram were much better, even before the CAT scan and MRI were introduced. So neurologists didn’t like it when Max and I computerized the electroencephalograph, and developed quantitative EEG; it was not a tool to diagnose tumor but to describe cerebral process. It’s a functional tool. Another problem was that no major company became interested in our computerized EEG.
AT: I see the problems you encountered.
TI: Another problem is that, after all these years, we still don’t know what is behind the electrical waves. What is the scientific basis to the chemical process of the brain, the relationship between electrical processes to changes in the dopaminergic or adrenergic system, etc? Fortunately we could relate the electrical changes to behavior.
AT: Before you and Max developed quantitative EEG you studied the effect of several drugs. Could you tell us something about your early research?
TI: I mentioned already my interest in promethazine. I wanted to know why some patients with phantom pain improved and others did not. Then, as I mentioned, I studied chlorpromazine. I was a Turkish citizen and I couldn’t get a salaried job in Germany, so Bayer gave a stipend to the University and I was paid from that to study EEG changes with compounds they developed. The goal was to find another chlorpromazine-like substance on which patients would not be slowed down and sedated. We screened dozens of compounds and eventually found one that was more powerful than chlorpromazine. It was butaperazine, eventually marketed in Europe.
AT: Was it marketed in America?
TI: No, because it also produced more side effects. In this country, everybody is more conscious about side effects than in Europe. After I moved to the United States we started computerized quantifications of the EEG and when Max and I started to publish the drug companies became interested and asked whether we could differentiate between antipsychotics, antidepressants and anxiolytics. I discovered the antidepressant effect of mianserin by quantitative EEG.
AT: How did that happen?
TI: Organon went to Max who was by that time in New York with a potential psychotropic substance and Max sent them to me in Missouri. I found it showed a similar profile to amitriptyline. To celebrate the discovery Max gave a party at his house in Long Island and invited me from St. Louis. At the party there was a lady, Mrs. Summer, an intellectual property lawyer. Max introduced us and suggested I tell her the mianserin story. She convinced me that I could obtain a patent for the drug. In the meantime, the Organon people asked me to go to Europe and I went with Marty Katz, who was a big shot at that time at NIMH. The first time I met the pharmaceutical company boss, he asked, “Do you really think mianserin has antidepressant effects/”. I said, “I think so” but in the meantime, I gave the drug to a former professor of mine in Turkey who gave it to 10 or 15 patients and thought it was a very good drug because it didn’t produce dry mouth and constipation and was effective without the side effects of tricyclics. At another clinic the drug was given to 25 or 30 patients and it looked like it had antidepressant effects. I showed these findings to the boss at Organon who recognized I had discovered the antidepressant effect of mianserin, and asked “What do you want”? I replied, “I just want appreciation, that’s all”. That was the first time in history that the antidepressant property of a drug was discovered by quantitative EEG.
AT: You were trained in Europe and started psychoharmacology there. What were the key differences between psychopharmacology there and here at the time you arrived in America?
TI: In Europe we were much more interested in psychopathology. Psychopharmacology started in Europe, and was relatively late coming to the United States where it entered a heavily analytically oriented environment in practice and academia. Even in Europe, if you were a psychopharmacologist, you couldn’t get a Chair in Psychiatry in the 1960's. In Germany there were nineteen Chairs, but only my Chairman, Professor Flűgel, was involved in neuropsychopharmacology. In Europe I used to put on my white coat when I saw patients and when I did that in Missouri the nurses complained that one should not upset the patients.
AT: By wearing a white coat?
TI: By wearing a white coat. Gradually, in the middle of sixties, changes began. It is fantastic what has occurred in the last twenty years, in neuroscience. But at the clinical level, I think we neglected our job. For example we give too high doses of medication. I started three of my patients on ten milligrams of amitriptyline twice a day. No doctor trained in America will give ten milligrams.
AT: That’s a very small dose.
TI: A very small dose. I have an obsessive compulsive patient who gets stimulated and becomes very nervous even given just one dose of fluvoxamine (Luvox). Medications should be titrated, starting with a low dose. There are all kinds of publications that it takes three weeks before the onset of antidepressant effects. That’s not true. We see the effects of an antidepressant on the brain, within three hours, very significant effects and cumulative effects within a week. Marty Katz and his group have done beautiful studies showing this. I don’t know whether you read their studies showing effects start in one week. That has a significant impact on the economy of treatment. Any patient that receives an antidepressant will tell you they are affected within three days. As a matter of fact, if the drug doesn’t have some effect by the second or third day it probably will not help. I have worked for fifteen years with treatment resistant schizophrenic patients and we realized that after long term treatment with neuroleptics their EEG patterns have changed. We don’t know what this pattern change means but we know that these patients become resistant to neuroleptics. We know that this has changed and possibly their receptors are blocked and don’t respond. If such patients are given five thousand milligrams of chlorpromazine it’s a complete waste of money.
AT: Leo Hollister said, before he died, that one of the problems in psychiatry is that you have people suffering from schizophrenia or depression and the drugs we have today are no better in dealing with illnesses than they were at the time psychopharmacology began. It seems that one of the things you’re suggesting is that it’s not necessarily that the drugs don’t work, but we don’t administer them properly?
TI: Exactly. I agree, partly, with Leo, but I believe even more that we don’t do a good job. We shouldn’t be satisfied, because none of the antipsychotics cure the illness. With antidepressants there is some improvement but not enough. They have a wonderful effect, a stimulant effect, a well being effect, almost like cocaine, but depression is still there. All of the antianxiety drugs produce, eventually, addiction if you look carefully. My best story is a patient taking an antidepressant with pretty good effects but not good enough, and I asked, “What do you need”? He replied “I don’t have money, and whatever you do I want to improve”. So, I said, “Why don’t you go to the gym and exercise till you are physically exhausted”? Six months later, he wrote me a letter and said, “My uncle in Oklahoma has an old mine so I went there and started to work, physically, as you said. I did this every day, and got exhausted until I hit silver. Now I’m, making money, I’m happy and I don’t need any chemical”.
AT: How come when we go to conferences we don’t hear that? I think I know the answer, but I want to hear what you have to say. We go to conferences like the ACNP and the CINP but in ine of these conferences are panels devoted to a drug vs. the treadmill. It’s all about this pill, that pill and another pill.
TI: Because these meetings don’t even accept clinicians any longer. You have to make a significant scientific contribution to get accepted.
AT: Is that true? I didn’t know that.
TI: People, to be accepted, have to have publications and a reputation and how can a clinician in the battlefield get the necessary reputation? They say those who don’t have it should be with the American Psychiatric Association, the Psychological Association, etc. I disagree with that.
AT: I interviewed Malcolm Lader in Paris this summer and he said one of the problems with the way programs at scientific meetings get structured is that people only attend if their way is completely paid. They usually got the money from one or another drug company. If they participate in the program usually, that person will be encouraged to mention some of the drugs these companies produce. Malcolm’s point is that, there’s no true intellectual integrity, where the truth can surface, if everyone talking science is in the pockets of the pharmaceutical industry.
TI: The ACNP was the most resistant society to the impact of the pharmacological industry.
AT: The most resistant?
TI: Until ten or fifteen years ago. It went for thirty or forty years without too much influence by outside forces. In the last ten or fifteen years, unfortunately, that’s not the case any longer. Once they dissolved the Psychopharmacology Branch of the NIMH many people didn’t get grants and became dependent on somebody outside the government to pay. When the Early Clinical Drug Evaluation (ECDEU) program was dissolved investigators became dependent completely on drug companies.
AT: Do you think patients are adversely affected?
TI: Not because of changes in the society.
AT: Looking back at your career what would you say have been the key contributions you’ve made?
TI: The detection of the effect of oral psychotropic drugs on the brain and the identification of differential profiles of drugs with different clinical effects such as antipsychotic or antidepressant. I discovered antidepressant properties of three drugs and patented them. First, I discovered the antidepressant effects of mianserin, as I told you. Then, I showed that the EEG effects of mesterolone, a synthetic androgen preparation, are similar to imipramine. We have done a big double blind study in a depressed population and shown that, indeed, it’s an antidepressant. A German company was very enthusiastic about it but since testosterone may produce prostate cancer the substance was not pursued further. In females it is known that estrogen helps menopausal depression and I showed that the conjugated estrogen, estradiol valerate, produces similar effects on the brain as antidepressants. .
AT: Do you think there will be a market for those things? I see testosterone patches and gels being advertised to men at doctor’s office in the United States for loss of libido?
TI: Gradually, it’s coming. It will be marketed after my patent expires. The fact that brain electrical activity produces such information is probably the most important contribution, which is not accepted.
AT: So, those are your contributions, discovering the drugs and the fact we have this technique to monitor the functioning of the brain.
TI: What I have also found, but haven’t published yet, is that with a certain type of quantification of the electroencephalogram, we can show a significant difference between Alzheimer’s patients and age-matched controls. We are initiating that as part of a diagnostic procedure. When we are young, in general and on average, we have sixty percent of activity in our brain in the occipital area, and then by the time we are sixty that declines to forty percent. When we are sixty or above and also demented, that declines to twenty percent. And, when we have advanced Alzheimer’s, it declines to ten or even five percent. That’s a significant decline due to age and dementia. Every effective cognitive activator with an effect in Alzheimer’s, produces an increase of occipital-α, so it reverses the decline. That kind of reversal I also discovered in schizophrenia with effective antipsychotic drugs. Every effective drug decreases the fast-β-activity in the EEG.
AT: That’s really interesting. What do you think of ECT?
TI: I think ECT is a wonderful, very effective treatment in certain patients and certain conditions, like certain catatonic stupors and some depressed patients. The problem that my friend Max Fink would never accept is that we don’t know what happens in the brain when we give ECT.
AT: We don’t know?
TI: We don’t and clinicians don’t want to know. They should do, at least, an EEG and memory tests before and after ECT, but they don’t. There are many publications that memory declines and there are psychological, behavioral and certainly cognitive changes.
AT: In your bibliography you have an article, Looking at the Electrical Activity of Lobotomized Brain and Non-Lobotomized Brain.
TI: Lobotomy was wonderful for certain types of patient. Aggressive patients who were killing people and could not be controlled by any means were not aggressive after lobotomy and became a different person. My brother had a very aggressive cat and one day a car hit the cat. The cat survived and now it is completely tame. So, lobotomy is wonderful for certain types of patients and you need to realize the consequences. Do you know that now in our hospitals chronic schizophrenic patients probably have the equivalent of a lobotomy?
AT: I didn’t know that. How is that so?
TI: By using high dosages of medication.
AT: I see. Max Fink and I have talked about people who resist ECT because it seems like a much more invasive violent procedure than prescribing drugs, which we think of as very benign, like taking a vitamin. It’s almost as if we’re programmed not to think about the impact of ECT and of these drugs on the brain. It’s a huge cultural problem.
TI: The fact remains that we have very invasive procedures which give good results, but without knowing what will happen in the years to come. There is the famous saying, father had a very successful operation, but, now, he doesn’t look like my father.
AT: Why do you think proponents of ECT are reluctant to figure out what’s happening to the brain? You are saying they don’t want to know because they’re scared to find out.
TI: Sure, the same thing is happening with anesthesiologists. We tried to convince anesthesiologists to take quantitative EEG measurements because there is a possibility of damage that can be reversed. The brain should be examined before anesthesia. I had a very simple operation, but just before the anesthesia, I said to the doctor, “You checked everything in my body, but not my brain”. He was shocked and asked, “What do you mean? We did a physical and a neurological exam”. I replied, “I know you did the neurological examination, but you really didn’t check out my brain”. He was shocked and angry.
AT: How expensive is it to do an EEG?
TI: You can have a twenty-five dollar EEG.
AT: So, there’s really no excuse not to use it, except that it takes extra time.
TI: And that people would say let me find out first what those findings with the EEG mean.
TI: The same happened when the electron microscope was invented; people asked why spend so much money to see much smaller objects than bacteria. Why do we need to see more? The answer is you want to see more, because eventually we will find something.
AT: So you think that if people keep doing it, it will eventually tell us something. When your students do these studies, what do they find?
TI: We are trying to use quantitative EEG for early detection of psychiatric disease because by the time you can use an MRI is too late. If there is already atrophy you will not be able to treat it effectively. We still have the problem of saying what a normal brain is. We get norms by analyzing our data base but the spectrum is wide. The best solution to overcome this problem is to have information on the brain from early on, as we have on the heart. You do check-ups from year to year and it’s very cheap in the sense that if you treat those illnesses early, you have much more success than if you treat them later.
AT: Let me ask you a couple more questions to fill in some of the information we have not covered. Who have your key mentors been?
TI: I made a big mistake, I didn’t have a mentor. When I moved from Erlangen to St.Louis I was too old to have Max as a mentor and he was more involved with administration than the laboratory. In Germany I published many papers with somebody named Bente and he was the first author because his name began with B. Unfortunately, I didn’t have a reputable mentor and I think Max probably had the same problem.
AT: He did.
TI: What we were trying to do was far ahead of our time. I think it still is.
AT: Do you have any regrets about the way your career developed?
TI: I’m really happy. I’m lucky I wasn’t killed because I deviated from the norm.
AT: Metaphorically, of course! Where do you see the profession headed? What do you think it’s going to be like fifty years from now?
TI: I think neuroscience will make it possible to understand things better by finding a pattern for certain psychiatric illnesses. If you have drugs, of which one has anticholinergic, another serotonergic and a third, noradrenergic activity but all show the same pattern on brain electrical activity, those biochemical differences have nothing to do with the effect of the drug on depression. When you live as long as I have, you know that every ten years we have another hypothesis for depression. In my lifetime, we had four different hypotheses and, obviously, none of them is true. Every one of them had a little bit of truth. Placebo is a wonderful drug; it has an effect in psychosis in about thirty percent of patients, in anxiety, fifty percent, and in depression, forty percent. It’s a wonderful drug. We don’t know the real cause of any psychiatric illness and therefore we don’t have a real treatment for any of them. Neuroscience will eventually help to find the cause. Fifty years or, hopefully, thirty years from now, neuroscience will have found something. In the meantime patients still need the kinds of treatments, psychological and pharmacological that we have.
AT: Can you think of anything else you would like to add?
TI: I’m setting up Alzheimer’s centers for early diagnosis in the underprivileged population. These are people who don’t have a job and don’t work. They don’t have relatives or friends to bring them to the doctor. In Harlem, we have the beginning of an epidemic of Alzheimer’s.
AT: That’s interesting.
TI: It’s very difficult because nobody cares and the system discourages you from offering those people better health. You cannot send a car to bring them to the center, because that is, according to Medicare, illegal. But, if you don’t do it, nobody comes. In thirty to forty years we will have ten to fifteen million people who will need twenty-four hour a day care. That’s a big, big problem. So, that’s why I’m starting these centers now.
AT: Any other work you want to mention?
TI: We studied the children of schizophrenic parents in Denmark. Mednick and Schulsinger started the study and I was involved with the electrophysiological part We published two articles in the American Psychiatric Association Journal, suggesting that a certain group of children would become schizophrenic; we predicted it in a sealed envelope. That study was supported by NIMH and WHO. I have also done the largest study on terrorists.
AT: Really, what did that involve?
TI: It involved 2,500 terrorists who were caught and convicted, because they either killed somebody or were at a killing scene.
AT: What did you find out?
TI: They were not compulsive, they were not neurotic and they were not sexually disturbed. They were normal, but had very low intelligence, far lower than the control population. Those killers were specifically profiled by the leadership of Turkey. They were nice kids, not too smart and not uncontrolled. They obtained marijuana first and then a gun. My results helped to control terrorism in Turkey.
AT: That’s great. You must have saved lots of innocent people. Maybe you’re not allowed to say this, but have you been approached by federal authorities in the United States to profile terrorists here?
TI: I’ve been approached, many times. But to finish the story in Turkey; I had an office in the research center there and a terrorist’s bomb killed almost everybody there. They were looking for me and couldn’t find me, but still they bombed the center.
AT: Did you worry about your safety after that?
AT: I don’t think I’d sleep again if that happened to me. Is there anything else you would like to add?
TI: I would like to say that the best drugs were discovered in psychiatry by accident and that looking at the effect of a substance on the electrical activity of the brain is the simplest method for identifying the potential therapeutic profile of a drug. We now have some data which indicate that the doses in which psychotropic drugs are used are counter-productive for achieving therapeutic effects.
AT: How long will it take to get those data published?
TI: Another ten years.
AT: I would like to interview you again in ten years time. Thank you very much. I really enjoyed this.
TI: I enjoyed it too. I’m free now, right?
AT: You sound like you’re in the electric chair! You’re free!