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Monday, 28.09.2020

In Celebration of George Gardos (1938 – 2019) by Thomas A. Ban

 

        On September 28, 2019, George Gardos, a distinguished psychiatrist and psychopharmacologist, passed away.

        Born and raised in Budapest, George began his medical studies in 1956 at the Medical (Semmelweis) University of Budapest but moved to England after the suppression of the Hungarian uprising in the same year. He completed his medical education at St. Bartholomew’s Hospital in London in 1962. Subsequently, he spent two years in Zimbabwe as assistant to a neurosurgeon. It was in Rhodesia in1964 that he published his first paper in the Central African Medical Journal on two cases of subdural hemorrhage complicating anti-coagulant treatment (Blackwell 2011).

        To obtain a master’s degree in psychology, George moved to the United States in the mid-1960s. While still working on his thesis, “on the plasticity of the nervous system in response to deflected auditory stimuli,” he became a research associate at the Massachusetts Mental Health Center (MMHC).  It was at the MMHC, in the late 1960s, that he noted that treatment with benzodiazepines might increase anxiety and published paper with his supervisors in 19968  on  the differential action of chlordiazepoxide and oxazepam on “hostility” in the prestigious  Archives of General Psychiatry (Gardos, Di Masci, Salzman and Shader 1968).

        By the end of the 1960s Dr. Gardos completed his residency training in psychiatry at the Boston State and Beth Israel Hospitals (1969) and joined the staff of Boston State Hospital where he became involved with the social adjustment and family care of discharged patients (Blackwell 2011). Then, in the early 1970s, in collaboration with Jonathan Cole, Medical Superintendent of the Hospital at the time, he studied dose-effect relationships with neuroleptic drugs. It was in the course of this research that he recognized the “dual action of thiothixene” (different in low from high doses) and published a paper coauthored by Cole (Gardos and Cole 1984).

        It was in the mid-1970s that George became in interested in the neurological side effects of neuroleptics, focusing on “late” effects in the course of chronic administration, and found an interaction between drug and disease-related factors in the pathogenesis of  tardive dyskinesia (TD) (Ban 2011b; Gardos, Cole and LaBrie 1977). 

        In the years that followed, TD has become the central theme of Dr. Gardos’ research. As the Principal Investigator of a National Institute of Mental Health-supported study he followed with his collaborators 200 patients with TD over a period of 15 years.  One third of his 44 original reports and two thirds of more than 110 publications are on various aspects of TD including measurement, severity, etiology, natural history, treatment and long-term outcome. As an expert on TD, he was consultant to the American Psychiatric Association’s Task Force on TD and co-editor of two books on the topic (Ban 2011b; Blackwell 2011; Gardos, Casey, Perenyi et al. 1984, 1994; Gardos and Cole 1984)

        From the late 1970s George was in private practice with a part-time position for some time at McLean Hospital. In 1994 he was appointed Associate Clinical Professor in the Department of Psychiatry, Harvard Medical School. Throughout the years he was a member of the International College of Neuro-Psychopharmacology and the American College of Neuropsychopharmacology (ACNP) (Blackwell 2011).

        George was interviewed by me for ACNP’s Oral History Series at the annual meeting of the College in San Juan, Puerto Rico, on December 9, 2003. The edited version of the interview was published in Volume Four, Psychopharmacology, of the series  (Ban 2011a; Levine 2011).

 

The Interview

TB: This will be an interview with Dr. George Gardos for the archives of the American College of Neuropsychopharmacology.  It is December 9, 1993.  We are at the annual meeting at the college in San Juan, Puerto Rico.  I am Thomas Ban.  Let us just start from the very beginning: where and when were you born? Say something about your background and so on.

GG: Thank you very much for asking me to do this.  It is sort of a celebration.  It reminds me of a few months ago, my father-in-law invited a lot of people to unveil his tombstone in the cemetery and he brought champagne, and everyone drank to the event. It’s very nice that I can do this while I’m still around here and working.  Let me say a few things about myself.

I was born in Hungary in 1938 and managed to get through the war. I stayed in Hungary and completed my high school and just when that happened, the 1956 revolution occurred.  That gave a window of opportunity to people who were shackled by the communist system to get out.  So even though I started medical school in 1956, together with another quarter million or so Hungarians I managed to get out to the West.  I ended up in London, England where I had family.  That is where I went to medical school at St. Bartholomew’s Hospital, which is part of the University of London and where I got my medical degree in 1962.  Interestingly, while in medical school I had practically no exposure to psychiatry, which was a deficiency of the English system then and probably of medical curricula elsewhere in those years. I recall walking up to the common room in the hospital where I would relax and play cards, to pass a lab of a Dr. Michael Pare. It was several years later I discovered he was doing pioneering work with MAO inhibitors.  The other funny memory I have is that there was a pharmacology exam I would have done well on if, in the oral exam, I hadn’t been asked whether I’d heard of chlorpromazine. I had absolutely no idea what it was for. The examiner explained it to me and I nodded wisely. Then, I forgot all about it! 

After I graduated from med school, I spent a year in Rhodesia trying to figure out which way I was going.  I was the assistant to a neurosurgeon, Lawrence Levy, there. He was the first important influence on my research career.  He was busy with his practice, but he was also interested in doing research, some animal experiments. So, he encouraged me to make clinical observations and follow them up. My first paper was published while I was still in Rhodesia, which is now called Zimbabwe.  It had to do with two cases of subdural hematoma resulting from anticoagulant therapy. My chief encouraged me to write it up and helped me with it. So, it got published in the Central African Journal of Medicine. That taught me the importance of making clinical observations and, if they were of value, to communicate them in a publication.   I also learned in Rhodesia that I was not cut out for surgery.  From Rhodesia I came to the United States as a graduate student in psychology.  I had an interest in mental health and ended up in psychiatry through the back door.  As a graduate student in experimental psychology I got my master’s degree.

TB: What was your master’s thesis on?

GG:  My thesis dealt with ability to rearrange the auditory environment. The subjects in my experiments were wearing “artificial ears” which deflected the direction of sound so that it appeared to be coming from the side, creating a conflict in determining where the sound came from.  It was a way of studying plasticity in the nervous system. 

TB: When was this?

GG: This was in 1965 and unfortunately my student visa was about to expire. So, I was headed back to England, but before leaving I took a trip to the West Coast to look around. On returning from the West Coast, just before starting to pack, I found out about a job opportunity for a research associate at the Massachusetts Mental Health Center with Al DiMascio.  He was the next major influence in my career. He interviewed me and we hit it off well. He helped me change my visa so I could stay and start to work in his lab at the Massachusetts Mental Health Center.

TB: Could you say something about the Massachusetts Mental Health Center in the mid-1960s?

GG: The Massachusetts Mental Health Center in 1965 was a vibrant, very exciting place, but also a place in turmoil because on one side of the building were the wards where the psychiatrists were in charge and anything but psychotherapy was frowned upon, and on the other side of the building were the laboratories were exciting research took place.  Some of the psychoanalysts on the clinical side were true believers. The research lab was run by Dick Shader and Al DiMascio and had young energetic psychiatrists like Carl Salzman and Roger Meyer. They did exciting work. I got involved in trials with benzodiazepines in symptomatic volunteers. I did a study comparing oxazepam and chlordiazepoxide in symptomatic volunteers, studying the effect of the drugs on hostility and finding a paradoxical effect. Subjects given chlordiazepoxide showed increased hostility whereas subjects given oxazepam did not.  Al DiMascio was my first mentor.  He was incredibly energetic, bright, and likable. He was also a true believer in the future of psychopharmacology.  In some ways he was very much ahead of his time.  He had a computer already and was learning to analyze data because he knew that computers were going to be the thing in the future.   

It didn’t take me long to realize that without a valid medical degree in the USA, I had only limited options so I decided to take the plunge and started my residency at the  Boston State Hospital where Milton Greenblatt had just initiated a number of pioneering community programs which started to empty the wards.  It didn’t take me long to realize that psychopharmacology was the future. Psychotherapy for schizophrenics didn’t seem to do much. So, I thought I would need to learn more about psychopharmacology and using medications. 

TB: So, you had your residency in psychiatry at the Boston Sate Hospital?

GG: I went to the Beth Israel Hospital in my third year for more traditional training. It was useful because at Beth Israel I got exposed to more verbal and educated patients than at Boston State.  After Beth Israel I returned to Boston State and stayed for the next 8 years.  My main reason for staying was the arrival of Jonathan Cole who took over as superintendent of the Hospital from Greenblatt and created a very exciting atmosphere. He did the same there as he did on the national level as head of the Psychopharmacology Service Center of the NIMH; he attracted people with interesting ideas and helped everyone to do research, to get funding and he supervised them. He attracted a number of researchers and I worked with quite a few.  Eventually there was a plan for a research institute to be built there.  

TB: Could you say something about your research?

GG:  I started under Jonathan Cole’s mentorship and I did a number of studies with antipsychotics.  I was interested in optimizing the use of psychotropic drugs and especially of antipsychotics. I did some studies to assess dose - effect relationships; I felt the dosage variable was not sufficiently appreciated and found that in low doses some drugs had completely different effects from high doses.  I noticed that small doses of neuroleptics could be used for conditions other than psychosis, such as anxiety and depression. I did a study on thiothixene and found that in low dose it had some antidepressant effect with improvement in mood and energy.  We used scales like the BPRS for measuring changes, as well as outcomes like participation in rehab programs and found that patients on low doses were more likely to participate. I studied new drugs developed for the treatment of anxiety. I did a pilot study with propranolol in high doses in schizophrenia and found that the substance was not safe to administer. I did an intriguing study on a medication called Thorastal, which was a combination of Thorazine (chlorpromazine) and Stelazine (trifluoperazine). This was a comparison study with the components of the combination and our findings did not even show a difference in sedation between the single drugs and the combination, which clinically did not make any sense. But findings in research studies do not always jive with what one sees in the clinic. Boston State in the 1970s was an exciting place, and some of our studies were directed at assessing how discharged patients fared.  I did some work with family care patients and studied their social adjustment. 

TB: Any other research projects you would like to talk about?

GG: We did a study way back at Boston State on clozapine. We had positive findings, but we didn’t see anything dramatic. Jonathan Cole went over to McLean Hospital from Boston State in the late 1970s. I joined him and stayed with him for years while I continued my work part-time at Boston State.  Jonathan Cole, besides being an eminent researcher, was also a superb clinician.  He had tremendous communication skills.  In the late 1970s when the literature was somewhat dogmatic with respect to monotherapy, I saw Jonathan’s patients walking out of his office with three or four prescriptions and they did well.  The major research program I was involved in at McLean was our tardive dyskinesia (TD) study.  It involved close to 200 patients who developed TD. We followed them for up to 15 years.  This enabled us to get data on epidemiology, risks factors, course and treatments. To summarize our findings, we came to the conclusion that tardive dyskinesia really was not as malignant as usually perceived. After five or ten years, patients managed well and got better rather than worse. The situation about TD changed radically with the arrival of the atypical antipsychotics in the mid 1990s, of which clozapine was the first and remains the gold standard.

TB: Would you like to comment on you experience with atypical antipsychotics?

GG: There are still major questions about the efficacy of atypicals. They don’t seem to be as effective in the office as one would like to see.  I combine them with more potent dopamine- D2 blockers to get a better response.

TB: Could you tell us something about some of your other projects in TD? 

GG: I had done a long-term follow-up study with Daniel Casey in Hungary where TD seemed to be less prevalent than here. This was an interesting study. I became impressed with the particular clinic where it was done because they used a great deal of drug combinations.  They didn’t seem to be more or less effective than monotherapy. The clinical findings with antipsychotics were comparable in Hungary and the USA.

TB: When did you start your private practice? 

GG: I started private practice on a part-time basis in the 1980s and I am still seeing many of my old patients. It is interesting to age with them. I have patients I have followed for 25 or 30 years. 

TB: Is there anything else you would like to add about you research or research in psychopharmacology in general?

GG: I am in some ways a dinosaur by insisting on clinical science.  In terms of my practice, I think the appearance of Prozac (fluoxetine) was a watershed.  It made my practice with drugs almost 50% easier overnight. I had the wonderful feeling I could now give a medication to a patient and I didn’t have to worry about getting called about side effects at night. Most of my patients for whom I prescribed the substance got better and liked to stay on the drug. Most patients today come with a drug history and that of course dictates the choice of drug to be used in treatment. Most psychiatric diseases are chronic and they are controlled but not cured with drugs.

TB: When were you elected a member of ACNP?

GG: In 1987. I am honored to be a member of ACNP and I look forward attending the Annual Meetings. I think this organization has done tremendous work for science and patients. 

TB: Thank you, George.

GG: Thank you, Tom, very much.

 

References:

Ban TA., editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Brentwood: American College of Neuropsychopharmacology; 2011a.

Ban TA. Preface. In Levine J, editor. Psychopharmacology. In: Ban TA. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume Four. Brentwood: American College of Neuropsychopharmacology; 2011, pp ix- xxix.

Blackwell BB.  Dramatis Personae. In: Levine, J, editor. Psychopharmacology. Volume Four in Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Brentwood: American College of Neuropsychopharmacology; 2011, pp. xlii -xcu.

Gardos G, Casey DE, Perenyi A, Cole JO, Kocsis E, Arato M, Conley C, Samson J. Ten-year follow-up study of tardive dyskinesia and drug-induced Parkinsonism. Psychiatria Hungarica 1994; 9:137-45. 

Gardos G, Cole JO. Tardive dyskinesia and affective disorder. In:  Gardos G, Casey DE, editors. Tardive Dyskinesia and Affective Disorders. Washington: American Psychiatric Press; 1984. p. 69-80.

Gardos G, Cole JO, La Brie RA. Drug variables in the etiology of tardive dyskinesia. Progress in Neuro-Psychopharmacology & Biological Psychiatry 1977; 1:147-54.

Gardos G, DiMascio A, Salzman K, Shader R. Differential actions of chlordiazepoxide and oxazepam on hostility. Arch Gen Psychiatry. 1968; 18(6):757-60.

Levine J, editor. Psychopharmacology. In: Ban TA, editor. An Oral History of Neuropsychopharmacology. The First Fifty Years. Peer Interviews. Volume Four. Brentwood: American College of Neuropsychopharmacology: 2011.

 

February 20, 2020