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Tuesday, 20.08.2019

In Memoriam
Ervin Varga (1925-2018)
by
Joseph Knoll

 

            Ervin Varga was born in Budapest, Hungary, in 1925 and died in Chicago, Ill., USA, in 2018. He was one of the internationally best known Hungarian psychiatrics of the post-World War II generation.

            Both Ervin and I were survivors of the Holocaust. Ervin’s family lost 40 members and the Knoll family lost nearly 50 members in the Holocaust. That this took place illustrates that a system promoted by hatred makes the society insane and anything and everything can happen. There was a resurgence of political anti-Semitism in our country, Hungary, when the Horthy era began in 1920. Miklos Horthy’s Hungary was the first country in Europe to codify the infamous Numerus Clausus Laws, which set quotas for the number of Jewish students in universities. This was the first step in mid-Europe in that long chain of deprivation of civil and human rights which culminated finally in the Holocaust. It is enough to illustrate the circumstances in Hungary, mentioning that the authorized leaders trebled the number of victims selected for the Auschwitz death camp, as requested by Hitler’s regime.

            Ervin Varga was my schoolmate. We were born in 1925 in Hungary. Both of us wanted to be physicians, however, in 1943 we were refused entry to the university, thus, we lost two years and received our MD degree in 1951. We both matriculated in the University of Medicine in Budapest (now Semmelweis University), where I obtained my MD. Ervin, however, continued and finished his studies in the eldest Hungarian University in Pecs and there received his MD. After getting his diploma in Pecs, Ervin returned to Budapest and started working in the Department of Neurology and Psychiatry came back immediately to Budapest and started working in the Department of Psychiatry of the Semmelweis University..

            Beginning in February 1949, I worked in the Hungarian Department of Pharmacology as a medical student, having been invited by the Head of the Department, Professor Bela Issekutz.  When I received my diploma in 1951, I had already worked in my own laboratory and continued my behavioral research. In the late 1950s I faced a problem which compelled me to start a structure-activity-relationship study which led to the development of the still world-wide used drug: selegiline/(-)-deprenyl (DEP). The DEP-story made my collaboration with Ervin imperative.

            In my behavioral research I used amphetamine and/or methamphetamine to stimulate the catecholaminergic neurons. My problem with the amphetamines was that as soon as the dose surpassed the 1-2 mg/kg level, the drug-induced, continuous, irresistible release of catecholamines from their intraneuronal stores in the brain stem neurons intensified, resulting in aimless hypermotility which blocked purposeful behavior. I decided to get rid of this side effect.

            In the early 1960s, monoamine oxidase (MAO) inhibitors represented a new type of central stimulation, so I planned to start the structure-activity-relationship study with methamphetamine containing a propargyl-group attached to the nitrogen. This group was known to form a covalent binding with the flavin in MAO and block the enzyme irreversibly. Out of a series of newly synthesized patentable methamphetamine derivatives, I selected
E-250 (later named deprenyl) as the most suitable for my further work. The first paper describing its beneficial pharmacological properties was published in 1964 (in Hungarian) and in 1965 (in English) (Knoll et al. 1964, 1965), and the (-) isomer [(-)-deprenyl (Selegiline)] was the developed drug. I proposed using DEP as a new spectrum antidepressant. Unfortunately, because 1960s’ Hungary was isolated from the Western world’s mainstream science, our results remained largely unnoticed.

            In 1964 I asked Ervin to test the antidepressant effect of racemic E-250. He published a preliminary note (in German) on the promising results of the on-going clinical trial with racemic E-250 in depressed patients (Varga 1965). Ervin wrote the first paper in English reporting that racemic E-250 is an efficient, prompt acting antidepressant (Varga and Tringer 1967). In 1971 they collaborated on the first paper demonstrating that DEP is a potent antidepressant (Tringer et al. 1971). In retrospect it is incredible that selegiline (DEP) with the indication to treat major depressive disorder was only first registered in the United States and marketed as the first transdermal antidepressant (Emsam) in 2006.

            Since I realized by 1965 that in animal experiments DEP antagonized the effect of tyramine, thus DEP is the unique MAO inhibitor, free of the cheese-effect, I asked Ervin to perform a preliminary study on volunteers to test this peculiar, therapeutically important behavior of DEP.

            Ervin confirmed that DEP is free of the “cheese effect” in humans. In a personal communication, he wrote: “Even provocative cheese consumption failed to produce headache or hypertensive crisis” (Knoll et al. 1968).

            In 1968 Ervin moved to the USA and discontinued forever his clinical studies with DEP. His convincing preliminary study, which confirmed that DEP is devoid of the “cheese effect,” was never completed and has remained unpublished.

            Sandler and his co-workers in London demonstrated that after pretreatment with DEP, Parkinsonian volunteers who had received levodopa or levodopa+carbidopa suffered no adverse pressor reaction after challenged with oral tyramine in considerably greater amounts than the dose likely to be encountered in a normal diet (Elsworth et al. 1978; Sandler et al. 1978). Thus, they acceptably confirmed finally that DEP is an MAO inhibitor free of the cheese effect, which aligned with our findings in animal experiments and with Ervin’s preliminary studies.

            In the Post-World War II period a communist totalitarian regime ruled Hungary.  In retrospect there can be little doubt that Ervin Varga was one of the most talented psychiatrists of great promise in the younger Hungarian post-war generation. He was deeply influenced by Semmelweis Professor of Psychiatry, Gyula Nyiro, who worked with Ladislas Meduna (1896-1964) in 1933 to introduce “shock therapy for psychotic patients.” According to Tom Ban, Nyiro provided a link between Wernicke’s nosology and Pavlovian reflexology, bridging psychopathology with pathophysiology. Unfortunately for Hungarian psychiatry, it was unavoidable Ervin fled in 1968.

            After getting his diploma in Pecs in 1951and returning to Budapest, Ervin worked hard on his thesis, “Schizophrenic Perception. An experimental investigation.” The dissertation, by now equivalent to a Ph.D. in the Western world, was in 1961 the highest rank scientific degree of the Hungarian Academy of Sciences, earning him a life-long monthly stipend. During this period Ervin also published nine English or German papers.

            After successfully defending his dissertation in 1961, he was lucky to arrange a one month visit to the Maudsley Hospital in London, the largest mental health training institution in the UK under the direction of Aubrey Lewis. He met Michel Shepherd in Maudsley and the meeting cemented a close and fruitful lifetime friendship. Ervin esteemed his visit to the Maudsley and his friendship with Michael Shepherd as change of fortune which changed his life.

            Returning to Hungary, Ervin took up his post as Assistant Professor and we discussed the plans for his new position, Director of a newly organized and well paid Psychopharmacological Unit. In the early 1960s I finally succeeded in convincing important leaders of in the Ministry of Health that to establish a firm basis for clinic pharmacological research was a pressing necessity in Hungary. We organized the network in selected clinics with the aid of the Hungarian Pharmaceutical Industry. In the early 1960s the revolutionary development of Neuropsychopharmacology was at its zenith. Ervin, considering his important, successful collaboration with the Department of Pharmacology in DEP research, was the selected leader whose intention was to organize in his unit clinical psychopharmacological research.

            I still regret that my reasonable hope that Ervin, obviously the best candidate to succeed Nyiro as the Head of the Department of Neurology and Psychiatry, failed to materialize when Professor Nyiro died towards the end of 1967. Thereafter Ervin and his wife Vera decided to leave Hungary.

            Ervin remained very active before he escaped from Hungary. During a seven-year period he published 27 papers in German and English. In 1966 He spent three months in London, supporting the work of Michael Shepherd and Jules Angst in carrying out a retrospective evaluation of 910 depressed patients treated at Maudsley between 1957 and 1963. After returning to Hungary, Ervin performed a study of 249 patients with severe depression treated at the Budapest Psychiatric Clinic with ETC, imipramine and phenelzine. The results confirmed the superiority of ETC over drug treatment.

            Ervin, who preferred Britain, moved to America in 1968. He started working with Nathan Kline at Rockland Psychiatric Center in New York. After two years he again visited the Maudsley where he received brilliant endorsements from both Shepherd and Sir Aubrey Lewis.

            Returning to New York he began work as an attending psychiatrist at Rockland Psychiatric Center from 1972-1976 and worked with George Simpson and Tom Cooper. Ervin published six papers in collaboration with Simpson and four papers in collaboration with Cooper.

            Ervin moved from Rockland and joined the Carrier Clinic in New Jersey, having been invited by Arthur Sugerman. They worked together for nine years and published four papers with Sugerman and10 total. By 1985 Arthur Sugerman stepped down as Medical Director of the Carrier Clinic and Ervin decided to enter private practice.

            Ervin retired after Vera’s death in July 2015. Ervin and Vera met in 1949 in the medical school at Pecs University and were married within three months. The happy marriage lasted 67 years, until Vera’s death. Ervin could not get over Vera’s death.

            Their two talented sons, Peter and John, born a year apart, were aged 13 and 14 when they escaped from Hungary. Peter is an Associate Professor of Pediatrics at the University of Chicago and an expert in non-invasive cardiac imaging. John is the John and Nancy Hughes Distinguished Professor of Rheumatology at Northwestern University and a national expert in Scleroderma and its treatment.

            Ervin’s life proves that, despite incredible sufferings and personal loss, having a healthy human brain, capable of fixing a proper acquired drive which makes existence reasonable, can lead to an enviably full, successful life.

            Regarding Ervin Varga’s life story I refer to his own book published in 2012: Living and Dying in Hungary: A Jewish Psychiatrist Looks Back; and to the brilliant retrospective essay: ERVIN VARGA: Family, Culture, Persona and Career. By Barry Blackwell. inhn.org/ Biographies, March 31, 2016.

 

References:

Elsworth JD, Glover V, Reynolds GP, et al. Deprenyl administration in man; a selective monoamine oxidase B inhibitor without the “cheese effect”. Psychopharmacology 1978; 57: 33-38.

Knoll J. Discovery of the enhancer regulation in the mammalian brain and the development of synthetic enhancer substances. A chance to significantly improve the quality and prolong the duration of human life. inhn.org/e-books, 2016.

Knoll J, Vizi ES, Somogyi G. Phenylisopropylmethylpropinylamine (E-250), a monoamine oxidase inhibitor antagonizing the effects of tyramine. Arzneimittelforschung 1968; 18: 109-112.

Knoll J, Ecsery Z, Kelemen K, Nievel J, Knoll B. Phenylisopropylmethyl-propinylamine HCl (E-250) egy új hatásspektrumu pszichoenergetikum. MTA V. Oszt. Közl. 1964; 15: 231-238.  

Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B. Phenylisopropylmethyl-propinylamine
(E-250) a new psychic energizer. Arch int Pharmacodyn Thér 1965; 155: 154-164.

Sandler M, Glover V, Ashford A, et al. Absence of “cheese effect” during deprenyl therapy: some recent studies. J Neural Transm 1978; 43: 209-215.

Tringer L, Haits G, Varga E. The effect of (-)E-250, (-)L-phenyl-isopropylmethyl- propinyl-amine HCl, in depression. in: V. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia (Ed.: Leszkovszky G), Budapest, Publishing House of the Hungarian Academy of Sciences, 1971, pp.111-14.

Varga E. Vorlufiger Bericht über die Wirkung des Prparats E-250 (phenyl-isopropyl-methyl-propinylamine-chlorhydrat). in: III. Conferentia Hungarica pro Therapia et Investigatione in Pharmacologia (Ed.: Dumbovich B). Budapest, Publishing House of the Hungarian Academy of Sciences, 1965, p.197-201.

Varga E, Tringer L. Clinical trial of a new type of promptly acting psychoenergetic agent (phenyl-isopropylmethyl-propinylamine HCl, E-250). Acta Med Hung 1967; 23: 289-295.

 

May 17, 2018