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Sunday, 21.04.2019

In Memoriam
Baron Shopsin (August 7, 1935 – June 7, 2017)
by
Thomas A. Ban

On June 7, 2017, Baron Shopsin, an emeritus fellow of the American College of Neuropsychopharmacology, passed away.

Born in New York on August 7, 1935, Shopsin had his early education there, graduating as a Far Eastern history major from Brooklyn College. He went to medical school in Belgium and after returning to the United States completed a residency in psychiatry at Cornell and New York University School of Medicine (Gershon 2011).

            Dr. Shopsin became involved in research with psychotropic drugs in the early 1970s by first conducting a series of clinical studies with lithium, in collaboration with Samuel Gershon, in which they compared its therapeutic effect to chlorpromazine in schizophrenia and to chlorpromazine and haloperidol in mania (Gershon and Shopsin 1973, 1975; Shopsin et al. 1975; Shopsin, Kim and Gershon 1975). Subsequently, in the mid-1970s, they showed that blocking the synthesis of serotonin by para-chlorophenylalanine reversed the therapeutic effects of imipramine and tranylcypromine, whereas blocking the synthesis of norepinephrine by α-methylparatyrosine did not (Shopsin, Friedman and Gershon 1956; Shopsin et al. 1975). They were among the first in the late 1970s to show the therapeutic effect of dopamine receptor stimulation by piribedil in depression (Shopsin and Gershon 1978). After contributing as a clinical investigator to the clinical development of several psychotropic drugs, e.g., clozapine, bupropion (Shopsin 1983; Shopsin et al. 1979), Baron remained involved over many years in developing psychotropic drugs as consultant to the pharmaceutical industry (Ban 2011; Gershon 2011).

            Baron Shopsin (BS) was interviewed by Andrea Tone (AT) for the “Oral History Series” of the ACNP at the annual meeting of the College on December 11, 2003, in San Juan, Puerto Rico (Ban 2011; Gershon 2011). The edited transcript presented here was first published in Volume Five (pp.333 – 40) of the series.

 

INTERVIEW

Baron Shopsin

Interviewed by Andrea Tone

San Juan, Puerto Rico, December 11, 2003

 

AT: My name is Andrea Tone, and we are at the 42nd annual meeting of the ACNP in San Juan, Puerto Rico.  It is 2003, and I am interviewing Dr. Baron Shopsin.  Tell us something about your upbringing, early education, and how you got drawn into the field of medicine.

BS: I was anticipating this interview would focus on the body of scientific work and contributions in collaborative and translational research that led to my early membership, in 1974, to the ACNP. While my life story may well be interesting the events that led me to medicine and a career as a research academic, teacher and clinician surely exceeds the scope of this interview.

AT: Tell us about these aspects of your life anyway.

BS: After graduating high school at the age seventeen, the Korean War abruptly and painfully ended my career as a professional musician - playing sax, clarinet and flute with the Mitchell Ayres Orchestra on the Perry Como Show - obliged to attend College or be drafted. The anticipated rapid end to the war never happened. I graduated two years later with a Liberal Arts degree but without a recognized major apart from some Japanese and Far Eastern history.

Living in Paris later on, I met an acquaintance on the Champs D’Elysée who was in transit to Belgium where he was entering medical school in Louvain.  To make a long story short, after a ski vacation in Austria that December, I left Paris and enrolled in L’Ecole de Medicine, L’ Universite Catholique de Louvain, Belgium, without ever having taken a science course in college other than biology. As a condition for eventual graduation, I was required to take courses in all the basic sciences, biophysics and catholic ethics for the first two years in addition to the usual first and second year medical school curriculum. I graduated Cum Laude six years later after five years of medical school and a year of rotating internship at the University Hospitals and Clinics in Louvain. After living in Europe during the formative years during the 1950s I was reluctant to return to the States in 1963. I left Europe but Europe remained in the fiber of my being. I still think to this day alternatively in French and English.

My fluency in French contributed to my eventual recruitment and long-term relationship as scientific consultant to a Paris based French Pharmaceutical company during the 1970s and 1980s.

AT: What did you do after returning to the States and graduation from medical school? At what point did you decide you wanted to do psychiatry?

BS: After the rotating internship year in Louvain, I was obliged to complete another rotating internship in the States as a requirement for taking the NY State Board Examinations for Physician Licensure, which I completed at Long Island Jewish Hospital in Queens/Nassau New York, an affiliate of Downstate Medical School. I started my residency in psychiatry at Cornell-NY Hospital, located on the fashionable upper east side of Manhattan on 69th Street, steeped in the academic atmosphere of medical and scientific excellence that embraced the combined campuses of Cornell-NY Hospital, The Rockefeller University and Memorial Sloan Kettering Cancer Institute. Earning $50 a month, in the midst of residency, in December 1965, I was drafted into the Navy during the Viet Nam War and spent two years on active duty as a commissioned officer. The first year was spent as General Medical Officer and Department Head aboard the US Duluth, part of a new fleet of Marine Attack Ships. I was the only physician with two enlisted corpsmen serving a crew of 600 marines, navy enlisted men and officers. The second year was served as a staff psychiatrist at the Navy Hospital, Camp Pendleton, a Marine Base Staging Area in southern California, for which I was given one-year residency credit. By now I was married to a Swede I met when she was working at her Embassy in NYC during my residency at Cornell. After discharge from the Navy in Jan 1969 I didn’t return to Cornell, choosing instead to complete residency at NYU-Bellevue Hospital Center, NYU School of Medicine. It was there, during the first six months of a research elective with Sam Gershon, Head of Neuropsychopharmacology Research, that I got irretrievably hooked on the sheer fun of carrying out cutting edge investigative work, side by side with Sam as one of the early pioneers in biological psychiatry and neuropsychopharmacology. I appreciated Sam’s infectious enthusiasm, his encouragement and appreciation of my research initiatives which led to my becoming a committed research psychiatrist throughout the remainder of my residency before graduating seamlessly into an academic career as a full time faculty member at NYU.

AT: Didn’t you have already several papers by the time you finished residency?

BS: I had about 10 publications by the time I finished residency. 

AT: Were they on lithium?

BS: About half were related to lithium, the others to schizophrenia and affective disorder. From 1969 throughout the 1970s and into the 1980s during the “Golden Age” of NYU psychiatry I was Associate Professor of Psychiatry and Chief of the Unit for the Study and Treatment of the Affective Disorders and Lithium Clinic at Bellevue. I was also associated with Nathan Kline in the most visible private practice for psychiatry in NYC during the 1970s where we also carried out clinical drug trials. We remained colleagues and friends until his untimely death in 1983. 

AT: Tell me about the Affective Disorders Unit.

BS: The Affective Disorders Unit and Lithium Clinic was the first of its kind in the United States, consisting of inpatient beds at Bellevue Psychiatric Hospital and a metabolic unit in the Endocrine Division of Bellevue General Hospital, which included outpatient clinics and staff offices in the privately endowed Millhauser Laboratories, directed by Arnold Friedhoff.

AT: So, you were involved in research in affective disorder?

BS: The studies relating to lithium ion necessarily involved investigational initiatives relating to the affective disorders. The studies with lithium contributed in the United States to FDA approval, marketing and clinical use of the lithium by psychiatrists as the first drug with therapeutic specificity for the manic phase of bipolar illness and as a prophylactic against acute recurrences of mania and depression. The first textbook related to the use of lithium in research and treatment was edited by Gershon and Shopsin; the book on Manic Illness edited by Shopsin contributed to the widespread use of lithium by practicing clinicians. The affective disorder research was focused on biomarkers potentially related to the molecular biology of depression. Many clinical drug trials with investigational compounds contributed data towards this end. 

AT: Can you say more about that?

BS: The effects of antidepressant drugs such as the tricyclic compounds and monoamine oxidase inhibitors on brain monoamines suggested an involvement of both catecholamines, i.e., norepinephrine and dopamine, and the indolamine serotonin (5-HT) in the pathophysiology of depression. Theories concerning the pathogenesis of depression were generally united in postulating a role for these different biogenic amines, but the specific amine or amines involved in either depression or the antidepressant effects of the tricyclics and MAO inhibitor drugs remained elusive.   Clinical studies exploring amine metabolism had largely concentrated on examining the different monoamines or enzyme systems in biological media such as blood, urine, and spinal fluid. I was spending a good deal of my time and energy doing just that. But attempts to scrutinize the concentrations of monoamines or their metabolites, i.e., NE, MHPG, 5-HT and 5-HIAA, in peripheral biological fluids had come to represent the metaphoric equivalent of looking at sewage. So, I had a brain storming session one sunny Sunday afternoon with Menek Goldstein, the Chair of Neurochemistry at NYU and by dinner time we had hammered out an innovative study paradigm that served to delineate the future scope of my work by focusing on synthesis inhibitor challenges rather than the detection of a potential chemical defect. It involved a small number of voluntary patients with each individual serving as his or her own control.

AT: Can you explain this to someone who is not familiar with the subject?

BS: In attempts to define more clearly the specific biogenic amine responsible for the antidepressant effect of the tricyclic and MAOI class drugs like imipramine (Tofranil) and tranylcypromine (Parnate), we treated patients with these drugs until showing clinical improvement. Then, we gave them either a selective norepinephrine synthesis inhibitor or a serotonin synthesis inhibitor. The reversal of depression in patients treated with imipramine and tranylcypromine was annulled when they were concurrently treated with PCPA, but not with α-MPT.  Parallel drug studies in animals showed that statistically significant reductions in brain catecholamine and indolamine concentrations occurred with combined imipramine and α-MPT or imipramine and PCPA treatment, respectively. In their entirety the data suggested what appeared to be an irreconcilable role for serotonin in the antidepressant effects of the tricyclic drug, imipramine and the MAOI tranylcypromine. The difficulty in getting the clinical studies done was obtaining the synthesis inhibitor drugs from pharmaceutical manufacturers and the inherent risk in treating patients concomitantly with an antidepressant and a synthesis inhibitor.

AT: What made you think at all that the culprit might be serotonin?

BS: The existing research pointed to norepinephrine and serotonin as the putative monoamines at the heart of both depression and antidepressant drug effects. The findings with serotonin using synthesis inhibition were not anticipated. It was a by-product of well-designed unbiased research. Our studies and published reports were never able to substantiate involvement of norepinephrine. I authored several reviews on the need for revision of the noradrenergic hypothesis based on the absence of documentation of an evidentiary nature. Some colleagues in Europe, notably Alec Coppen in the UK and Herman Van Praag in the Netherlands, suggested the involvement of serotonin based on the measurement of peripheral biomarkers, but the theory and funding for NE research in the USA was so mindlessly entrenched that a serotonergic theory of depression was never a serious contention before my synthesis inhibitor studies furnished good and sufficient proof of the concept.

AT:  So you published your findings, and what was the response?

BS: The paper published in Archives of General Psychiatry in 1976, by Shopsin et al. entitled Parachlorophenylalanine Reversal of Tranylcypromine Effects in Depressed Patients served as the metaphoric shot heard round the world that triggered widespread recognition of the role of serotonin as the pivotal monoamine underlying the therapeutic effects of the tricyclic and MAOI class antidepressant drugs and as pathogenic in depression. The Archives paper synthesized the data and recorded the effects of PCPA to induce a robust and rapid depressive relapse in endogenously depressed patients who had shown an incontrovertible antidepressant response to the MAO inhibitor, tranylcypromine. Our findings served as the basis for the discovery, and development of a series of more serotonin selective and potent 4-alkylpiperidine derivatives such as Indalpine, Viqueline and Pipequeline, of which Indalpine, became the first marketed SSRI (Upstène) “Blockbuster” drug worldwide, except the United States. It was marketed in 1982, several years before the commercial availability in the United States of fluvoxamine and then fluoxetine in 1988.

AT: What was the response to the marketing of Indalpine in France and your involvement with Pharmuka the company involved with this drug?

BS: My name was celebrated in Europe and in particular of course in France as a consequence of the media coverage of my involvement with Pharmuka. I was the “American Professor” whose research led to the discovery and marketing of Indalpin. 

AT: Did Indalpine get to the United States?

BS: Yes, but in never came to market. I represented Pharmuka in the United States with the FDA in obtaining an IND for the investigational use of Indalpine and Viqueline, and carried out and published the first clinical trials in the United States with Indalpine in depressed outpatients. Having established offices in New York City, Pharmuka was setting up to conduct the necessary clinical trials in the US in anticipation of eventual marketing but the timing was wretched. Zimelidine, another SSRI, marketed in Scandinavia in 1983, was soon withdrawn due to the occurrence of Guillain Barré Syndrome, a serious neurological disease. In a smouldering climate of concerns about potential adverse neurological effects with SSRI's Indalpine ran into trouble around the issue of some patients developing adverse haematological effects. Meanwhile, under the socialist government of Mitterrand during the 1980s, Pharmuka and its scientists were absorbed by the industry giant Rhône-Poulenc, and the fate of Indalpine with it. In or about 1987 Rhône Poulenc abruptly pulled the drug off the market. There are other examples of wrong timing for good dugs: Wellbutrin is one of them.

AT: Wellbutrin?

BS: It’s a fantastic antidepressant.  We did the original open and dose-ranging studies with it and I used it with excellent results. Burroughs Welcome wrong mindedly decided to conduct clinical trials with it in people with bulimia. On the eve of its commercial availability some of them developed seizures and the fate of Wellbutrin was sealed. Epilepsy is the death knoll for an investigational drug.

AT: Why is epilepsy more stigmatized than other side effects?

BS: A grand mal seizure while driving in New York City traffic is more ominous than a dry mouth.   

AT: I am struck by your comment about Wellbutrin being a very potent antidepressant. Many of the SSRIs are now being marketed for both depression and anxiety, and one of the things about Wellbutrin is that it supposedly exacerbates anxiety.

BS: The aim of psychopharmacology should be to come up with new drugs having diagnostically related pharmacological specificity, like lithium for manic illness. Most antidepressants have anxiolytic effects as well but anxiety and depression are regarded by most people as opposite sides of the same coin. However, anxiety accompanying depression is not the same anxiety as the primary illness. Therapeutic specificity is not incompatible with the ability of an antipsychotic drug to put someone to sleep but it is incompatible with FDA approval to market the drug for use as a sleeping pill.

AT: So why are pharmaceutical companies reluctant to market drugs targeted to a specific diagnosis?

BS:  I don’t think they’re reluctant; they probably don’t have a drug that fits the bill. If they did there would be no rational reason why they wouldn’t.  To date the only drug with diagnostically related pharmacotherapeutic specificity is lithium for the treatment of the acute manic phase of bipolar illness.   

AT: So why aren’t they developing them?

BS: Because the current entrenched reluctance of industry to carry out research unrelated to serotonin has delayed the search for newer, better antidepressants and will continue to result in more marketing of drugs that are the same. They make billions by the sale of SSRIs and aren’t in a rush to change things by spending billions on R&D to find new drug the cost for which has become prohibitive. The older antidepressant drugs that targeted all the brain monoamines will be reintroduced as new antidepressants, better than SSRIs because they affect the availability at central receptor sites of not one but multiple neurotransmitter systems. They will reinvent the wheel to generate more income for different flavours of the same compounds. Since the 1990s I have been calling the attention of ACNP colleagues to the role of excessive exposure and overstimulation of receptors in the brain to the essential excitatory amino acid glutamate with resulting effects in modulating synaptic plasticity, learning and memory. All of the existing antidepressant drugs are antagonists of some aspect of glutamatergic activity.  Investigational scrutiny of glial cells, especially astrocytes, as pivotal players can no longer be neglected in understanding how the brain works in depression. Depression is the phenotypic expression of the disordered, unregulated molecular biology of glutamatergic neuronoglial transmitter events in brain. This is the bottom line answer to your question relating to the failure of industry to come up with drugs that have diagnostically related therapeutic specificity in depression. Development of a dug with an inhibitory action of glutamatergic activity drug will not be easy.

AT: You are quite right we should be looking at things more specifically. Well, back to your career. What are your key contributions to the field of neuropsychopharmacology?

BS:  I’ve already talked about my studies with synthesis inhibitors and Indalpine. I also contributed to knowledge on the antithyroid and goitrogenic effects of lithium; on the immuno-adjuvant effect of lithium; on the effect of lithium on white call count, etc. I was involved in clinical studies with clozapine, penfluridol, pimozide, loxapine, bromocriptine, Wellbutrin, Wiqueline and many others. I published textbooks on Lithium, and on Manic Illness as I told you, and also on the Psychobiology of Childhood.

AT: Thinking back to when you entered psychiatry and where it is now, what do you think have been the most significant changes in the field?

BS: Psychiatry has been in decline for over a decade, replaced by a system of mental health care presided over by paraprofessionals who include every type and stripe of social workers, certified mental health workers, practical nurses, nurse practitioners, physician assistants, counselors of all sorts, everyone but psychiatrists! Psychiatrists are token participants at best in most hospitals, outpatient clinics and mental health facilities throughout the US, for medico-legal reasons. We in the ACNP, who pioneered the revolution called biological psychiatry hoped to change the theory and practice of psychiatry but got more than we wished for. We created a monster that has done more harm than good. We made scientific advances but failed to translate them into practical therapies or applied to applicable patients, for the well being of the public we serve. The psychiatrists and non-physician mental health care workers being trained are ill equipped. Incidence and prevalence statistics show mental illness has become epidemic; drugs are prescribed or abused by everyone starting in childhood. Children are prescribed drugs as if they were M & M’s, whilst more and more adults and children have allegedly become “treatment resistant,” and more children commit suicide. The pharmaceutical companies are making untold billions, advertising directly to the public via newspapers, magazines, TV and computer websites suggesting that patients ask their doctor about a prescription. Alcoholics and abusers of prescribed or illicit stimulants and opiates are misdiagnosed as bipolar or treated as such by labelling them dual diagnostic cases for third party payment reasons. The system is broken. Psychiatrists without an idea about pharmacology bill themselves as psychopharmacologists because they give drugs; they no longer have the time or inclination to speak to patients. We’ve created a monster. If you listened to the history lecture the other night, it was clear that diagnostic accuracy and specificity are irrelevant to some of us; it doesn’t matter what type of depression, unipolar, bipolar, neurotic, induced or associated with the use of illicit drugs. We are told, as long as there are depressive features, the practicing clinician should give an antidepressant. 

AT: So you’re not sure patients or society have benefited, at least in the United States, or are better off today than they were 30 or 40 years ago?

BS: Thirty or forty years ago, is a long time ago for comparisons. Forty years ago it was too early for the mentally ill to have benefitted from the advances brought about in the “Golden Age” of neuropsychopharmacology in the 1970s-1980, the real “Decade of the Brain.” The 1970s and 1980s were the best of times for cutting edge psychiatric care available from physician-scientists who were able to stabilize and maintain more than 85%-90% of the patients who walked into their private practices or clinics. We saw few treatment resistant patients and needed only one drug, given to the appropriate patient in adequate dosages for sufficient time, to do the trick in most cases. Those were the best of times. 

AT: We need to wrap up it up now. Thank you..

BS: OK. You’re welcome.

 

References:

Ban TA. Preface. In: Gershon S, editor. Neuropsychopharmacology. In: Thomas A. Ban, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume Five.   Brentwood: American College of Neuropsychopharmacology; 2011, pp. ix – xxxix.

 

Gershon S. Introduction & Dramatis Personae. In: Gershon S, editor. Neuropsychopharmacology. (In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume Five.)  Brentwood: American College of Neuropsychopharmacology; 2011, pp. xlix - lviii.

 

Gershon S, Shopsin B, editors. Lithium:  Its Role in Psychiatric Research and Treatment. New York: Plenum Press; 1973.

 

Shopsin B. Bupropion’s prophylactic effect in bipolar affective illness. J Clin Psychiatry  1983; 44: 163-9.

Shopsin B interviewed by Adrea Tone. In: In: Gershon S, editor. Neuropsychopharmacology. (In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume Five.)  Brentwood: American College of Neuropsychopharmacology; 2011, pp. 333 -40.

 

Shopsin B, Friedman E, Gershon S. Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients. Arch Gen Psychiatry 1976; 33: 811-9.

 

Shopsin B, Gershon S. Cogwheel rigidiy related to lithium maintenance Am J Psychiatr 1975; 132: 526-8.

Shopsin B, Gershon S. Dopamine receptor stimulation in the treatment of depression: Piribedil (ET-495.) Neuropsychobiology 1978; 4: 1-14.   

Shopsin B, Gershon S, Goldstein M, et al. Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacology Communications 1975; 1: 238-49.

Shopsin B, Gershon S, Thompson S, Collins P. Psychoactive drugs in mania.  A controlled comparison of lithium carbonate, chlorpromazine and haloperidol. Archives of General Psychiatry 1975; 32: 34-42.

Shopsin B, Kim SS, Gershon S. A controlled study of lithium vs chlorpromazine in acute schizophrenia. The British Journal of Psychiatry 1971; 119: 435-40.

Shopsin B, Klein H, Aronson M, et al. Clozapine, chlorpromazine and placebo in newly hospitalized acutely ill schizophrenic patients: a controlled, double-blind, placebo comparison. Arch Gen Psychiatry 1979; 36: 657-74.

 

April 12, 2018