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Saturday, 24.06.2017

Barry Blackwell: Joel Elkes: An Integrative Life

Barry Blackwell’s reply to Ross Baldessarini’s comment

 

        Ross Baldessarini’s cogent comments on his personal interactions with Joel Elkes and how these helped shape his career are valuable additions to developing a better understanding of Joel’s contribution to the evolving relationship between clinical psychiatry, neuroscience and behavioral medicine.

       Building on his undergraduate excellence in organic chemistry, Ross was diligent and determined in plotting his future and the education necessary to secure its foundations. After internship in internal medicine and a bench research fellowship in neuropsychopharmacology at NIMH, he explored a career in psychiatry and was disappointed at the two leading programs he visited in America. So Ross consulted Seymour Kety, the head of his research program. Kety had recently vacated the Chair of Psychiatry at John Hopkins he occupied for less than a year, feeling unprepared for the task without having any formal training in the discipline. Seymour suggested Ross speak to Joel Elkes, head of the NIMH neurosciences research program at St. Elizabeth’s. He was about to take the Chair of Psychiatry and its residency training program at Johns Hopkins that Kety had vacated.

    Ross describes Joel’s tenure at Johns Hopkins (1963-1974) as an interlude after the mostly serendipitous discovery of all the major categories of psychotropic drugs and scientific proof of their efficacy by means of randomized controlled trials (RCT’s). When Frank Ayd and I invited all the pioneers who made these discoveries to describe them in their own words in 1970, we made the following editorial comment in the book that followed, Discoveries in Biological Psychiatry (Ayd & Blackwell, 1971): “Compared to the fruitful years recorded here, biological psychiatry has fallen on more barren times. It is not unusual for an era of productivity to be followed by the kind of slack interval in which we are currently becalmed.” (p.8). Little did any of us know that the “slack interval” would last more than half a century.

   Joel’s contribution to the scientific process of ratifying the original discovery was one of three such papers in different countries; Britain (Elkes & Elkes 1954), France (Delay, Deniker & Harl 1952), and Canada (Lehmann & Hanrahan 1954). Ross describes the Elkes’ study as “primitive”, a word that might apply to all three, although theirs is the only one to include elements of control. All three were conducted on diagnostically heterogeneous groups of agitated, psychotic asylum patients. The title of Joel’s paper was, Effects of chlorpromazine on the behavior of chronically overactive psychotic patients. He was always adamant that this was not linked to any specific diagnosis. The title of Heinz Lehmann’s paper was, A new inhibiting agent for psychomotor agitation and manic states. It included 72 agitated psychotic patients with 12 different diagnoses. But the results and comments made by Pierre Deniker of his work with Jean Delay (3 reports, all in 1952 and in French) are the most prescient and compelling (Deniker 1970 in Discoveries in Biological Psychiatry):

       “Psychiatric wards 20 years ago still included agitated patients who did not respond to common therapeutic procedures. Logically a new drug was tried in cases resistant to all existing therapies. Manic excitation and, more generally, psychotic agitation, immediately became the indication of choice. We had scarcely treated 10 patients, with all due respect to fervent adherents of statistics, when our conviction proved correct. It was supported by the sudden great interest of the nursing personnel who had always been reserved about innovation.

       Deniker and Delay’s further detailed observations, were more nuanced but equally valuable. They distinguish between what later became known as the positive and negative symptoms of schizophrenia. “Agitated aggressiveness and delusional conditions of schizophrenia improved. Contact with patients could be re-established but deficiency symptoms did not change markedly.” This is what secured the patient’s release from asylum care and contributed to their failure to thrive in community.

       Finally, speaking for the providers of treatment, Deniker comments, “Paradoxically some assumed a certain opposition between chemotherapy and, on the other hand, socio-therapy and psychotherapy. They actually benefit from one another and are inseparable.”

       However primitive and unsophisticated the trial methodology may appear to have been, skilled clinicians like Deniker, Lehmann and Elkes were able to harvest essential details to inform sound clinical practice. The shortcomings of RCT’s, which we recognized almost a half century ago (Blackwell & Shepherd 1968), were slow to permeate the field until the value of real life effectiveness studies in addition to artificial efficacy designs was recognized.

       At the same conference where Deniker made his remarks in 1970, Joel Elkes gave an opening presentation titled, Beginning in a new science (Elkes 1971). Seven years into his tenure at Hopkins (1963-1974), he confines his comments to his neuroscience accomplishments at Birmingham UK and Washington DC. Beneath this silence lie hints about his thoughts for the future when he concludes his presentation with the following: “Psychopharmacology is, for the first time, compelling the physical and chemical sciences to look behavior in the face, enriching both these sciences and behavior. If there is discomfiture in this encounter it is hardly surprising, for it is in this discomfiture that there may well be the germ of a new science …there is here no conflict between understanding the way things are and the way people are, between the pursuit of science and the giving of service. Where does one find a field as rich and powerful as ours?”
        This makes clear why he titled his new department, Psychiatry and the Behavioral Sciences. Further evidence of this is contained in the few articles he published during his tenure at Hopkins. There are only three. On meeting psychiatry; a note on the medical student’s first year (Elkes 1965, a); Psychoanalysis and the community (Elkes 1965, b) and Behavioral pharmacology in relation to psychiatry (Elkes 1967).     

      Joel’s remarks at the Baltimore Conference, and his literary oeuvre at Hopkins predict his future interest and contributions in medical education, the humanities and a clinical biopsychosocial perspective. These ideas incubated in mid-life (39-50) at Johns Hopkins, were refined (but still largely silent) at McMaster, coming into full bloom at Louisville until his retirement where he continued to write and paint.

      With hindsight it seems clear that by 1970 Joel and Ross, as well as the pioneers at large, already saw the limitations of a clinical “pharmacocentric idealbut perhaps only Joel clearly distinguished neuroscience and behavioral science. This was an innovative but poorly understood posture that may have irritated both the psychoanalysts and traditional clinical psychiatrists.

      Ross attributes Joel’s discomfiture at Hopkins to an inability to garner “significant resources” to pursue a more biological approach. A more sustainable hypothesis is that his behavioral aspirations were triggered by concluding his psychoanalysis in mid-life and a deeply felt need to find better ways to improve medical education and clinical practice. Like Kety, he had no formal training in psychiatry but was self-taught by clinical exposure to patients both he and his wife saw in a Birmingham asylum. He was not about to repeat Kety’s failure due to a singular reliance on neuroscience; as the Chair of Psychiatry in a premier medical school, he saw the need for a broader vision. A common feature in the biographies of pioneers in psychopharmacology, including both Joel and Ross, is a shared belief that drugs alone are never enough.

       The final question, perhaps the most important, is whether Ross Baldessarani’s residency experience, under Joe Elkes’ tutelage, impaired his career. The answer is unequivocally revealed in a 22 page interview between Ross and David Healy in 1998, for the Oral History of Neuropsychopharmacology (Baldessarani 1998).

       This archive documents many contributions and accomplishments including a benevolent postscript to the story of Ross’s frustrated attempt to study lithium in bipolar disorder during his residency, which I hope will become an important addition to the half century history of this unique substance compiled by members of the INHN network (Blackwell et al 2013).

       By the time Ross began his residency in 1963, lithium was in widespread use worldwide for the treatment of acute mania, except in America where the FDA banned its use due to its toxic and occasionally fatal effects when used as an adjunct to treat hypertension. This ban was not lifted until the mid-1970’s, but, in the early 1960’s, Scandinavian psychiatrists had begun its use to prevent future episodes of recurrent bipolar disorder, an indication with broad implications. As a junior resident, Ross took the intrepid step of applying for an Investigational IND to study lithium which the FDA granted.

       Ross does not reveal his hypothesis or trial design, which was never accomplished, apparently because senior colleagues in medicine objected to a “mere psychiatrist using such a toxic agent clinically.”  Why Ross and his Chairman Joel Elkes chose not to proceed seems surprising since it was 15 years since lithium’s safety had been established by an Australian study in 100 patients monitored by routine plasma levels (Noack & Trautner 1951). Six years later the Trautner team (Sam Gershon was now a member) fully defined the excretion and retention levels of lithium and its effect on ionic balance in humans (Trautner, Morris, Noak, & Gershon 1955). Such interference by members of one department in the affairs of another would be highly unusual but Ross took it to heart and continues to berate himself for “extraordinary poor judgment and risk taking.”

       A quarter of a century after Ross completed his residency, in the early 1990’s, he became reacquainted with lithium in a series of studies showing that in patients taking psychotropic drugs for prolonged periods, often for ‘prophylaxis’, abrupt or rapid discontinuation was much more dangerous than gradual tapering off medication. This was first demonstrated with lithium, then with neuroleptics in schizophrenia and antidepressants, where there was an increased risk of suicide.

During the time I was writing Joel Elkes’ biography we had several conversations by phone and in person. While it became clear his time at Johns Hopkins and departure were difficult and troubled, he was scrupulous in avoiding discussion of details and individuals. What was also clear is that with the passage of time, his role and contributions became increasingly acknowledged and appreciated. He was proud to be a Distinguished Lifetime Professor and contributed several of his wonderful paintings to hang on the walls of his former Department.

 One of the rewards of history is to share the bard’s insight that sometimes, “All’s Well That Ends Well (Shakespeare, circa 1607).

References

Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia: JB Lippincott Co; 1971

Baldessarani R, interviewd by David Healy. In Ban TA,editor. An Oral History of Psychopharmacology. Volume 5. Neurosychopharmacology (Gershon S, editor) Brentwood: AmericanCollege of Neuropsychopharmacology; 1998, pp. 13-35

Delay J, Deniker P, Harl JM. Traitment des etats d’excitation et d’agitation par une method medicamenteuse de l’hibernotherapie. Ann Med-psychol 1952; 110: 67-237.

Deniker P. Introduction of neuroleptic chemotherapy into psychiatry. In Ayd FJ, Blackwell B, editors, Discoveries in Biological Psychiatry. Philadelphia: JB Lippincott Co; 1971, pp. 55-164.

Elkes J. On meeting psychiatry: A note on the medical student’s first year. Amer.J.Psychiat. 1965a; 122: 121.

Elkes J. Psychoanalysis and the community. Masserman JH, editor. Science and Psychoanalysis. New York: Grune and Stratton; 1965b.

Elkes J. Behavioral pharmacology in relation to psychiatry. In Gruhle HW, Jung R, Meyer-GrossW, Muller M, editors. Psychiatrie der Gegenwart.  Berlin/Heidelberg/New York, Springer Verlag, 1967; 929-1036.

Elkes J, Elkes C. Effects of chlorpromazine on the behavior of chronically overactive patients. Brit Med. J. 1954; 1: 560-565.

Lehmann HE, Hanrahan GE. New inhibiting agent for psychomotor excitement and manic states. Arch.Neurol.Psychiat. 1954; 71:227- 237.

Baldessarani R. in An Oral History of Psychopharmacology (Series ed. Ban T) Volume 5 (Ed. Gershon S) Interview by David Healey 1998; 13-35

Noack CH, Trautner EM. The lithium treatment of maniacal psychosis. Med. J. Aust. 1951; 2:219-222.

Trautner EM, Morris R, Noak CH, Gershon S. The excretion and retention of ingested lithium and its effect on ionic balance in man, Med. J. Aust. 1955; 2: 280 291,

 

Barry Blackwell

May 26, 2016