Ross Baldessarini’s comment
I first met Joel Elkes in 1965, under somewhat unusual circumstances. Following a year of internal medicine at Boston City Hospital, and during a laboratory research fellowship in neuropsychopharmacology at the National Institute of Mental Health (NIMH) in Bethesda, Maryland (1964–1966), I became increasingly interested in training in psychiatry. However, following two nationwide visits to leading US training programs, I came away skeptical and unconvinced that the field was keeping up with progress in general medicine and surgery, and considered pursuing a laboratory career. The NIMH research program director at the time was Seymour Kety [1915–2000], who had recently chaired the Department of Psychiatry at Johns Hopkins in Baltimore (1961–1962), but without training in clinical psychiatry, found it a difficult fit and left in less than a year. He suggested that I contact his good friend and colleague, Joel Elkes [1913–2015], who then led a major and innovative program of neuroscience research with a psychiatric orientation, at the St. Elizabeth’s Hospital laboratories in Washington DC, associated with the NIMH, and was about to take the chair at Johns Hopkins.
I called Joel to ask for an appointment to discuss psychiatric training and the future of the field in this country. He invited me to visit at his home nearby, in Bethesda. This memorable first encounter included having tea in his very English-style rose garden, where he showed me a collection of his own recent, modern paintings, and laid out a remarkable vision for the future. Quite convincingly, he predicted that psychiatry was about to enter a new era, based on what would soon become known as “neuroscience.”
At the time, the only obviously clinically relevant component of such science was the emerging application of effective and tolerably safe medicines to treat psychotic and major mood disorders and some anxiety disorders. Examples of each of these innovative treatments had been discovered (more by serendipity than by rational, scientific prediction) and initially tested by 1960—between 1949 (lithium) and during the 1950’s (chlorpromazine, chlordiazepoxide, clozapine, iproniazid, imipramine (Baldessarini 2013). Indeed, a major contribution to Elkes’ reputation was his early trial of chlorpromazine with his first wife Charmian (Bourne) Elkes [1920–1995], at his innovative experimental psychiatry program at the University of Birmingham, England, which opened in 1951 [Elkes 1995; Elkes and Elkes 1954].
This study [Elkes and Elkes 1954] is worthy of comment and re-reading, if only to appreciate how far the design, analysis, and reporting of experimental therapeutic trials have come in the past half-century. At its time, the study was as advanced as any in general medicine by including efforts at double-blinding and use of a placebo-control. It is appropriately considered a landmark study in psychopharmacology. By today’s standards, however, it seems frankly primitive. It used a within-subject, crossover design and neither specifically contrasted average outcomes with placebo versus chlorpromazine, nor controlled for drug-discontinuation and carryover artifacts. The study was hampered by lack of knowledge of appropriate drug-dosing, or of times in which improvement and worsening might be expected to occur after starting or stopping chlorpromazine. Exposure times were increased from two weeks initially, to six weeks, later during the conduct of the trial, and there were 2–7 changes per person between drug and placebo over approximately 22 weeks. Drug doses were determined empirically during the trial, and are reported as total grams given per patient rather than as daily mean doses (which averaged approximately 150 mg/day). Diagnoses also varied: most of the 27 subjects, 48.2%, had probable manic-depressive disorders (bipolar or melancholic), 40.7% had schizophrenia-like, chronic psychotic or delusional conditions, and 8.1% were demented, but all were chronically ill, currently agitated and difficult to manage clinically. “Definitely beneficial” responses with chlorpromazine (sometimes followed by worsening with placebo) were found in only 7/27 cases (25.9%), with a nonsignificantly higher response rate among mood-disorder subjects (4/11 [36.4%]) than in psychotic (3/13 [23.1%]) or demented (0/3 [0.0%]) patients (chi 2 = 1.54; p=0.22). Data for responses during drug-versus-placebo phases are not provided, and assessments were impressionistic, severely limiting interpretation of the findings. Notably, although this trial is widely considered a first controlled test of the phenothiazine for schizophrenia, the majority of subjects and most responders were manic-depressive.
At our initial meeting, Joel reviewed this and other developments in which he had been involved in England and the US, including early studies of the structure of myelin, the differential pharmacology of catatonia (worsened with amphetamine and improved with amobarbital), on the neurophysiological and behavioral effects of anticholinesterases and muscarinic antagonists, and promotion of the concept of regional, cerebral neurochemistry. His work in neurochemistry followed the tradition of Johann Ludwig Thudicum [1829–1901], another British immigrant from Germany (Elkes was born in the former Königsberg in eastern Germany in 1913 and raised in Lithuania before moving to England at age 17) (Elkes 1995; Blackwell 2015]. He considered this work as only the beginning of a new, more biomedical era in psychiatric therapeutics [3]. He also expressed great optimism for the pursuit of biological contributions to the causes and pathophysiology of major mental disorders, in part based on the questionable, highly pharmacocentric idea [Baldesarini 2013] that knowledge of the actions of new drugs might lead to testable hypotheses about a biology of the illnesses for which they provided symptomatic benefits. Finally, he outlined his hopes for the Department of Psychiatry and Behavioral Sciences at the Henry Phipps Psychiatric Clinic at Johns Hopkins, which he was about to chair, and encouraged me to apply there for residency training.
Suffice it to say that Elkes’ views, enthusiasm and achievements were highly persuasive, and led me to apply to return to Hopkins. I had finished medical school there in 1963, having been taught in freshman year by John Whitehorn [1894–1974], successor to Adolf Meyer [1866–1950] as the second director of the department of psychiatry. Almost from the beginning, and consistently throughout my years at the Phipps Clinic (1966–1969), I was forced to conclude that Joel’s biological vision was, at best, premature, with limited direct clinical relevance. Nevertheless, in the years since then, a more biomedical and descriptive approach to clinical psychiatry, with a very heavy reliance on psychopharmacology, has come to dominate the field [Baldessarini 2013, 2014).
In the US, the biomedical approach forced a previously dominant psychodynamic perspective aside, at least from leadership positions in academic, publishing, governmental, administrative and other organized aspects of the field. It has also had a profound impact on clinical practice, particularly in shifting toward the application of psychotropic drug treatments rather than psychotherapy [Baldessarini 2013, 2914]. This impact on clinical practice has often been dramatically effective, and has profoundly changed the nature of psychiatric training and practice, and altered the organization of psychiatric facilities and services. Nevertheless, it can risk loss of other progress, particularly clinical progress, made over the past century [2014]. Moreover, the hope that a neurobiological approach would succeed at the level of explaining the causes of major mental illnesses, or support a more rational, experimental, psychiatric therapeutics continues largely to be elusive [Baldessarini5]2013, 2014). However, the scientific contributions of biological psychiatry and of neuropsychopharmacology, in particular, have been stunning. They include spectacular technical advances in brain imaging, cerebral metabolism and genetics that are being applied usefully to clinical problems as well as advancing molecular understanding of the actions of known (but not necessarily of innovative) psychotropic drugs [Baldessarini 2013]. Nevertheless, the promise of a clinical psychiatry, based on methods arising in Europe and North America from the late 19th century and refined by clinical experts (including psychoanalysts) throughout the 20th century, has remained elusive.
I received intensive and appropriate clinical training and experience at the Phipps Clinic (1966–1969), where I also met my wife, then a psychiatric nursing supervisor. In addition, I owe a specific debt of gratitude to the late Charmian Elkes, who was a favorite clinical supervisor and first introduced me to the then rather un-American concept that there was a lot more to psychotic illness than schizophrenia. The insight first arose in reviewing with her the case of a seemingly psychotic and very hypersexual adolescent female patient. Charmian encouraged me to read deeply into the European literature on manic-depressive illness, which gradually became a sustained and sustaining interest. My earliest interests in bipolar disorder in Baltimore included an ill-advised, but successful effort as a resident to obtain permission (Investigational New Drug [IND] authorization) from the US Food and Drug Administration to supervise use of lithium carbonate for the entire Johns Hopkins medical center. This manifestation of my extraordinarily poor judgment and risk-taking led to interesting comments by senior colleagues in internal medicine, who predicted disaster by encouraging mere psychiatrists to use such a toxic agent clinically.
His years at Hopkins (1965–1973) appeared to be frustrating to Joel Elkes. Barry Blackwell, in his recent biographical notes on Elkes (Blackwell 2015], suggests that an essential problem at the Phipps Clinic in the 1960’s was a clash between highly entrenched and influential psychoanalysts versus anyone who would pursue a biomedical orientation. However, combining work in basic neuroscientific research with strong clinical interests had been a tradition initiated by neuropathologist Adolf Meyer (chairman, 1909–1941) and continued by his successor, John Whitehorn (chairman, 1945–1960), who had been a chemist at Harvard, working with Otto Folin [1866–1934] at McLean Hospital, as well as by Elkes’ immediate predecessor, Seymour Kety (chairman, 1961–1962). I suspect that Elkes’ greater challenge was to command sufficient resources with which to establish major new laboratory and clinical research programs, as he had known in Birmingham and at St. Elizabeth’s, and to exercise the administrative skills required to bring his hopes to fruition. However, I agree with Blackwell that Joel Elkes’ career was an “integrative life” [4].
Programs aimed at integrating basic neuroscientific research with clinical studies in psychiatry departments were widely known long before Elkes moved to Hopkins, and well before he established such a program at the University of Birmingham. These include McLean Hospital (1888), the New York Psychiatric Institute (1895), the Illinois Psychiatric Institute (1907), the Phipps Clinic itself (1913), the German Institute for Psychiatric Research in Munich (1917) led by Emil Kraepelin [1856–1926], and many other “psychopathic institutes” that developed at university medical centers in the early 20th century. Their impact on training, research, and practice has been and continues to be profound. Nevertheless, there is a risk that their scientific contributions may remain largely parallel developments to progress in the clinical assessment and treatment of the severely mentally ill. The vision espoused by Joel Elkes and his predecessors at the Phipps Clinic, aimed at integrating basic neuroscience with clinical research and improved clinical care was premature and has been followed by decades of still-unfulfilled expectations. Nevertheless, it sustains many of us working in biological psychiatry and neuropsychopharmacology in retaining optimism about continued contributions of neuroscience to clinical psychiatry and in pursuing efforts to integrate neuroscience into psychiatry, while not ignoring the considerable progress in clinical psychiatry over the past century [Baldessarini 2013, 2014].
References
Baldessarini RJ. Chemotherapy in Psychiatry, third edition. New York: Springer Press, 2013.
Badessarini RJ. The impact of psychopharmacology on contemporary psychiatry. Can J Psychiatry 2014; 59:401–405.
Blackwell B. Joel Elkes: an integrative life (August 2015). Accessible at: http://inhn.org/fileadmin/Biographies/Elkes_by_Blackwell.pdf (accessed 2 January 2016).
Elkes J. Psychopharmacology: finding one’s way. Neuropsychopharmacology 1995; 12:93–111.
Elkes J, Elkes C. Effect of chlorpromazine on the behavior of chronically overactive psychotic patients. Br Med J 1954; 2(4887):560–564.
[Supported in part by a grant from the Bruce J. Anderson Foundation.]
Ross J. Baldessarini
March 10, 2016