Max Fink: Donald F. Klein – Clinician Researcher in Experimental Psychiatry At Hillside Hospital 1959-1976*
Donald Klein joined the Department of Experimental Psychiatry at Hillside Hospital, NY, in the fall of 1959, from Creedmoor Psychiatric Center and the Federal Narcotic Addiction Center at Lexington, Ky. He had graduated from the Downstate Medical Center in Long Island. At that time the new psychotropic drugs - chlorpromazine, imipramine, reserpine - and new sedatives were prescribed and monitored by the physicians of the Department of Experimental Psychiatry at Hillside. He was appointed to supervise and monitor medication treatments. We collaborated until I left to establish the Missouri Institute of Psychiatry in St. Louis in July 1962. Don was appointed to replace me and remained until he moved to Columbia University with Edward Sacher in 1976.
Experimental psychiatry was a unique department in a 200-bed inpatient facility, supported by a lay Board of Directors, mainly Jewish, that had been organized in the 1930s. Its Medical Board was filled with psychoanalysts and the training was focused on psychoanalytic psychotherapy, but the treatment programs included electroshock, insulin coma, group and individual therapies. When the new psychotropic drugs were introduced to the hospital in 1954, their experimental nature led the hospital Medical Board to support a separate service to prescribe and monitor the new drugs. A Department of Experimental Psychiatry was established under my leadership.
I graduated from NYU Bellevue on June 12, 1945, interned and spent the next years in neurology and psychiatry. On January 2, 1952, I enrolled at Hillside Hospital for an additional year of residency training in psychiatry. For the first three months I was assigned to the insulin coma and electroshock units and over the year assumed more time on these services. I opened a private practice office in neurology in 1953, but continued to supervise these services on a half time basis. In 1953 I trained in electroencephalography at the Mount Sinai Hospital and later that year established a clinical EEG unit at Hillside. A research question was developed: what was the significance of the EEG changes that occurred during each seizure and that peristed for days and weeks after each seizure? An application for funding to NIMH was approved for a study "EEG of Electroshock" (M-927) and with the award the Medical Board established the Department of Experimental Psychiatry.
We examined the relation of the slowing of EEG frequencies during the ECT course and clinical improvement. The study team tested various forms of electricity to stimulate the seizure, compared the efficacy and behavior effects of different electrode placements, compared seizure to non-seizure treatments, compared electric to flurothyl inhalant seizures and measured the changes in psychological tests associated with treatment. In 1961 I summarized our experiences in a report that became the core material of the studies described in my 1979 book Convulsive Therapy: Theory and Practice.
The laboratory of experimental psychiatry grew rapidly, especially as new psychiatric medicines began coming on the scene. Two full time clinical psychiatrists, John C. Kramer and Donald F. Klein, took part in dose-finding medication studies and behavior changes measured using the Lorr Behavior Rating Scale. My neurology training colleague, Martin Green, led the EEG studies and Joseph Jaffe studied the changes in recorded speech patterns. The psychologists Robert L. Kahn, Max Pollack, Nathaniel Siegel, Hyman Korin, Ira Belmont, Eric Karp and George Krauthamer joined the department to tease out changes in patient responses to the Rorschach, California F Scale and Hollingshead and Redlich Social Class psychological tests, as well as responses to tachistoscopic exposure to complex images.
Additional funding came from the NIMH ECDEU program, from private foundations and from the Hospital. By 1958, I closed my office and dedicated full time to Hillside research.
Once we saw the acute benefits of chlorpromazine (CPZ) we established an RCT study of 50 insulin comas or CPZ to 1200 mg/day. By 1958 we reported that CPZ was as effecive, safer, with fewer risks and less expensive than ICT. The ICT unit closed.
The introduction of imipramine (IMI) in 1957 raised the question: for whom was CPZ and IMI relevant, at what dosages and with what required testing for safe management? It was to answer this question that I sought an MD psychiatrist and Don joined the Department with responsibility with John C Kramer and residents to supervise psychotropic drug administrations in the hospital.
The agents were approached as dissecting tools: which behaviors that were measurable were altered, in what patterns, for which patients? The criteria for diagnosis were wholly subjective, the singular DSM-I had been introduced in 1952, and were not reliable. Such was particularly true for the Hillside faculty that competitively used either the Kraepelin/Bleuler criteria or the analytic focus on principal symptoms of hysteria, obsessions, phobias, depression or psychosis. We did not know which medications to prescribe for which patients.
In seeking to identify the indications, we examined the rating scales and identified the items that showed the most change. We identified neuropsychologic response patterns and then in 1961 Kahn and I described behavior patterns that changed with electroshock. We applied that model to the changes induced by imipramine and then by the phenothiazines. These experiences led to the concept of "pharmacologic dissection," the measurement of changes in behaviors in response to drugs. This model became Don's signature contribution to psychopharmacology.
Klein and Kramer described withdrawal symptoms to imipramine, suggesting that tolerance developed with chronic use. We peremptorily discontinued IMI and CPZ at the end of six weeks of treatment for those who did not fare well, finding that each patient developed fever, headache, nausea, rhinorrhea of a URI. But as it was common on withdrawal, it was so reported, a first finding in psychopharmacology.
We confirmed the antidepressant efficacy of imipramine but also described the efficacy of chlorpromazine as an antidepressant in patients with psychotic melancholic depression. In anxious phobic adolescent patients, especially those with panic states, imipramine successfully resolved their anxieties. The finding contributed much to Don’s later studies of anxiety states. Among adolescents with psychosis, imipramine worsened their condition, a warning of a risk that had not been defined earlier.
When I left Hillside in July 1962, Don was appointed to replace me. He continued medication trials but gradually the EEG, ECT, neuropsychology research ended. Although ECT continued as a clinical service, research studies of it ended for close to four decades until I brought the NIMH-supported CORE ECT studies to Hillside Hospital in 1997.
Over the next few years, we met at various ACNP, NCDEU, APA meetings. In 1966 I returned to New York to join the faculty of New York Medical College. I developed EEG and clinical studies of opioids, opioid antagonists, cannabis and hashish in the US and Athens, Greece, and ECT studies at Gracie Square Hospital in New York. A report by Pitts and McClure in the NEJM in 1967 attracted my interest. They asserted that an infusion of lactate precipitated anxiety, tachycardia and systemic distress in patients with a history of anxiety disorder and not in their siblings or spouses. I asked a senior resident at Metropolitan Hospital, Michael A. Taylor, to look into this study. We obtained samples used by Pitts and proceeded to infuse subjects in the EEG laboratory. We confirmed the finding, described the EEG effects of lactate and applied to NIMH for a grant to undertake a systematic study (a grant, MH 21306, for $58,510 was awarded in 1971). Our patients were derived from Metropolitan Hospital but the directors insisted we pay overhead funds to the hospital. As the award was a fellowship type, without overhead, we cancelled the study.
On November 9, 1976, I received a letter from Don asking whether I would share my experience with lactate and anxiety. I shared our reports, confirming the Pitts and McClure suggestion. They may have been helpful in his lifetime study of the physiology and clinical aspects of lactate infusion, carbon dioxide and anxiety.
He became interested in catatonia and brought to my attention a report of an 8-year old girl who stopped eating and drinking after a viral infection and who was hospitalized for more than a year before being returned to her family in partial remission. We agreed that she was catatonic and asked the report’s authors whether not testing and treating for catatonia had not been unethical. The authors offered a complex rejoinder without explaining the failure to test with barbiturates or benzodiazepines.
When catatonia scholars encouraged the DSM-5 commissioners to view catatonia as an independent clinical entity, Don joined the 130 signatories.
His major contribution was in defining panic disorder. Medline cites 144 citations with extensive psychopharmacology collaborators including Ira Glick, Michael Liebowitz, Jack Gorman, Myrna Weissman, Dan Pine, Fred Quitkin and many others he taught as residents and launched the careers of John Kane and Jeffrey Lieberman.
He described endogenomorphic depression, was active in the 2006 Copenhagen Melancholia Conference that defined the syndrome as a primary clinical syndrome, not a descriptor as defined by the DSM; was active on the DSM-III commission; and much more.
Don Klein tolerated fools poorly, was sharp tongued in his critique of presentations, including some of my own. I very much regret that our research interests did not mesh more often.
Fink M, Kahn RL. Behavioral patterns in convulsive therapy. Arch Gen Psychiatry. 1961; 5(1):30-6.
Fink M. Convulsive Therapy: Theory and Practice.Neww York: Raven Press; 1979.
Fink M, Klein DF, Kramer JC. Clinical efficacy of chlorpromazine-procyclidine combination, imipramine and placebo in depressive disorders. Psychopharmacologia 1965; 7(1): 27-36.
Fink M, Klein DF. “An ethical dilemma ....” Psychiatric Bulletin. 1995; 19: 650-1 (letter).
Francis A, Appiani F, Bertelsen A, Bolwig TG, Braunig P, Caroff SN, Carroll BT, Cavanna AE, Cohen D, Cottencin O, Cuesta MJ, Daniels J, Dhossche D, Fricchione G., Gazdag G, Ghaziuddin N, Healy D, Klein DF, Krüger S, Lee JWY, Mann SC, Mazurek M, McCall WV, McDaniel WW, Northoff G, Peralta V, Petrides G, Rosebush P, Rummans TA, Shorter E, Suzuki K, Thomas P, Vaiva G, Wachtel L. Catatonia in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. J ECT 2010; 26:246-8.
Fink M, Karp E, PollackM, Klein DF, Blumberg AG, Belmont I, Karp E, Kramerb JC, Willnner A. Comparative studies of chlorpromazine and imipramine. 1. Drug discrimibnation patterns. In Bradley PB, Flugel F, Hoch P, editors. Neuro-Psychopharmacology. Amsterdam: Elsevier; 1964, pp. 370-2.
Klein DF, Fink M. Psychiatric reaction patterns to imipramine. Amer. J. Psychiat. 1962; 119: 432-8.
Klein DF, Fink M. Behavioral Reaction Patterns with Phenothiazines. Arch Gen Psychiatry. 1962; 7(6):449-59.
Klein DF, Fink M. Multiple item factors as change measures in psychopharmacology. Psychopharmacologia Psychopharmacologia. 1963; 4:43-52.
Kramer JC, Klein DF, Fink M. Withdrawal Symptoms Following Discontinuation of Imipramine Therapy. Amer. J. Psychiat. 1961; 118: 549-50.
Kramer JC, Klein DF, Fink M. Imipramine as an adjunct to phenothiazine therapy. Compr Psychiatry. 1962; 3:377-80.
Pitts FN Jr, McClure JN Jr. Lactate metabolism in anxiety neurosis. N Engl J Med. 1967;
Pollack M, Karp E, Krauthamer G, Klein DF, Fink M. Neuropsychologic response pattern of some psychotropic druggs. In: Rothlin E, editor. Neuro-Psychopharmacology. Amsterdam: Elsevier; 1961, pp. 381-4.
Pollaqck M, Klein DF, Willner A, Blumberg AG. Imipramine-induced behavioral disorganization in patients: physiological and psychological correlates. In: Wortis J, editor. Recent Advances in Biological Psychiatry. New York: Plenum Press; 1965, pp. 53-61.
*Based upon records from the Max Fink Archives, Special Collections, Main Library, Stony Brook University, Long Island, NY. Archivist: Kristen Nyitray.
December 26, 2019