Wednesday, 01.04.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era

Background to An Oral History of the First Fifty Years
Starting Up (Volume One):  5. Interviewees
(Bulletin 37)

 

        Starting Up (Volume 1) covers the state of the art in psychiatry and pharmacology at the time of the emergence of neuropsychopharmacology. It includes transcripts of 22 videotaped biographical interviews with clinicians and basic scientists of whom all but one (Robert Cohen) were affiliated with ACNP. It is a distinguished group; 14 (Ayd, Brady, Carr, Cook, Dews, Domino, Elkes, Freedman, Gottschalk, Hollister, Kurland, Lehmann, Sarwer-Foner and Turner) were founders and seven (Cook, Detre, Elkes, Freedman, Hollister, Lasagna and Lehmann) past-presidents of the College; three (Hippius, Hollister and Lehmann) were past presidents of CINP.

The interviews were conducted from 1994 to 2004 and, with the exception of six (Carr, Cohen, Freedman, Hippius, Kurland and Szára), they were done at ACNP’s annual meetings. One of the interviews (Hippius) was conducted at CINP’s biennial congress, another (Carr’s) in Nashville and four at the home of the interviewee.

The 22 interviewees were interviewed by 13 interviewers. Eleven of the interviewers were peers of the interviewees, knowledgeable in the same field; one (Tone) was a medical historian; and one (Engelhardt) was a mental health professional and former associate of the interviewee. Ten of the interviewers conducted one interview and three conducted multiple interviews, i.e., Bunney: 2, Ban: 3 and Hollister: 4.

By the time the editing of Volume 1 began, four of the interviewees (Carr, Hollister, Turner and Wortis) and one of the interviewers (Hollister) had passed away.

 

Contributions of Interviewees

Four of the interviewees (Wortis, Cohen, Gottschalk and Sarwer-Foner), all psychiatrists, had some background in psychoanalysis. Joseph Wortis was psychoanalyzed by Sigmund Freud himself. He did not become a psychoanalyst but introduced insulin comatreatment and convulsive treatment with pentylenetetrazol (Cardiazol, Metrazol) in the United States (Wortis and Lambert 1939).In the early 1960s, Wortis studied the effects of chlorpromazine on brain tissue preparations (Wortis and Jackim 1982).

Robert Cohen was analyzed by Frieda Fromm-Reichman. In 1952 he moved from Chestnut Lodge, one of the fortresses of psychoanalysis, to the National Institutes of Health; during the 1960s and ’70s he was the moving force in developing the intramural research program of the National Institute of Mental Health (NIMH).

Louis Gottschalkwas trained under Franz Alexander and Thomas French at the prestigious Chicago Institute for Psychoanalysis. He became interested in objective measurements and developed an instrument with the capability of monitoring drug-induced changes by content analysis of speech (Gottschalk 1995).

Gerald Sarwer-Foner,in parallel with his psychoanalytic training, became involved in the clinical evaluation of the new psychotropic drugs, e.g., reserpine, imipramine, phenelzine, perphenazine, trifluoperazine and haloperidol (Sarwer-Foner 1957). His postulation that psychotropic drugs exert their effect by shifting “psychic defenses” was lauded by the psychoanalytic establishment. The idea was that in contrast to some of the old drugs, such as the barbiturates, which enforce defenses like regression, denial and projection, some of the new drugs facilitate the operation of more constructive defense mechanisms, such as isolation, rationalization and sublimation, allowing the patient’s ego to work through to a better adaptation tothe reality principle (Lehmann 1993). Alternative psychodynamic formulations were proposed by Azimaand Ostow (Azima 1959; Ostow 1962).

Two of the interviewees (Szára and Domino) made their mark in the arena of research that deals with model psychoses.Steven Szára was first to describe the psychomimetic properties of dimethyltryptamine (DMT), a psychotoxic end product of tryptophan metabolism (Szára1956).His negative findings about the presence of adrenochrome in the plasma of normal subjects and schizophrenic patientswas the coup de gráce of the adrenochrome hypothesis of schizophrenia (Hoffer, Osmond Smythies 1954; Szára, Axelrod and Perlin 1958).

Edward Domino was instrumental to the research that led from phencyclidine (Sernyl)to psychomimetic arylcyclohexylamines, e.g., ketamine, a group of drugs which selectively reduce the excitation of mammalian neurons induced by aspartate–like amino acids (Domino 1964; Domino, Chodoff and Corssen 1966).

Eight of the interviewees (Hippius, Lehmann, Hollister, Ayd, Kurland, Turner, Freedman and Detre), all psychiatrists, contributed to the introduction of new psychotropic drugs: seven in the United States and one, Hippius, in Germany. Hanns Hippius was also instrumental in training a cadre of psychiatrists involved in research in the new field (Benkert and Hippius 1974; Kalinowsky and Hippius 1969).

Heinz Lehmann, a Canadian psychiatrist, was the first to report in 1954 on the therapeutic effect of CPZ in psychotic patients in North America (Lehmann and Hanrahan 1954).The impact of his paper was so profound that in 1957 he was presented with the prestigious Lasker Award of the American Public Health Association for “bringing the full practical significance of CPZ to the attention of the medical community.” Lehmann was also first in North America to report on the effects of imipramine in the treatment of depression (Lehman, Cahn and deVerteuil 1958).

Leo Hollisterwas one of the leading figures in the introduction of new psychotropic drugs, e.g., reserpine, in the United States(Hollister et al. 1955). A sharp observer, Hollister noted that CPZ and reserpine not only controlled productive (positive) psychopathology, e.g., hallucinations and delusions, but made patients talk and interact with their environment. He was the first to report withdrawal reactions after prolonged high-dose use of several drugs, including CPZ, meprobamate and chlordiazepoxide (Hollister 1978).

Frank Aydwas among the first to report on the therapeutic and adverse effects of numerous psychotropic drugs, including chlorpromazine andamitriptyline, in the 1950s and ’60s (Ayd1955, 1960). A prolific writer, he was quick to disseminate in his Newsletter newly emerging findings with psychotropic drugs in an era when findings in clinical research still traveled slowly. His Lexicon of Psychiatry, Neurology and the Neurosciences was to become a standard reference (Ayd 2000).

Albert Kurland was Principal Investigator of one of the first Early Clinical Drug Evaluation Units (ECDEU), a program of the PsychopharmacologyServiceCenter, sponsored by the NIMH. He was one of the first, in the mid-1950s, to compare the effects of chlorpromazine and reserpine in the treatment of schizophrenia (Kurland 1956).Kurland was to become a proponent of LSD treatment of alcoholismintroduced by Hoffer and Osmond (Hoffer and Osmond 1968; Kurland et al.1967).

William Turner was one of the investigators in the ECDEU program. He collaborated in the 1950s and’60s with Sydney Merlis in the clinical evaluation of trifluoperazine and numerous other new psychotropic drugs (Merlis and Turner 1961). To pursue their investigations in an inpatient setting in a large mental hospital, Turner adopted the Malamud-Sands Rating Scale for use by the ward personnel in the assessment of change in patients (Turner, Krumholz and Merlis 1962).Turner was to become a proponent of the use of diphenylhydantoin in the control of aggression.

Alfred Freedman was instrumental inextending pharmacological treatment with psychotropic drugs from adult to child psychiatry. He was the first in the 1950s to study the effects of diphenhydramine, iproniazid, imipramine, iproniazid and promethazine in children (Freedman, Efron and Bender 1955).In the 1970s and ’80s he contributed to the evaluation of the effects of cyclazocine, naloxone, etc., in narcotic addiction (Freedman et al.1970).

Thomas Detre was involved in clinical investigations with reserpine and some of the other new drugs in the 1950s (Detre and Jarecki 1971).As clinical director of Yale’s New Haven Hospital during the 1960s, he was in the forefront in breaking the resistance of the psychoanalytic establishment to using psychotropic drugs (Detre 2004).

The steadily growing number of new psychotropics in the late 1950s created a need for the adoption of a clinical methodology for the demonstration of therapeutic efficacy. Louis Lasagna played an important role in the introduction of the placebo-controlled randomized clinical trial in psychopharmacological research (Lasagna 1955).He was also instrumental in developing clinical pharmacology into a distinct medical discipline in the United States (Lasagna 1998).

Registration of the new drugs called for adequate toxicity requirements to secure their safe use. Requirements were tightened after the thalidomide disaster in Europe in which the substance, taken as a hypnotic by pregnant mothers, caused phocomelia in the newborn. In the development of “regulatory toxicology,” Jelleff Carr played an important role in the United States (Carr 1996).

Four of the interviewees (Brady, Cook, Dews and Stein) were instrumental in introducing behavioral pharmacology in the study of the new psychotropic drugs (Iversen and Iversen 1981).  The roots of behavioral pharmacology lie in the research of Ivan Petrovich Pavlov, a Russian physiologist who studied the effects of bromides and caffeine, and of Horsley Gantt, his American disciple, who studied first the effects of alcoholacetylcholine and adrenaline, and then CPZ and reserpine,on conditioned reflex (CR) behavior. Gantt was referred to as the first American psychopharmacologist by Wagner Bridger, an American psychiatrist who himself studied the effects of mescaline on the CR (Freile and Gantt 1944; Gantt 1935; Gledman and Gantt 1958; Pavlov 1927, 1941; Stoff, Bridger and Gantt 1987). Pavlov and Gantt recognized that non-specific properties of a drug, e.g., color of the capsule, and events that regularly occur prior to its administration could become signals for eliciting the specific effects of a substance.This recognition was further elaborated by the American behaviorist school.Joseph Brady demonstrated that drugs not only have signal function, as do all other signals in the environment (classical paradigm of conditioning), but also function as “reinforcers” of activities that control behavior (instrumental-operant paradigm of conditioning). In the 1940s, Brady developed a conditioned emotional response (CER) in animals and during the 1950s he studied the effects of the new psychotropic drugs on the CER (Brady 1956, 1959).

Peter Dews was the first to recognize the role of the operating schedule of reinforcementon the behavioral effects of drugs. He also showed that if two different events maintain response on a fixed interval schedule, then a given drug will affect each behavior pattern in the same way (Dews 1953, 1955).

Leonard Cook was first to show that CPZ and drugs with similar clinical effects differ from barbiturates and “old-time” sedatives by selectively blocking the conditional avoidance reflex, while leaving the unconditional escape response unaffected (Cook 2000; Cook and Catania 1964; Cook and Wesley 1957).

Larry Stein was instrumental in bridging behavioral pharmacology with neurochemistry. He was the first to demonstrate the reward augmenting effect of dopamine agonists, such as apomorphineand high dose amphetamine (Baxter et al. 1974; Stein et al. 1974).

The remaining two interviewees (Elkes and Gershon) contributed to bridging basic and clinical research in neuropsychopharmacology. Joel Elkes conducted the first blind, controlled, crossover clinical trial with CPZ in chronic psychotic patients(Elkes and Elkes 1954).He also explored the effects of amobarbital, amphetamine and mephenesin on catatonic stupor(Ban 2001).In collaboration with Philip Bradley, Elkes was first to study the effects of centrally acting drugs on the electrical activity of the brain in conscious animals (Bradley and Elkes 1957; Elkes, Elkes and Bradley 1954). The concept of signal transduction in the brain was shifting during the 1950s from a purely electrical to a chemically mediated event; Elkes mapped the cholinesterases responsible for the formation and breakdown of acetylcholine in various areas of the central nervous system (Elkes and Todrick 1955).He recognized that inhibition of the enzyme has an effect on the emergence of various inborn reflexes (Elkes, Eyars and Todrick 1955). Acetylcholine was the first neurotransmitter identified in the brain. The role of acetylcholine in mental integration, as reflected in consciousness and memory, was to become one of the major areas of neuropsychopharmacological research.

While looking for pharmacological antagonists of morphine in the early 1950s, Samuel Gershon discovered that tetrahydroaminoacridine (THA), a cholinesterase inhibitor, antagonized both morphine-induced sedation and coma as well as the aberrant behavior induced by atropinergic (anticholinergic) drugs, e.g., Ditran. His discovery yielded, many years later, the introduction of THA in the treatment of dementias. Gershon spearheaded research using drugs in the elucidation of the underlying molecular changes in psychopathology (Gershon and Olaria 1960; Soares and Gershon 1995).He was first with his collaborators to show that the administration of amphetamine, a dopamine agonist, could induce not only “paranoid excited hyperactive states” but also symptoms like “anergia” (Angrist and Gershon 1970).He and his collaborators were also the first to show that pharmacological interference with the formation of serotonin by the administration of p-chlorophenylalanine blocked the therapeutic effect of antidepressants, whereas interference with the formation of norepinephrine by the administration of α-methylparatyrosine left the therapeutic effect of antidepressants unaffected (Shopsin et al. 1975).Gershon was a member of Trautner’s team that defined the therapeutic window for lithium treatment. He provided further substantiation for the specificity of lithium treatment in manic-depressive disease and was first to report on the effectiveness of lithium in the prophylactic treatment of bipolar affective disorder (Gershon and Trautner 1956).Gershon’s research was instrumental in introducing lithium treatment in psychiatry in the United States (Gershon and Yuwiler 1960).

In Volume 1 the personal stories of the interviewees began in a period in which the brain is perceived an impenetrable “black box” and mental disease was conceptualized as the result of interaction between psychological and social factors.

The background of the interviewees varied widely. Their only common feature was that they all participated in starting up the new field.

 

References:

 

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Ayd FJ. Treatment of psychiatric patients with Thorazine. South Med J 1955; 48: 177–86.

Ayd FJ. Amitriptyline (Elavil) therapy of depressive reactions. Psychosomatics 1960; 1: 320–5. 

Ayd FJ. Lexicon of Psychiatry, Neurology and the Neurosciences. Second Ed. Philadelphia: Lippincott Williams & Wilkins; 2000.

Azima H. Psychodynamic alterations concomitant with Tofranil administration. Can Psychiatr Assoc J 1959; 4: 172–81.

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Ban TA. Academic psychiatry and the pharmaceutical industry. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 429 – 41. 

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September 27, 2018