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
Neurophysiology (Volume Two): 2. Interviewees Contributions
As in the first volume, the 21 transcripts in this volume are based on videotaped interviews with 21 interviewees. From the group, 12are trained psychiatrists (Aghajanian, Andreasen, Bloom, Callaway, Feinberg, Fink, Gillin, Hartmann, Itil, Kaim, Sugerman and Weinberger) andtwo (Aghajanian and Bloom) are involved exclusively in basic research. From the remaining nine interviewees, one (Kessler) is a radiologist, four (Delgado, Kety, Longo and Sokoloff) are MDs and four (Bradley, Holzman, E. Killam and K.Killam) are PhDs, all involved in different areas of research in neurophysiology related to neuropsychopharmacology. All but two interviewees (Bradley and Longo) are ACNP members; six (Callaway, Delgado, Fink, Kety, E. Killam and K. Killam) were founders; and two (E. Killam and K. Killam) were presidents of the College.
All interviews were conducted duringa period from 1993 to 2007 and, with the exception of two, were done at the annual meetings of the College. Ofthe two interviews done between annual meetings, one (Kaim’s) was conducted in Washington DC and the other (Bradley’s) in London, England.
The 21 interviewees were interviewed by 12interviewers. Nine of these (Joel Braslow, William Bunney, Jonathan Cole, Leonard Cook, Eva Killam, Keith Killam, Irwin Kopin, David Kupfer and Steven Potkin) conducted one interview apiece. Of the remaining three, one (Andrea Tone) conducted two interviews; another (Leo Hollister) conducted three;and the third (Thomas Ban) conducted seven. In one instance, instead of an external interviewer, two interviewees (Keith Killam and Eva King Killam, husband and wife) interviewed each other. Ten of the interviewers are peers of the interviewees and two (Braslow and Tone) are medical historians. One of the latter (Braslow) is also a trained psychiatrist.
By the time the editing of Volume Two was completed, seven of the interviewees (Philip Bradley, Christian Gillin, Philip Holzman, Seymour Kety, Eva Killam, Keith Killam and Arthur Sugerman) and four of the interviewers (Jonathan Cole, Leo Hollister, Eva Killam and Keith Killam) had passed away.
Contributions of Interviewees
In the following some of the contributions of interviewees to the development of neuropsychopharmacology are reviewed.
Five interviewees (Fink, Callaway, Itil, Kaim and Sugerman) were engaged in studying the effects of psychotropic drugs with the employment of the EEG in humans.In the 1950s Samuel Kaim studied the effect of new drugs on the seizure threshold in epileptics with Metrazol (pentylenetetrazol) (Kaim and Rosenstein 1960). He also employed the EEG for monitoring drug effects (Hollister et al. 1963). Kaim was among the first to note that chlordiazepoxide in alcohol withdrawal could prevent seizures in delirium tremens (Kaim and Klett 1972; Kaim, Klett and Rothfeld 1969).
Enoch Callawayintroduced in the 1960s the “two-tone method” for studying event related potentials (ERPs) in schizophrenia (Callaway, Jones and Layne 1965; Malerstein and Callaway 1969). He found significantly lower two-tone correlations in schizophrenia than in normal controls or in hospitalized psychiatric patients with another diagnosis. Callaway also revealed that two-tone correlations increased with clinical improvement, approaching normal values with effective phenothiazine treatment (Callaway 1968, 1975, 2004, 2007).
Max Fink was one of the first (in 1958) to report on the effects of chlorpromazine (CPZ) on the human EEG (Fink 1959). Fink introduced in the early 1960s electronic frequency analysis in the evaluation of the electroencephalogramand set up the first EEG laboratory employing digital computer technology to study the effect of psychotropic drugs (Fink 1969, 2004; Fink, Itil and Shapiro 1967).
Turan Itil also reported in 1958 on the EEG effects of chlorpromazineand spearheaded research during the 1950s on the effects of antipsychotic and antidepressant drugs on the human EEG (Bente and Itil 1959; Itil 1964, 1961, 1998).In the 1960s Itil and Fink in collaboration developed “the quantitative pharmaco-EEG” for screening and classifying psychotropic drugs, monitoring changes in the course of treatment and predicting treatment outcomes in individual patients (Fink, Shapiro, Hickman and Itil 1968; Itil, Shapiro and Fink 1968; Sugerman 1964, 1967).
In the 1960s, Arthur Sugerman was among the first to employ quantitative EEG in the screening and evaluation of new psychotropic drugs (Sugerman 1964; Sugerman and Herrman 1967). Sugerman was also one of the first researchers to show that treatment with antipsychotics by increasing the amplitude variability of brain waves corrected the reduced amplitude variability in schizophrenia(Goldstein and Sugerman 1969; Sugerman 2000).
Three of the interviewees (Hartmann, Feinberg and Gillin) were engaged in studying the effects of psychotropic drugs on the sleep EEG. Ernest Hartmanndiscovered in the 1960s that drugs which increased norepinephrine (NE) levels in the brain decreased D-sleep (Hartmann 1969, 1978).He also noted that L-DOPA could increase nightmares and induce vivid dreams (Hartmann 1968; Hartmann, Russ andOldfield 1980).
Irwin Feinberg revealed during the 1960s that the relative excess of fast (beta) activity in the EEG seen in schizophrenia is associated with an increased number of awakening periods and decreased amount of time spent in deep-sleep stages (Feinberg, Braun, Koresko and Gottlieb 1969; Feinberg, Koresko and Gottlieb 1965). Feinberg divided hypnotics into GABAergic modulators (e.g., barbiturates, benzodiazepines), which decrease, or even eliminate deep Stage 4 sleep, and glutamate antagonists, which increase deep sleep (Feinberg, Maloney and Campbell 2000). He also demonstrated that GABAergic modulators increased only “subjective sleeping time” whereas glutamate antagonists also increased the duration of sleep (Feinberg, Campbell, Schepp and Anderson2002; Feinberg, Walker, Price, Price, Floyd and March 1977).
J. Christian Gillin demonstrated in the 1980s that REM induction is mediated by muscarinic M2 receptors (Gilli, Sutton, Ruiz et al. 1991; Velazques-Moctezuma, Gillin and Shiromani 1989). He also showed that selective serotonin reuptake inhibitors lose their REM-suppressing effect with tryptophan depletion (Evans, Kelsoe, Rapaport, Resovsky, Sutton and Gillin 2002); Landott, Kelsoe, Rapaport and Gillin2003; Moore, Gillin, De Modena et al. 1998). Gillin was a member of the team thatstudied the effect of sleep deprivation on brain metabolism (Wu, Gillin, Buchsbaum et al. 1992; Wu, Gillin, Schachat et al. 2008).
Five interviewees (Kety, Sokoloff, Kessler, Andreasen and Weinberger) were engaged in studying the effects of psychotropic drugs on CBF and brain metabolism. Seymour Kety developedin the mid-1940s, in collaboration with Carl Schmidt, the first method for measuring overall cerebral blood flow (CBF) and metabolism in man (Kety and Schmidt 1948). The Kety-Schmidt nitrous oxide method was sensitive to the effects of barbiturates, insulin coma and electroshock (Kety, Woodford, Harmel, Freyhan, Appel and Schmidt 1948). In the mid-1950s Kety with his collaborators also developed the first method for studying regional cerebral blood flow (rCBF) and metabolism with the use of trifluoriodomethane (TFDM) (Landau, Freygang, Rowland, Sokoloff and Kety 1955).
In the late 1970s Louis Sokoloff, a disciple of Kety, replaced oxygen consumption with glucose utilization and developed an autoradiographic method with deoxyglucose for measuring rCBF and metabolism in man (Sokoloff, Reivich, Kennedy et al. 1977). Subsequently, by replacing deoxyglucose (DG) with fluorodeoxyglucose (FDG), Sokoloff rendered the method suitable for use with a scanner and opened the path for the introduction of positron emission tomography (PET) (Reivich, Kuhl, Greenberg et al. 1977; Phelps, Huang, Hoffman, Selinand Sokoloff 1979; Sokoloff 2004).
Robert Kesslerwas a member of the team thatintroduced cerebral glucography into psychiatric research with PET in the early 1980s (Buchsbaum, Ingvar, Kessler et al. 1982). The team showed that the “anteroposterior gradient” of glucose use (“hypofrontality”) was decreased statistically, not only in schizophrenia, as shown by SPECT imaging, but also in affective illness (Buchsbaum, DeLisi, Holcomb and Kessler1984; Ingvar and Franzen 1974).
Nancy Andreasenin the mid-1980s introduced magnetic resonance imaging (MRI) in the study of schizophrenia. She revealed thalamic abnormalitiesand smaller frontal lobes in schizophrenia than in the normal population (Andreasen, Arndt, Swayze et al. 1994; Andreasen, Nasrallah, Dunn et al. 1986). In the mid-1990s Andreasen postulated that a dysfunctional prefrontal-thalamic-cerebellar circuitry was the culprit for the cognitive dysfunction in schizophrenia (Andreasen, O’Leary, Cizadlo et al. 1996).
Daniel Weinberger introduced, in the mid-1980s, topographical imaging with the use of radioactive xenon in the study of schizophrenia (Weinberger, Berman and Zec 1984).He found that administration of the Wisconsin Card Sorting Test (WCST) did not produce an increase in CBF in the dorsolateral prefrontal cortex of this population (Goldberg, Weinberger, Berman, Pliskin and Poss1987). Weinberger was among the first to combine molecular genetic research with functional brain imaging in the study of schizophrenia (Weinberger, Egan, Bertolino et al. 2001; Wonodi, Mitchell, Stine et al. 2006).
One of the interviewees,Philip Holzman, discovered in the mid-1970s that an abnormality of the smooth pursuit eye movement (SPEM), a discrete neurological deficit, was present in 80 percent of patients with schizophrenia and in 40 percent of the first degree relatives of these patients (Ban 2002; Holzman, Levy and Proctor 1976; Holzman, Proctor and Hughes 1973). He perceived the population with an abnormality of SPEM as an alternative phenotype of the schizophrenic population and determined that a single gene could account for the tracking dysfunction (Hartman, Russ, Oldfield et al. 1980).The gene was located by Arolt and his associates in the mid-1990s on the short arm of chromosome 6p (Arolt, Lencer, Nolte, Pinnow and Schwiger 1996).
Four interviewees (Longo, E. Killam, K. Killam and Bradley) were engaged in research studying the effect of psychotropic drugs on the activity of the brain in animal models. Vincenzo Longoin 1954was first to report on the “synchronizing” effect of chlorpromazine (CPZ) on the EEG of rabbits (Longo, Von Berger and Bovet 1954). He suggested that the action of CPZ was on midbrain reticular formation structures and classified CPZ as a “ganglioplégique central” (Bovet and Longo 1956; Longo 1956, 2000). In the early 1960s Longo presented his findings in neurophysiological research with centrally-acting drugs in rabbits in an “electroencephalographic atlas for pharmacological research” (Longo 1956).
The Killams, Eva and Keith, were among the first (in the 1950s) to study the effects of the new psychotropic drugs on the brains of animals by using electrophysiological measures (Killam 1956; Killam and Killam1957, 1959).Eva King Killam was first to report on the effect of mephenesin on the brain stem reticular formation [i]and to demonstrate the differential effect of anesthetics and interneuronal blocking agents on EEG arousal and recruitment responses evoked from the brain stem (Killam 1968; King1954, 1956; King and Unna 1954). Keith F. Killam studiedthe effects of psychotropic drugs on evoked electrical activity of the brain (Killam 1957). He was the first to report on the effect of psychotropic drugs on pathways of the reticular formationand on the reticular formation in general (Killam 1963; Killam and Killam 1958).The Killams developed a screening test in baboons for anticonvulsants (Killam, Naquet and Bert 1966; Weinberger and Killam 1978).
In the early 1950s Philip B. Bradley introduced chronic implanted electrodes in studying the effects of psychotropic drugs on the electrical activity of the brain in conscious cats(Bradley and Elkes 1953, 1953b, 1954).In the late 1950s he suggested that central depressants and stimulants, such as barbiturates and amphetamines, act directly on arousal mechanisms in the brain stem, whereas antipsychotics and psychotomimetics like CPZ and LSD act indirectly, via afferent collaterals on arousal mechanisms (Bradley 1958; Bradley and Kay 1958).Bradley was among the first to study the effects of centrally acting drugs on the electrical activity of single neurons (Bradley 1959, 2000; Bradley and Mollica 1958).
One of the interviewees, José Manuel Rodriguez Delgado,was first to employ chronic implanted electrodes in humans to study the effects of electrical and chemical stimulation of specific brain areas (Delgado 1952, 1955; Delgado, Hamlin and Chapman 1952).He also explored the use of chronic implanted electrodes in the treatment of schizophrenia, epilepsy and depression (Delgado 1977).
Two interviewees (Aghajanian and Bloom) were engaged in research on the study of the neurophysiology of neurotransmitters. By studying the firing rate of single neurons, George K. Aghajanian revealed during the 1970s some of the essential properties of serotonergic,noradrenergicand dopaminergic neurons (Aghajanian and Asher 1971; Aghajanian, Cederbaum and Wang1977; Aghajanian, Warren and Sheard 1968). In collaboration with Steve Bunney, Aghajanian showed that antipsychotics and amphetamines affect single cell activity of dopaminergic neurons in the opposite direction (Bunney and Aghajanian 1978). He also demonstrated that serotonergic neurons continuously release 5-HT in slow tonic firing[ii]whereas the tonic firing of noradrenergic neurons is reactive to sensory stimulation (Aghajanian and Wang 1978; Bunney and Aghajanian 1976; Bunney, Walters, Robert and Aghajanian1973).
During the 1960s and 1970s Floyd E Bloom characterized the neuroanatomy and neurophysiology of the NE system by employing microiontophoresis and electron microscopy combined with fluorescence histochemistry (Bloom 1968, 1978; Moore and Bloom 1979).In the 1980s and 1990s Bloom contributed to the characterization of neuropeptides and “other mediators” (Bloom 1985; Hokfelt, Bartfai and Bloom2003; Koob and Bloom 1982).
The contributions of Aghajanian and Bloom provide a bridge between neurophysiology and neuropharmacology, covered in Volume 3 of this series.
Interviewees included in Volume 2 entered the field at different stages in the development of NPP. Hence, the transcripts cover 50years of history during which various neurophysiological methods were in the forefront at the different periods for studying the action of psychotropic drugs in the brain.
By the 1970s the emphasis on neuronal processing at the site of the synapse had shifted from electrical to chemical transmission and, with this shift, the conceptual framework of the operation of the brain changed. While the EEG has remained a most useful guide for clinicians in the use of psychotropic drugs, the information generated with the employment of brain imaging techniques about the differential effect of drugs on signal transduction and regional brain metabolism in clinically distinct psychiatric populations was to provide more specific cues than the EEG for research in NPP.
Max Fink, the editor of this volume, is a clinical psychiatrist. He was one of the leaders in moving American psychiatry, embedded in psychoanalysis, into the neuropsychopharmacological era. Fink was also instrumental in rendering the EEG a suitable instrument for clinical research in the pharmacotherapy of psychiatric disorders. His Introduction and Dramatis Personae complements the information in the transcripts.
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