Sunday, 12.07.2020

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

Diverse Topics (Volume Eight): 2a. Interviewees Contributions

(Bulletin 67)

 

 

             Volume 8 includes transcripts of 24 videotaped biographic interviews with 19 psychiatrists, two basic scientists (Koslow and Maickel), one neurologist (Kleinman), one internist/clinical pharmacologist (Ackenheil) and one clinical psychologist (Frank).  All but two of the interviewees (Ceskova and Gaszner) were affiliated with the American College of Neuropsychopharmacology (ACNP); and five (Charney, Coyle, Davis, Nemeroff and Shader) were past-presidents of the College.

             The interviews were conducted during a period from 1997 to 2008 and, with the exception of two, at the annual meeting of the College. One of these two interviews, Ceskova’s, was conducted at the Collegium Internationale Neuropsychopharmacologicum’s (CINP) biennial Congress in Paris and the other, Shader’s, was conducted at Tufts University (his work place,) in Medford, Massachusetts.

            The 24 interviewees were interviewed by 13 interviewers. Eleven of the interviewers were peers of the interviewees and two, Braslow and Tone, were medical historians (Braslow is also a psychiatrist). Of the 13 interviewers, four conducted more than one interview: Tone conducted seven, Ban four and Hollister and Bunney two each.

            By the time Volume 8 was published, three of the interviewees (Ackenheil, Maickel and Tollefson) and one of the interviewers (Hollister) had passed away (Ban 2011a; Salzman 2011).

 

Contributions of Interviewees

 

             Four of the interviewees (Ackenheil, Maickel, Cole and Koslow) were first, second and third generation representatives of Brodie’s school at the US National Institute of Health (NIH) where development of neuropsychopharmacology began. Roger Maickel, a disciple of Bernard Brodie himself (from 1958 to 1965), was among the first in the 1960s to use drugs with known effects on biogenic amine systems as “tools” to examine neuronal processes involved in the response of the hypothalamus-pituitary-adrenocortical system to cold exposure (in the rat) (Maickel, Cox, Saillant and Miller 1968). His research in the 1980s contributed to opening the path for neuropharmacological studies in stress (Krishnan, Nash and Maickel 1991; Maickel and Zabik 1980; Nash and Maickel 1985). In the 1960s Maickel, in collaboration with Frank Miller and Ray Cox, developed a procedure for the extraction of monoamines from the rat brain and a spectrophotofluorimetric assay for the determination of norepinephrine (NE), serotonin (5-HT) and the 5–HT metabolite, 5-hydroxyindole acetic acid (5-HIAA) (Maickel 2004; Maickel, Cox, Saillant and Miller 1968; Pradham and Dunn 1986).

             Manfred Ackenheil was a fellow of Norbert Matussek, one of the German disciples of Brodie, in Hanns Hippius’ Department of Psychiatry at Ludwig Maximilian University in Munich. He was a member of Matussek’s team that showed that the human growth hormone (HGH) response to clonidine, a postsynaptic α-receptor agonist, is significantly reduced in patients with endogenous depression compared to normal subjects and patients with schizophrenia and neurotic depression (Matussek 1966, 1998; Matussek, Ackenheil, Hippius et al. 1980).  Ackenheil’s theory that clozapine differs in its mode of action from the other neuroleptics by its predominant effect on mesolimbic dopamine structures was one of the first steps in a chain of events that led to the dividing of antipsychotics in the 1980s into “atypical” and “typical” neuroleptics (Ackenheil 1981; Ackenheil, Brau, Burkhard et al. 1976). Ackenheil and Matussek were first to offer a psychopharmacology program in a university department of psychiatry in Germany (Müeller-Oerlinghausen 2000).

             Stephen Koslow was a fellow at the National Institute of Mental Health (NIMH) in the laboratory of Erminio Costa, a disciple of Brodie. In the 1970s he developed, in collaboration with Flaminio Cattabeni, a method to measure indolalkylamines in the pineal gland of the rat, using multiple ion detection with mass fragmentography (Cattabeni, Koslow and Costa 1972; Koslow, Cattabeni and Costa 1972). In the 1980s Koslow contributed to the information on the cerebrospinal fluid (CSF) and urinary concentration of biogenic amines and their metabolites in depression and mania (Koslow, Maas, Bowdeen et al. 1983).  In the 1990s his interest shifted to neuroinformatics (Koslow and Subramaniam 2005). By setting up data bases from his position at NIMH that would allow access to all information generated in neuroscience for analyses, Koslow helped open a new perspective for research and education in neuropsychopharmacology (Koslow and Hirsch 2004).

             Joseph Coyle, a student of Solomon Snyder, was a fellow in the laboratory of Julius Axelrod, a disciple of Brodie. By embracing classical enzymology, immunochemistry, ligand binding and molecular biology, his research reflects the rapid advances in technology during the last quarter of the 20th century.  Coyle’s separation of the dopamine transporter from the NE transporter in the late 1960s was instrumental for the demonstration of dopamine receptor blockade with neuroleptics (Coyle and Snyder 1969a,b; Horn, Coyle and Snyder 1971; Snyder and Coyle 1969). Coyle was first to show that antiparkinsonian drugs inhibit dopamine uptake in the corpus striatum (Robinson and Coyle 1987). Central to Coyle’s research is the role of glutamate in brain development and psychopathology.  In the 1980s he demonstrated that a selective lesion of the nucleus basalis, produced by the injection of glutamate agonists, resulted in cholinergic deficit, similar to that seen in Alzheimer’s disease (AD), and hypothesized that in the pathomechanism of AD over-activation of N-methyl-D-aspartate (NMDA) receptors by glutamate plays a role (Coyle, Price and DeLong 1989). Coyle’s hypothesis triggered research that contributed to the introduction   of memantin (Namenda), a substance that blocks NMDA receptors and prevents the effect of glutamate on the receptor in the treatment of AD (Coyle and Puttfarcken 1993). By producing a lesion of striatal neurones with kainic acid, Coyle developed an animal model for Huntington’s chorea; by producing a selective lesion in the brain by methoxymethyl acetate (MAM), he developed an animal model for schizophrenia (Coyle and Schwarcz 1976;  Wolfe, Sasich, Lurie et al. 2005). The schizophrenia model assumes that NMDA receptor hypofunction is at the core of the disease (Coyle 2006). In the 1990s Coyle became the Founding Chairman of Harvard’s Consolidated Department of Psychiatry and editor-in-chief of the Archives of General Psychiatry of the American Medical Association.

             Seven of the interviewees (Ebert, Charney, Heninger, Henn, Mandell, Mathé and Nemeroff) have contributed to the re-evaluation of diagnostic concepts in psychiatry with the employment of biological measures. They have also contributed to the transformation of psychiatric education from psychoanalytical to biological in the USA during the 1960s, ‘70s, ‘80s and ‘90s.  Of special importance in this respect was George Heninger’s contribution: at least six future departmental chairmen of psychiatry in the United Sates - Dennis Charney, Pedro Delgado, David Kupfer, Christopher McDougel, Eric Nestler and Thomas Uhde - were trained in his unit at Yale. In the1960s Heninger had shown diurnal variations in cerebral evoked responses (Heninger, Roger, McDonald et al. 1969). Subsequently, in the 1970s, with the use of spectral analysis, he revealed correspondence between the therapeutic and the evoked response to treatment with lithium in manic patients (Heninger 1978). There was no correspondence between the therapeutic and evoked response to treatment with chlorpromazine in schizophrenia (Heninger and Speck 1966). Heninger was first in the mid-1970s to report on interspecies differences in metabolizing lithium, with cats closer to humans than rats and monkeys closer than cats. His finding of differences in somatosensory evoked responses between the rat and the cat invalidated findings of many years of lithium research, including some of his own findings (Heninger and Sheard 1976). In the early 1980s Heninger was also among the first to report on lithium augmentation of antidepressant treatment in refractory depression (Heninger, Charney and Steinberg 1983). In the 1990s he was member of research teams which studied the effect of fluvoxamine on yohimbine-induced anxiety and panic disorder, the role of serotonin in the neurobiology of depression and the effects of ketamine in depression (Berman, Capiello, Anand et al. 2000; Delgado, Price, Miller et al. 1994; Goddard, Woods, Sholomskay et al. 1993). In 1997, together with Duman and Nestler, Heninger proposed a molecular and cellular theory of depression (Duman, Heninger and Nestler 1997). 

             In 1981 Dennis Charney published on the role of changes in receptor sensitivity in the mechanism of action of antidepressants (Charney, Menkes and Heninger 1981). In 1982 he was among the first to show that combined administration of naltrexone and clonidine is a safe, effective and rapid treatment of abrupt withdrawal from methadone (Charney, Riordan, Kleber et al. 1982). Charney was member of the team that demonstrated a reduction of hippocampal volume, as measured by magnetic resonance imaging, with a decrease of hippocampal-based memory function in post-traumatic stress disorder (PTSD) (Bremner, Randall, Scott et al. 1995; Bremner, Scott, Delaney et al. 1993; Charney 2004;  Charney, Deutsch, Krystal et al. 1993). They also showed hippocampal volume reduction in major depression and increase of hippocampal volume with corresponding changes in memory function after the administration of serotonin re-uptake inhibitors (Bremner, Narayan, Staib et al. 1993). The findings of Charney’s team, with the employment of positron emission tomography (PET) and functional magnetic resonance imaging  (MRI), point to the involvement of ventral prefrontal-striatal structures in the pathophysiology of bipolar disorder and with morphometric measures indicate a prominent decrease in amygdala volume in both adolescent and adult bipolar patients (Blumberg, Leung, Skindlarski et al. 2003; Blumberg, Martin, Kaufman et al. 2003). In the early years of the 21st century Charney was among the first to study the antidepressant effect of ketamine and the effectiveness of an N-methyl-D-aspartate antagonist in the treatment of depression (Berman, Capiello, Anand et al. 2000; Zarate, Singh, Carlson et al. 2006).

             In the 1960s Arnold Mandell reported on the induction of hepatic tryptophan pyrrolase activity with elevated urinary corticoid excretion, cleavage of the indole ring and marked reduction of urinary serotonin metabolites in depression (Mandell and Knapp 1979; Rubin and Mandell 1966, 1969). He also demonstrated changes in plasma corticosteroid concentration after electrical stimulation of the hippocampus and amygdala (Mandell, Chappman, Rand and Water 1963). In the 1970s, in collaboration with Segal, Mandel showed behavioural activation in rats during intraventricular infusion of NE and progressive motor activation with an increase of stereotypies during long-term administration of d’amphetamine (Segal and Mandell 1970, 1974). In collaboration with Knapp, Mandell defined the role of high affinity uptake of tryptophan into serotonergic neurons in the regulation of serotonin biosynthesis in the brain and demonstrated the effect of narcotic drugs on serotonin biosynthetic systems (Knap and Mandell 1978; Mandell and Knap 1977). In 1978 Mandell suggested that in the regulation of tyrosine and tryptophan hydroxylase activity “redundant mechanisms” are involved in the brain (Mandell 1978).

             In the late 1970s Michael Ebert developed a technique for cannulating the lateral ventricle for continuous collection of CSF in monkeys. He also established with his team that only about one fifth of urinary 3-methoxy-4-hydroxy phenyl glycol (MHPG) is derived from the central nervous system (CNS) (Ebert, Kartzinel, Cowdrey and Goodwin 1980). In a series of studies conducted on eating disorders in the 1980s Ebert and his associates found higher levels of CSF opioid activity, irregularities in CNS monoamine metabolism and abnormalities in plasma and CSF arginine and vasopressin in patients with anorexia nervosa (Gold, Kaye, Robertson and Ebert 1983; Kaye, Ebert, Raleigh and Lake 1984; Kaye, Pickar, Naber and Ebert 1982). They also found a decrease in calorie intake in normal weight patients with bulimia and lower indices of 5-HT turnover rate in the brain of anorexic patients with bulimia than in anorexic patients without bulimia (Gwirtsman, Kaye, Obarzanek et al. 1989; Kaye, Ebert, Gwirtsman and Weiss 1984). In the 1990s Ebert was involved in measuring the corticotrophin–releasing hormone, NE, MHPG, 5-hydroxyindoleacetic acid and tryptophan in the CSF of alcoholic patients (Geracioi, Loosen, Ebert et al. 1974).  

             Aleksander Mathé was first to demonstrate that prostaglandins play a role in the pathogenesis of asthma (Mathe, Hedquist, Holmgren and Svanborg 1973). He was also among the first to show changes in some prostaglandins in the CSF of patients with schizophrenia (Mathe, Sedvall, Wiesel et al. 1980). Mathé’s demonstration with Jeanette Miller of lithium’s effect on early gene (cFos) expression has opened up a new avenue in the study of lithium’s mode of action (Mathe, Miller and Stenfors 1995).

             Charles Nemeroff’s research focused on the detection of changes in psychiatric disorders that might provide targets for rational pharmacological treatments. One such target he identified was the corticotropin releasing factor (CRF) that he found elevated in depression (Nemeroff, Biserte, Akil and Fink  1992; Nemeroff, Krishnan, Reed et al. 1993; Nemeroff, Owens , Biserte et al. 1988; Nemeroff, Widerlow,  Biserte et al. 1984; Owens and Nemeroff  1991). He had also shown that early life stressors and child abuse may lead to an elevation of CRF (Bradley, Binder, Epstein et al. 2008;  Coplan, Andrews, Roslum et al. 1996).    Since injection of CRF into the brain of animals produced behavioral changes similar to those seen in depressive and anxiety disorders in human, Nemeroff suggested the development of CRF antagonists for the treatment of depression and anxiety (Heim, Mletzko, Purselle et  al. 2005; Owens and Nemeroff 1999a,b). Nemeroff was a member of the team that reported on a novel  transgenic mouse  for gene targeting within cells  that express the CRF (Martin, Ressler, Jasnow et al. 2010). In another line of research, Nemeroff found increased neurotensin gene expression in the striatum with “typical,” and in the nucleus accumbens with “atypical,” antipsychotic drugs (Kinkead, Shahid, Owen  and Nemeroff 2006; Nemeroff 1980). Assuming that the increase in neurotensin gene expression in the striatum might be predictive of liability for developing extrapyramidal symptoms (EPS), whereas the increase in neurotensin gene expression in the nucleus accumbens might be predictive of therapeutic efficacy, Nemeroff raised the possibility that neurotensin receptor agonists might represent a novel class of antipsychotic drugs (Binder, Kinkead, Owens  and Nemeroff (2001a,b, 2004).

             Fritz Henn’s discovery, in the early 1970s, that astrocytes have high affinity glutamate and gamma-aminobutyric acid (GABA) uptake systems opened up a new area of research that led to studies on the role of the glutamatergic drugs in mental disorders (Henn and Hamberger 1971). In another line of research Henn was first to show that neurogenesis in the hippocampus is related to stress and unrelated to depression (Vollmayr, Simonis, Weber, Gass and Henn 1993). In collaboration with B. Vollmayr he introduced two “out bred lines of rats” for depression research, the congenitally helpless strain and the resilient line, and he was member of the team that studied sensory information processing in neuroleptic naïve first episode schizophrenic patients with the employment of functional MRI (Braun, Weber-Fahr, Tost, Ruf  and Henn 2002; Henn and Vollmayr 2004).

 

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April 25, 2019