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): 2b. Interviewees Contributions

(Bulletin 68)



            Of the remaining 13 interviewees in Volume 8, two (Kenneth Davis and Kleinman) were involved in research using material from brain banks. Joel Kleinman, working in the brain bank he established at NIMH, identified potential susceptibility genes for schizophrenia (Kao, Wan, Kleinman et al. 2010; Law, Lipska, Weickert et al. 2006).He was member of the teams that reported on a primate-specific brain isoform of KCNH2 that affects neuronal repolarization and risk for schizophrenia and found that DISC1 splice variants are upregulated in schizophrenia (Huffaker, Chen, Nicodemus et al. 2009; Nakata, Lipska, Hyde et al. 2009). Kleinman’s research with Daniel Weinberger implicated DARP-32 in human fronto-striatal cortical structure function and cognition (Ban 2011 a,b; Myers-Lindenberg, Straub, Lipska et al. 2007;  Salzman 2011).

            In the mid-1970s Kenneth L. Davis found selective loss of cholinergic neurons in Alzheimer’s disease (Davies and Maloney 1976). Subsequently, Davis with his associates demonstrated that physostigmine, a cholinesterase inhibitor, improved learning in normal subjects (Davis, Mohr, Tinklenberg et al. 1978). He followed up these findings and in the 1980s showed enhancement of memory processes in Alzheimer’s disease with multiple-doses of intravenous physostigmine (Davis and Mohr 1982). Davis’ findings contributed to the revival of interest in tacrine and to developing cholinesterase inhibitors for the treatment of AD (Davis, Thal, Gamzu et al. 1992). In an entirely different area of research, Davis and his associates found dysregulation of myelination associated with white matter changes in schizophrenic brains (Davis, Stewart, Friedman et al. 20001; Hakak, Walker, Lie et al. 2001).

            One of the interviewees, Paul Leber, contributed to the shaping of drug regulation relevant to the approval of psychotropic drugs for clinical use in the 1980s and 1990s; his efforts had a great impact on clinical drug development and teaching of pharmacotherapy with psychotropic drugs. Leber, a pathologist and psychiatrist in the employment of the US Food and Drug Administration (FDA), spearheaded the implementation of the double-blind, placebo-controlled randomized clinical trial (RCT) in the clinical development of psychotropic drugs and advanced the view that only RCTs with a placebo arm could provide unambiguous findings about efficacy (Leber 2000). He emphasized the “threats” that the employment of “enrichment strategies” in sample selection represents and the “hazards” of making “inferences” about clinical applications from statistical probabilities (Leber 1989, 2002; Leber and Davis 1998). He also addressed special methodological issues related to clinical investigations designed for showing changes in the progression of Alzheimer’s Disease (AD) (Leber 1997).

            Two of the interviewees (Beasley and Tollefson) worked for pharmaceutical companies for some time during their professional career. Garry Tollefson led Eli Lilly’s team in the early 1990s that developed and launched olanzapine for the treatment of schizophrenia (Tollefson 1996; Tollefson and Singer 1997; Tollefson and Taylor 2000). Prior to joining Lilly, Tollefson, developed an erythrocyte model for studying the effect of drugs on muscarinic receptors (Tollefson, Sanogles and Frey 1982; Tollefson, Sanogles, Frey, Tuason and Nicol 1982).

            Charles Beasley led Eli Lilly’s Phase IV team of fluoxetine which revealed that the frequently encountered “activation” and occasional “paradoxical sedation” in the course of treatment is dose dependent (Beasley, Sayler, Bossomworth and Wernicke 1991; Beasley, Sayler, Weiss and Potvin1992). He also reported on possible interaction between fluoxetine and monoamine oxidase inhibitors (Beasley, Massica, Holligenstein et al. 1999). In the 1990s, in response to reports of suicide attributed to fluoxetine, Beasley coordinated the analysis of information in controlled clinical trials that “failed to support the hypothesis of increased suicidality” with the drug (Beasley, Ball, Nilsson et al. 2007; Beasley, Dornseif, Bossomworth et al. 1991). He also participated in clinical studies with olanzapine in the treatment of schizophrenia (Beasley, Tollefson, Tran et al. 1996). Prior to joining Lilly, Beasley was among the first to report that a blunted thyrotropin stimulating hormone (TSH) response in the thyrotropin releasing hormone (TRH) stimulation test is predictive of responsiveness to haloperidol (Beasley, Magnussen, Garver et al. 1988).

            Three of the interviewees (Frank, Gaszner and Judd) were engaged in research related to affective disorders or antidepressants. In the 1970s Lewis Judd demonstrated that chronic administration of lithium to normal subjects has a slowing effect on cognition. He also showed that pre-treatment with lithium has a “dampening effect” on symptoms of experimental intoxication with cocaine and alcohol (Judd, Hubbard, Janowsky et al. 1977a,b). In a 12-year prospective study Judd and his associates found that patients with unipolar depression are ill 60% and asymptomatic less than half of their lifetime (Judd, Akiskal, Maser et al. 1998). They also reported that full recovery from a manic or depressive episode without residual symptoms is predictive of good prognosis (Judd, Akiskal, Schettler et al. 2002, 2003).

            In a series of studies conducted in the early 1980s in normal subjects Peter Gaszner, in collaboration with Elemer Szabadi and Christopher Bradshaw, demonstrated differences in peripheral anticholinergic activity among tricyclic antidepressants (Gaszner, Szabadi and Bradshaw 1980; Szabadi, Gaszner and Bradshaw 1980). They had also shown adrenergic blocking effect with neuroleptics (Szabadi, Gaszner and Bradshaw 1981). In the 1990s Gaszner was a member of the international team that demonstrated the efficacy of reboxetine in major depression (Ban, Gaszner, Aguglia et al. 1998). In collaboration with Thomas Ban, he developed a composite diagnostic evaluation to study the therapeutic profile of drugs used in the treatment of mania (Gaszner and Ban 1998).

            Ellen Frank, in collaboration with David Kupfer, contributed information on the effectiveness of maintenance therapy with antidepressants (Frank, Kupfer, Perel et al. 1990). She was a member of the team that developed, in the early 1990s, consensus definitions for terms used in clinical studies with psychotropic drugs, such as response, remission, recovery, relapse and recurrence (Frank, Prien, Jarrett et al. 1991). Frank with her associates reported on disruption of social rhythm at the onset of a unipolar or bipolar affective episode (Malkoff, Schwartz, Frank et al. 2000). She also explored the usefulness of interpersonal and social rhythm therapy of bipolar I disorder and of individual psychotherapy and pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) of depression (Frank, Cassano, Recci et al. 2011; Frank, Kupfer, Thase et al. 2005).

            Five of the interviewees (Cešková, Glick, Salzman, Shader and Stahl) were intensively involved in educational activities with psychotropic drugs. Based on a series of clinical studies Ira Glick reported that psychoeducational family intervention (PEFI) did not compensate for using neuroleptics in an inadequate dose in the treatment of schizophrenia; that only in psychotic patients with bipolar disorder could family therapy improve the outcome of pharmacological treatment; and that “working with the families” of hospitalized schizophrenic, bipolar and unipolar depressed patients added to the effectiveness of pharmacological treatment (Clarkin, Carpenter, Hull et al. 1998; Glick, Stekoli and Hays 2011; Glick, Suppes, De Battista et al. 2001). In 2009 Glick recommended the reintegration of family therapy training in psychiatric residency training programs (Rail and Glick 2009). In collaboration with David Janowsky, Carl Salzman and Richard Shader, Glick developed a “model” psychopharmacology curriculum for psychiatric residents (Glick, Janowsky, Salzman and Shader 1984, 1993; Glick, Salzman and Cohen 2007). Glick was also involved in studying the effect of several factors on treatment outcome, e.g., duration of hospitalization, combining pharmacological with psychological treatment (Glick 2004; Glick and Hargraves 1979).

            Richard Shader was a member of the team that developed the model curriculum for teaching psychopharmacology in 1993. In the late 1960s Shader was first, with DiMascio, Salzman and Harmatz, to report on hostility induced by some benzodiazepines, e.g., chlordiazepoxide (DiMascio, Shader and Harmatz 1969; Salzman, DiMascio, Shader and Harmatz 1969). During the 1970s, in collaboration with David Greenblatt, Shader contributed to knowledge on the pharmacokinetics of various benzodiazepine drugs (Shader, Georgatas, Greenblatt et al. 1978; Shader, Greenblatt, Harmatz 1977). Shader and Greenblatt also co-authored a book published in 1974 and a paper published in 1981 on benzodiazepines in clinical practice (Greenblatt and Shader 1974; Shader and Greenblatt1981).

            Carl Salzman was also a member of the team that developed the model curriculum and as a Harvard professor of psychiatry he was instrumental in implementing the curriculum. Involved with Richard Shader in research with benzodiazepines, Salzman became chairman of APA’s Task Force that reported on benzodiazepine dependence, toxicity and abuse (Salzman 1990). In the 1990s Salzman’s focus of interest shifted to geriatric psychopharmacology and he became involved in clinical investigations with psychotropic drugs in the aged (Burrows, Salzman,  Satlin et al. 2002; Salzman 1998, 2001, 2004). In the mid-1990s Salzman and his associates published findings on the effect of fluoxetine on anger in symptomatic volunteers with borderline personality disorder (Salzman, Wolfson, Schatzberg et al. 1995).

            In the1980s and ‘90s Eva Cešková conducted clinical investigations with various neuroleptics, e.g., haloperidol, risperidone (Ban and Cešková 1980; Cešková and Svestka 1993). In the early years of the 21st century her research switched to exploring the use of biological measures in the assessment of changes in the course of treatment with neuroleptics and in the prediction of treatment response (Cešková  2004; Drybcak, Hrobak et al. 2001; Cešková, Drybcak, Lorinc 2003; Cešková, Prikryl, Kasparek and Kucerova 2007; Cešková, Prikryl, Kasperek and Ondrusova 2003, 2005).

            Stephen Stahl, a disciple of Herbert Meltzer, in the mid-1970s used the platelet as a diagnostic tool for the study of biogenic amines in psychiatric and neurologic disorders (Stahl 1977). In 1976 he co-authored with Meltzer one of the first reviews on the dopamine hypothesis of schizophrenia (Meltzer and Stahl 1976). As the founding chairman of the Neuroscience Education Institute in San Diego, Stahl was involved in teaching pharmacotherapy with psychotropic drugs to psychiatrists, primary care physicians and nurse practitioners worldwide. In his Essential Psychopharmacology and some of his other publications, he advocates the “preventive” use of psychotropic drugs, e.g., the use of β-blockers immediately after trauma to block the rise of norepinephrine to prevent post-traumatic stress disorder (Stahl 2000, 2008). In 1999 Stahl suggested the combining of clinical experience with guidelines in the selection of an atypical antipsychotic drug for the treatment of schizophrenia (Stahl 1999). Stahl was member of the team that proposed adding olanzapine or other atypical antipsychotics as an augmentation strategy in treatment resistant major depression (Shelton, Tollefson, Tohen et al 2001).

            As in all prior volumes, interviewees included in Volume 8 entered the field at different stages in the development of neuropsychopharmacology. Probably because of the diverse topics, Volume 8 reflects more than any of the prior volumes the emergence of a new psychiatry in which neuropsychopharmacology plays a prominent role.




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Beasley C, Masica D, Heiligenstein JH, Wheadon DE, Zerbe RL. Possible  monoamine-oxidase inhibitor and serotonin uptake inhibitor interaction; fluoxetine clinical data and  preclinical findings. J Clin Psychopharmacol 1993; 13: 312-20.

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Cešková E, Prikryl R, Kasparek T, Ondrusova  M. Prolactin levels  in risperidone treatment  of first-episode schizophrenia. Int J Psych Clin 2003; 8: 1-7.

Cešková E, Prikryl R,  Kasparek T,  Ondrusova M. Psychopathology and treatment responsiveness  of patients with first-episode schizophrenia.  Neuropsychiatric Dis Treat 2005; 1: 179-85.

Cešková E, Svestka J. Double-blind comparison of risperidone and haloperidol in schizophrenic and schizoaffective psychoses. Pharmacopsychiatry 1993; 26: 21

Clarkin JF, Carpenter D, Hull J, Wilner P, Glick I. Effects of psychoeducational intervention for married patients with bipolar disorder and their spouse. Psychiatric Serv 1998; 49: 531-3.

Davies P, Maloney AJF. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 1976; 2: 1403-4.

Davis KL, Mohr RC. Enhancement of memory processes in Alzheimer’s disease with multiple-dose intravenous physostigmine. Am J Psychiatry 1982; 139: 1421-4.  

Davis KL, Mohr RC, Tinklenberg JR, Pfefferbaum A, Hollister LE, Kopell BS. Physostigmine: improvement of long-term memory process in normal humans. Science 1978; 201:  272-4. 

Davis KL, Stewart DC, Friedman JJ, Buchsbaum M, Harvey PD, Hof PR, Buxbaum J, Haroutunian V. White matter changes in schizophrenia: Evidence for myelin related  dysfunction. Archives of General Psychiatry 2003; 60: 443-56.

Davis KL, Thal LJ, Gamzu ER, Davis CS, Woolson RF, Gracon SI, Drachman DA, Schneider LS, Whitehouse PJ, Hoover TM, et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease. The Tacrine Collaborative Study Group. New England Journal of Medicine 1992; 327: 1253-9.

DiMascio A, Shader RI, Harmatz J. Psychotropic drugs and induced hostility. Psychosomatics 1969; 10: 46-7.

Frank E, Cassano GB, Recci P, Thompson WK, Kraemer HC, Fagiolini A, Maggi L, Kupfer DJ, Shear MK, Houck PR, Calugi S, Grochocinski VJ, Scocco P, Buttenfield J, Forgione RN. Predictors and moderators of time to remission of depression with interpersonal psychotherapy and SSRI pharmacotherapy. Psychological Medicine 2011; 41: 151-62.

Frank E, Kupfer DJ, Perel JM, Cornes C, Jarrett DB, Mallinger AG, Thase ME, McEachran AB, Grochocinski VJ. Three-year outcomes for maintenance therapies in recurrent depression. Archives of General Psychiatry 1990; 47: 1093-99.

Frank E, Kupfer D, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, Grochocinski V, Houck P, Scott J, Thompson W, Monk T. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Archives of General Psychiatry 2005; 62: 996-1004. 

Frank E, Prien R, Jarrett RB, Keller MB, Kupfer DJ, Lavori P, Rush AJ, Weissman MM. Conceptualization and rationale  for consensus definitions of terms in major depressive disorder: Response, remission, recovery, relapse and recurrence. Archives of General Psychiatry 1991; 48: 851-5.

Gaszner P, Ban TA. CODE-HD Composite Diagnostic Evaluation of Hyperthymic Disorders. Budapest: Animula; 1998.

Gaszner P, Szabadi E, Bradshaw CM. Comparison of the peripheral anticholinergic activities of desipramine and amitriptyline in healthy volunteers. Br J Clin Pharmacol 1980; 9: 112-3.

Glick ID. Adding psychotherapy to pharmacotherapy: data, benefits and guidelines for integration. Am J Psychotherapy 2004; 58: 186 – 208.

Glick ID, Hargreaves WA. Psychiatric Hospital Treatment for the 1980s; A Controlled Study of Short Versus Long Hospitalization. Lexington: Lexington Press; 1979.  

Glick ID, Janowsky DS, Salzman C, Shader RI. A Model Psychopharmacology Curriculum for Psychiatric Residents. Nashville: American College of Neuropsychopharmacology; 1984.

Glick ED, Janowsky DS, Salzman C, Shader RI. A proposal for a model psychopharmacology curriculum for psychiatric residents. Neuropsychopharmacology 1993; 1993; 8: 1-5.

Glick ID, Salzman C, Cohen BM. Improving the pedagogy associated with the teaching of psychopharmacology. Acad Psychiatry 2007; 31: 211-7.

Glick I, Stekoli AM, Hays S. The role of family and improvement in treatment maintenance, adherence and outcome for schizophrenia. Journal of Clinical Psychopharmacology 2011; 31: 81-5. 

Glick ID, Suppes T, De Battista C, Hu RJ, Marder S. Psychopharmacologic treatment strategies for depression, bipolar disorder and schizophrenia. Ann Int Med 2001; 134: 625-34.

Greenblatt DJ, Shader I. Benzodiazepines in Clinical Practice. New York: Raven Press; 1974.

Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, Haroutinian V, Fienberg AA, Genome wide expression analysis reveals dysregulation  of myelination related genes in chronic schizophrenia. PNAS 2001; 98: 4746-51.

Huffaker SJ, Chen J, Nicodemus KK, Sambataro F, Yang F, Mattay V, Lipska BK, Hyde TM, Song J, Rujescu D, Giegling I, Mayilyan K, Soghoyan A, Caforio G, Bertolino A,  Meyer-Lindenberg A, Chang J, Egan M, Goldberg T, Kleinman JE,  Lu B,  Weinberger DR. A primate specific brain isoform of KCNH2 affects cortical physiology, neuronal repolarization, and risk of schizophrenia. Nat Med 2009; 15: 509-18.

Judd LL, Akiskal HS, Maser JD, Zeller  PJ, Endicott J, Coryell W, Paulus M,  Kunovac JL, Leon AC, Műller TI, Rice JA, Keller MB. A prospective 12-year study of sub-syndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry 1998; 59: 530-7.

Judd LL, Akiskal HS, Schettler PJ, Coryell W,  Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, Keller MB. A prospective investigation of the natural history  of the long-term  weekly symptomatic  status of  bipolar II  disorder. Arch Gen Psychiatry 2003; 60: 261-9.

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, Keller MB. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59: 530-7.

Judd LL, Hubbard B, Janowsky DS, Huey LY, Altewell PA. The effect of lithium carbonate upon affect, mood and personality of normal subjects. Arch Gen Psychiatry 1977a; 34: 346-51.

Judd LL, Hubbard B, Janowsky DS, Huey LY, Takahashi KI. The effect of lithium carbonate upon the cognitive function of normal subjects. Arch Gen Psychiatry 1977b; 34: 355-7.

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Leber P. Slowing the progression of Alzheimer’s disease: Methodological issues. Alzheimer Disease and Associated Disorders   1997; 11 (supplement 5): S10-S21.

Leber P. The use of placebo control groups in the assessment of psychiatric drugs. An historical context. Biological Psychiatry 2000; 47: 699-706.

Leber P. Not in our methods, but in our ignorance. Arch Gen Psychiatry 2002; 59: 279-80.

Leber P, Davis CS. Threats to the validity of clinical trials employing enrichment strategies for sample selection. Controlled Clinical Trials 1998; 19: 178-87.

Malkoff-Schwartz S, Frank E, Anderson BP, Hlastala SA, Luther JF, Sherrill JT, Houck PR, Kupfer DJ. Social rhythm  disruption  and stressful life  events  in the onset  of bipolar and unipolar  episodes. Psychological Medicine 2000; 30: 1005-16.

Meltzer HY, Stahl SM. The dopamine hypothesis of schizophrenia: a review. Schizophrenia Bull 1976; 2: 19-76.

Meyer-Lindenberg A, Straub RE, Lipska BK, Verschinski BA, Goldberg TE, Callicott JH, Ega ME, Huffaker  SS, Mattay VS, Kolachana BS, Kleinman JE, Weinberger DR. Genetic evidence  implicating DARPP-32 in human fronto-striatal structure, function, cognition. J Clin Invest 2007; 117: 672-82.

Nakata K, Lipska BKI, Hyde TM, Ye T,  Newburn EN, Morita Y, Vakkalanka  R, Barenhoim  M, Sei Y, Weinberger DR, Kleinman JE. DISC1 variants are upregulated in schizophrenia and associated with polymorphisms.  Proc Natl Acad Sci (USA) 2009; 106: 15872-8.

Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Harrison PJ, Kleinman JE, Weinberger DR. Neuroregulin (NRG1) transcripts are differentially expressed in schizophrenia and regulated by 5’SNPs associated with the disease. Proc Natl Acad Sci (USA) 2006; 103: 6747-52.

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Salzman C, Di Mascio A, Shader RI, Harmatz JS Chlordiazepoxide: Expectation and hostility. Psychopharmacology 1969; 18: 38-45.

Salzman C, Wolfson AN, Schatzberg, Schatzberg A, Looper J, Henke R, Albanese M, Schwartz J, Miyawaki E. Effects of fluoxetine  on anger  in symptomatic volunteers  with borderline personality disorder.  J Clin Psychopharmacol 1995; 15: 23-8.

Shader RI, Georgatas A, Greenblatt DJ, Harmatz JS, Allen MD. Impaired absorption of desmethyldiazepam from chlorazepate by magnesium aluminum hydroxide. Clin Pharmacol Ther 1978; 24: 308-15.

Shader RI, Greenblatt DJ.  The use of benzodiazepines in clinical practice. Br J Clin Pharmacol 1981; 11 (supplement 1); S5-S9.

 Shader RI, Greenblatt DJ, Harmatz JS, Franke K, Koch-Weser J. Absorption and disposition of chlordiazepoxide in young and elderly male volunteers. J Clin Phramacol 1977; 17: 709-18.

Shelton RC, Tollefson GD, Tohen M, Gannon KS, Jacobs T, Burns W, Bymaster FP, Zhang W, Spencer K, Feldman PD, Stahl SM, Meltzer HY. A novel augmentation strategy for treatment–resistant depression. Am J Psychiatry 2001; 158: 131-4. 

Stahl SM. The human platelet: a diagnostic research tool for the study of biogenic amines in psychiatric and neurologic disorders. Arch Gen Psychiatry 1977; 34: 509-16.

Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 1999; 60 (supplement 10):  31-40.

Stahl SM. Essential Psychopharmacology. Second edition. New York: Cambridge University Press; 2000.

Stahl SM. Essential Psychopharmacology. Third edition. New York: Cambridge University Press; 2008.

Szabadi E, Gaszner P, Bradshaw CM. The peripheral anticholinergic effect of tricyclic antidepressants: comparison   of amitriptyline and desipramine in healthy human volunteers. Br J Psychiatry 1980; 137: 433-9.

Szabadi E, Gaszner P, Bradshaw CM. An investigation on the adrenoreceptor blocking properties of neuroleptics in  the human iris in vivo.  Brit J Clin Pharmacol 1981; 11: 4167.

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May 2, 2019