Monday, 24.02.2020

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

Special Areas (Volume Seven): 5b. Contributions of Interviewees

(Bulletin 64)


           Seven of the interviewees from Volume Seven (Akiskal, Clayton, Dunner, Eichelman, Endicott, Halbreich and Halmi) were engaged in research related to diagnostic end-points in psychopharmacologic research (Ban 2011; Blackwell 2011). In the late 1960 Paula J Clayton was instrumental in introducing Karl Leonhard’s diagnostic concept of “bipolar disorder” in the United States and in the early 1980s in perpetuating Kasanin’s diagnostic concept of “schizoaffective disorder” (Clayton 1982; Clayton, Halikas and Maurive 1972; Kasanin 1933; Leonhard 1957; Winokur, Clayton and Reich 1969). One of the recurring themes in Clayton’s research was the separation of symptoms of bereavement from symptoms of depression (1979, 1990). In the 1970s Clayton was a member of a team which studied the relationship between nortriptyline plasma levels and therapeutic response (Ziegler, Clayton, Taylor et al. 1976). In the 1990s she co-authored paper with Jules Angst and his associates in Zurich on mortality of patients with mood disorders (Angst, Stansen, Clayton and Angst 2002).

In the mid-1970s Jean Endicott, in collaboration with Robert Spitzer and Eli Robins, developed Research Diagnostic Criteria (RDC) for a Selected Group of Functional Psychoses (Spitzer, Endicott and Robins 1975, 1978). In collaboration with Spitzer she also developed the Schedule of Affective Disorder and Schizophrenia (SADS) (Endicott and Spitzer 1978). The RDC and SADS, together with Feighner’s Research Diagnostic Criteria, provided the bridge between the DSM-II and the DSM-III (American Psychiatric Association 1968, 1980; Feighner, Robins, Guze, Woodroff, Winokur and Munoz 1972). During the 1980s and ’90s, Endicott contributed with her research to the recognition of “premenstrual dysphoric disorder” as a distinct diagnostic entity (Endikott, Amsterdam, Erikson et al. 1999).

Searching for a unifying hypothesis of affective disorders, Hagop Akiskal studied sub-affective disorders, such as dysthymia, cyclothymia, and bipolar II disorder, in the “borderline realm” (Akiskal 1981; Akiskal and McKinney 1978). In 1983 he critically reviewed the relationship between personality and affective disorder and presented his findings on the psychopathology of chronic depressive subtypes (Akiskal 1983a; Akiskal, Hirschfeld and Yerevenian 1983). In the 1990s, further pursuing the same line of research, he introduced the concept of “bipolar spectrum disorders”; provided evidence for switching from unipolar to bipolar II disorder; and described prototypes of bipolar I, II, III and IV disorders (Akiskal 1983a,b; Akiskal, Maser, Zeller et al. 1995; Akiskal and Pinto 1999).

            Studying the genetics of manic-depressive illness in collaboration with Elliot Gershon, David Dunner, in the late 1960s, identified what was to become known as “bipolar II disorder” (Dunner, Gershon and Goodwin 1976). Subsequently, studying factors which might be related to failure in responding to lithium, in collaboration with Ronald Fieve, Dunner was among the first to describe “rapid cycling” patients (Dunner 1987; Dunner and Fieve 1974; Dunner, Fleiss and Fieve 1976; Dunner, Patrick and Fieve 1877; Fieve, Kimbaracki and Dunner 1976; Goodnick, Dunner and Fieve 1981). They also proposed a classification of bipolar affective disorder (Dunner, Russek, Russek and Fieve 1982). During the 1980s and ’90s Dunner was involved in the clinical evaluation of several psychotropic drugs, including adinazolam, alprazolam, fluoxetine, citalopram, paroxetine, etc. (Dunner and Dunbar 1982; Dunner, Hendricksen, Bea et al. 2002; Dunner, Ishiki, Avery et al. 1986; Dunner, Myers, Khan et al. 1987: Dunner, Schmaling, Hendricksen et al. 1998).     

            Using a specially devised assessment form for the detection of premenstrual symptoms in the mid-1980s, Uriel Halbreich, in collaboration with Jean Endicott, found a diversity of premenstrual changes and linked these changes to gonadal hormone secretion (Halbreich Endicott, Goldberg and Nee 1986; Halbreich, Endicott, Schacht and Nee 1982).  They also revealed a relationship between premenstrual dysphoric changes and depression (Halbreich and Endicott 1985). In the 1990s Halbreich suggested that “menstrually related disorders” are valid diagnostic end points and embarked on studies on the relationship between gonadal hormones and these disorders (Halbreich 1990a, 1993). He also explored the use of progesterone antagonists and sertraline in the treatment of the premenstrual dysphoric syndrome (Halbreich 1990b; Halbreich and Smoller 1997). In his early research Halbreich found a difference in growth hormone response to dextroamphetamine between depressed patients and normal subjects and between postmenopausal women and normal young men (Halbreich, Asnis, Halpern et al. 1980; Halpern, Sachar, Asnis et al. 1982). In 1990 he reported on the effects of estrogen replacement in the treatment of postmenopausal disorders (Halbreich 1990c).

            Focusing on eating disorders in her research, Katherine A Halmi, in the late 1970s, reported on the effectiveness of cyproheptadine, a serotonin antagonist, in the treatment of “anorexia nervosa” (Goldberg, Halmi and Eckert 1979). She followed up her findings with a comparative study of cyproheptadine and amitriptyline, and by comparing the effectiveness of cyproheptadine in bulimic and non-bulimic anorexia nervosa patients (Eckert, Halmi and March 1986; Halmi, Eckert, La Du and Cohen 1986).  With the employment of biological measures during the 1980s Halmi found similarities between anorexia nervosa and depression (Halmi 1981, 1992). Halmi was a member of the team which identified in 2002 a susceptibility gene for anorexia nervosa on chromosome 1 (Grica, Halmi, Fichter et al. 2002).

            In a series of experiments conducted in the rat in the early 1970s, Burt Eichelman found that social setting influenced physiological response to electric shock (Williams and Eichelman 1971). Focusing on the pharmacology of aggression in his research he revealed the effect of sub-cortical lesions on shock-induced aggression (Eichelman 1979). He then demonstrated that 6-hydroxydopamine administration facilitated aggressive behaviour (Eichelman, Thoa and Ng 1982). In the mid-1980s Eichelman reported that combined treatment with tryptophan and trazodone has a favourable effect on aggressive behaviour (O’Neil, Page, Adkins and Eichelman 1986). In 1990, in recognition of the pharmacological heterogeneity of the population displaying aggressive and violent behaviour, Eichelman developed The Carolina Nosology of Destructive Behaviour (Eichelman 1988; Eichelman and Hartwig 1990).



Akiskal HS. Subaffective disorder, dysthymia, cyclothymia, and bipolar II disorders in the “borderline realm.” Psychiat Clin North America 1981; 4: 25-45.

Akiskal HS. Dysthymia: Psychopathology of proposed chronic depressive subtypes. Am J Psychiatry 1983a; 140: 11-20.

Akiskal HS. The bipolar spectrum. New concepts in classification and diagnosis. In: Grinspoon L, editor. Psychiatry Update: The American Psychiatric Annual Review. Washington: American Psychiatric Association; 1983b. p. 271-92.

Akiskal HS, Hirschfeld R, Yerevanian BI. The relationship of personality to affective disorders: a critical review. Archives of General Psychiatry 1983; 40: 801-10.

Akiskal HS, Maser JD, Zeller P, Endicott J, Coryell W, Keller M, Warshaw M, Clayton P, Goodwin FK. Switching from unipolar to bipolar II. An 11 year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry 1995; 52: 114-23. .

Akiskal HS, McKinney WT. Depressive disorders. Towards a unified hypothesis. Science 1978; 182: 20-5.

Akiskal HS, Pinto O. The evolving bipolar spectrum – Prototypes I, II, III and IV. Psychiatr Clin North America 1999; 22: 517-34.

American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders. Second edition. DSM-II. Washington: American Psychiatric Association; 1968.

American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders. Third  Edition. DSM-III. Washington: American Psychiatric Association; 1980.

Angst F, Stansen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders. Follow-up over 34 to 38 years. Journal of Affective Disorders 2002; 68: 167-81.

Ban TA. Preface. In: Blackwell B, editor. Special Areas. (In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume Seven. Brentwood: American College of Neuropsychopharmacology; 2011, pp. ix –xxxiii.  

Blackwell B, editor. Special Areas. (In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume Seven.) Brentwood: American College of Neuropsychopharmacology; 2011.  

Clayton PJ. The sequelae and non - sequelae of conjugal bereavement. Am J Psychiatry 1979; 186:-1530-4.

Clayton PJ. Schizoaffective disorder. J Nerv Ment Dis 1982; 170: 646-50.

Clayton PJ. Bereavement and depression. J Clin Psychiatry 1990; 51: 34-8.

Clayton PJ, Halikas JA, Maurive WL. The depression of widowers. Br J Psychiatry 1972; 120: 71-80.

Dunner DL. Stability of bipolar II affective disorder` as a diagnostic entity. Psychiatr Ann 1987; 17: 18-20.

Dunner DL, Dunbar GC. Optimal dose regimen of paroxetine. J Clin Psychiatry 1992; 53 (supplement 2): 21-6. 

Dunner  DL, Fieve RR. Clinical factors of lithium prophylaxis failure.  Arch Gen Psychiatry 1974; 30: 229- 33.

Dunner DL, Fleiss  JL, Fieve RR. The course and development of mania in patients with recurrent depression. Am J Psychiatry 1976; 133: 905-8.

Dunner DL, Gershon ES, Goodwin FK. Heritable factors in the severity of affective illness. Biol Psychiatry 1976; 11: 31-42.

Dunner LD, Hendricksen HE, Bea C, Budech CB, Friedman G. Dysthymic disorder: Treatment with citalopram. Depression and Anxiety 2002; 15: 18-22.

Dunner DL, Ishiki D, Avery DH, Wilson LG, Hyde TS. Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: A controlled study. J Clin Psychiatry 1986; 41: 458-60.

Dunner DL, Myers J, Khan A, Avery D, Ishiki D, Pyke R. Adinazolam: A new antidepressant. Findings of a placebo-controlled, double-blind study  in outpatients with major depression. J Clin Psychopharmacol 1987; 7: 170-2.

Dunner DL, Patrick V, Fieve RR. Rapid cycling manic depressive patients. Compr Psychiatry 1977; 18: 561-6.

Dunner DL, Russek FD, Russek B, Fieve RR. Classification of bipolar affective disorder subtypes. Compr Psychiatry 1982; 23: 186-9.

Dunner DL, Schmaling  KB, Hendrickson  H, Becker J, Lehman A. Cognitive therapy vs  fluoxetine  in the treatment of dysthymic disorder. Depression 1998; 4: 34-41.

Eckert ED, Halmi KA, March P. Comparison of bulimic and non-bulimic anorexia nervosa patients in treatment.  Psychol Med 1987; 17: 891-8.

Eichelman BJ. Effects of subcortical lesions on shock-induced aggression in the rat. Journal of Comparative Physiological Psychology 1979; 74: 33-9.

Eichelman BJ. Towards a rational pharmacotherapy for aggressive and violent behavior. Hospital and Community Psychiatry 1988; 39: 31-9.

Eichelman BJ, Hartwig A. The Carolina Nosology of Destructive Behavior. J Neuropsychiatr & Clin Neurol 1990; 2: 288-96. 

Eichelman BJ, Thoa NB, Ng KY. Facilitated aggression in the rat following 6-hydroxydopamine  administration. Physiol Behav 1982; 8: 1-3.

Endicott J, Amsterdam J, Erikson E, Frank E, Freeman E, Hirschfeld A, Ling F, Parry B. Is premenstrual dysphoric disorder a distinct diagnostic entity? J of Women’s Health & Gender Based Medicine. 1999; 8: 663-70.

Endicott J, Spitzer RL. A diagnostic interview: the Schedule for Affective Disorder and Schizophrenia  Archives of General Psychiatry 1978; 35: 337-44.

Feighner JP, Robins E, Guze SB, Woodroff RA, Winokur G, Munoz R. Diagnostic Criteria  for Use in Psychiatric Research. Arch Gen Psychiatry 1972; 26: 57-63.

Fieve RR, Kumbaracki T, Dunner DL. Lithium prophylaxis of depression in bipolar I, bipolar II and unipolar patients. Am J Psychiatry 1976; 133: 925-30. 

Goldberg SC, Halmi KA, Eckert ED. Cyproheptadine in anorexia nervosa. British Journal of Psychiatry 1979; 134: 167-70.

Goodnick PJ, Dunner DL, Fieve RR. Bipolar II – A distinct diagnostic entity. Isr J Psychiatry Research 1981; 18: 221-7.

Grica DE, Halmi KA, Fichter MH, Strober M, Woodside DR, Treasure JT, Kaplan AS, Magistretti PJ, Goldman D, Bulik  CM, Kaye WH, Berettini WH. Evidence for a susceptibility gene  for anorexia nervosa  on chromosome 1.  The American Journal of Human Genetics 2002; 70: 787-92.  

Halbreich U. Gonadal hormones and antihormones, serotonin and mood. Psychopharmacol Bull 1990a; 26: 291-5.

Halbreich U. Treatment of premenstrual syndromes with progesterone antagonist (RU-486): political and methodological issues. Psychiatry 1990b; 53: 407-9.

Halbreich U. Estrogen replacement in postmenopausal disorders. Biol Psychiatry 1990c; 28: 369-71.

Halbreich U. Menstrually related changes and disorders: conceptualization and diagnostic consideration. Neuropsychopharmacology 1993; 9: 25-9.

Halbreich U, Asnis GM, Halpern F, Tabrizi MA, Sachar EJ. Diurnal growth hormone response to dextroamphetamine in normal young men and postmenopausal women. Psychopharmacology 1980; 5: 339-44.

Halbreich U, Endicott J. The relationship of premenstrual dysphoric changes to depressive disorders. Acta Psychiat Scand 1985; 71: 331-8.

Halbreich U, Endicott J, Goldstein S, Nee J. Premenstrual changes and changes in gonadal hormones. Acta Psychiat Scand 1986; 74: 5676- 86. 

Halbreich U, Endicott J, Schacht S, Nee J. The diversity of premenstrual changes as reflected in the Premenstrual Assessment Form. Acta Psychiat Scand 1982; 65: 46-65.

Halbreich U, Sachar EJ, Asnis GM, Quitkin F, Nathan RS, Halpern FS, Klein DF. Growth hormone response to dextroamphetamine in depressed patients and normal subjects. Arch Gen Psychiatry 1982; 39: 189-92.

Halbreich U, Smoller JW. Intermittent luteal phase: sertraline treatment of dysphoric premenstrual syndrome.  J Clin Psychiatry 1997; 58: 399-402.

Halmi KA. Catecholamine metabolism in anorexia nervosa. Journal of Psychiatry and Medicine 1981; 11: 251-4.

Halmi KA, editor. Psychobiology and Treatment of Anorexia Nervosa and Bulimia Nervosa. Washington: American Psychopathological Association; 1992.

Halmi KA, Eckert ED, La Du TJ, Cohen T. Anorexia nervosa: treatment efficacy of cyproheptadine and amitriptyline. Arch Gen Psychiatry 1986; 43: 177-81.

Kasanin J. The acute schizoaffective psychoses. Am J Psychiatry 1933; 90: 97- 126.

Leonhard K. Aufteilung der endogenen Psychosen. Berlin: Akademie-Verlag; 1957.

O’Neil IJ, Page N, Adkins WN, Eichelman BJ. Tryptophan-trazodone treatment of aggressive behavior. The Lancet 1986; 328: 859-60.

Spitzer RL, Endicott J, Robins E. Research Diagnostic Criteria for a Selected Group of Functional Psychoses. New York: New York State Psychiatric Institute; 1975.

Spitzer R, Endicott J, Robins E. Research Diagnostic Criteria: rational and reliability. Arch Gen Psychiatry 1978; 35: 773-82.

Williams RB, Eichelman BJ. Social setting influence on the physiological response to electric shock. in the rat. Science 1971; 174: 613-4.

Winokur G, Clayton PJ, Reich T. Manic Depressive Illness. Mosby: St. Louis; 1969.

Ziegler VE, Clayton PJ, Taylor JR, Tee B, Biggs JT. Nortriptyline plasma levels and therapeutic response. Clin Pharmacol Ther 1976; 20: 458-63.


April 4, 2019