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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
Neuropsychopharmacology (Volume Five): 4c. Contributions of Interviewees)
(Bulletin 53)


           Three interviewees (Carroll, Graden and Brown) in Volume Five, were engaged in research centered on the dexame thas one suppression test (DST).Bernard Carroll was first in 1968 to use the DST for complementing clinical information on depressive illness (Carroll, Martin and Davies 1958).In 1970 he found, in collaboration with William McLeod and Brian Davies, that suppression of the morning rise of cortisol by dexame thas one was predictive of a favorable response to treatment with antidepressants  (McLeod, Carroll and Davies 1970). During the 1970s Carroll developed the DST for the “neuroendocrine identification” of depressed patients and for the study of the “neuroendocrine regulation” of depressive illness (Carroll and Curtis 1976; Carroll, Curtis and Mendels 1971; Carroll, Feinberg, Souse, Rawson and Greden 1981). In the 1980s he developed a self-rating instrument, The Carroll Rating Scale for Depression, for measuring the severity of depression (Feinberg and Carroll 1986; Greden, De Vigne, Albala,Tarrika, Buttenheim, Eiser and Carroll 1982).

           In the early 1980s John F. Greden, a disciple of Carroll, demonstrated that normalization of DST was a laboratory indicator of improvement in depression (Grunhaus, Tiongco, Roehrich, Eiser, Feinberg and Greden 1985). Greden introduced “speech-pause time” as a marker of psychomotor retardation to complement the characterization of patients with endogenous depression (Greden, Albala, Smokler, Gardner and Carroll 1981).

           Walter A. Brown was first to report that some depressed patients with increased pituitary adrenocortical activity are intolerant to several of the selective serotonin re-uptake inhibitors (Brown, Arato and Shrivastava 1986). He also corroborated findings that patients with increased pituitary adrenocortical activity did poorly on placebo (Brown 2007).

           Two of the interviewees (Prange and Whybrow) were focused in their research on thyroidhormones. In the early 1960s Arthur J Prange noted that “imipramine mortality” in mice was dependent on the thyroid status of the animals and with the employment of desipramine, he linked the increase in toxicity to NE (Prange 1964; Prange and Lipton 1962; Prange, Lipton and Love 1963, 1964; Prange, Wilson, Rabon and Lipton 1969). In the late 1960s Prange demonstrated that the antidepressant effect of imipramine was enhanced by the addition of thyroid hormone and in the early 1970s showed that the thyrotropin releasing hormone (TRH) has antidepressant effects when given alone ((Prange 1982; Prange, Wilson, Lara, Alltrop and Preese 1972). During the 1980s and 1990s Prange contributed to characterizing the behavioral effects of several neuropeptides, including neurotensin and oxytocin (Caldwell, Prangeand Pederssen 1986; Pedersen and Prange 1979;   Prange 1992).    

           Peter C. Whybrow contributed to the body of information on mental changes in thyroid gland dysfunction and on the relationship between thyroid function and the response to l-iodothyronine in depression (Whybrow, Coppen, Prange, Noguera and Bailey 1972; Whybrow, Prange and Treadway 1969). In the 1990s, in collaboration with Michael Bauer, Whybrow found a relationship between Grade I hypothyroidism and rapid cycling and demonstrated the effectiveness of adjuvant thyroxine in treatment refractory rapid cycling patients (Bauer and Whybrow 1990; Bauer, Whybrow and Winokur 1990; Gyulai, Bauer, Bauer, Garcia-Espana, Cnaan and Whybrow 2003).

           The remaining four interviewees (Belmaker, Goodwin,  Lewy and Post) were engaged in research related to the neuropsychopharmacology of bipolar disorders. Frederick K.Goodwin was among the first in the United States to demonstrate the therapeutic effect of lithium in mania and in depression (Goodwin and Ebert 1973; Goodwin, Murphy and Bunney 1969). He was also among the first in the United States to study central dopamine function in affective disorders. In collaboration with Sack, Goodwin showed that dopamine is the culprit of psychotic symptoms in mania (Goodwin and Sack 1974).

           In the late 1970s Alfred J Lewy developed an assay for the detection of melatonin in human plasma and demonstrated that light suppresses melatonin secretion from the pineal gland in humans (Lewy, Emens, Jackman and Yuhas 2006; Lewy and Markey 1978; Lewy, Wehr, Goodwin et al. 1980). In the 1980s Lewy developed bright light treatment for manic-depressive disease with a seasonal mood cycle and for phase typed chronobiologic sleep and mood disorders (Levy, Kern, Rosenthal and Wehr 1982; Levy, Sack and Singer 1985). He was a member of the team that described Seasonal Affective Disorder and its treatment with “light therapy” (Rosethal, Sack, Gillin, Lewy et al. 1984). In the 1990s Lewy showed that melatonin shifts human circadian rhythm according to a phase-response curve and introduced melatonin treatment for winter depression, as well as for some other conditions (Lewy, Ahmad, Jackson and Sack 1992; Lewy, Bauer, Cutler and Sack 1998).

           In the mid-1970s Robert Haim Belmaker found that lithium blocked the rise of cyclic adenosine monophosphate (cAMP) to epinephrine in humans (Ebstein, Belmaker Grunhaus and Rimon 1976). He had also shown that lithium inhibits adrenergic and cholinergic increases in guanasine triphosphate (GTP) binding in rat cortex (Avissar, Schreiber, Danon and Belmaker 1988). In the early 1980s Belmaker was first to demonstrate that treatment of depression with salbutamol, an adrenergic agonist, produced sub-sensitivity of the β-adrenergic adenylate cyclase in humans (Lerer, Ebstein and Belmaker 1981). Based on his findings, in a series of “add on” studies Belmaker reported that the effectiveness of a combination of lithium carbonate and haloperidol in schizoaffective disorder was unrelated to whether the illness was dominated by affective or schizophrenic symptoms and that the effectiveness of a combination of carbamazepine and haloperidol in excited psychoses was unrelated to diagnosis (Biederman, Lerer and Belmaker 1979; Klein, Bental, Lerer and Belmaker 1984).

           In the mid-1970s Robert M Post noted that repeated administration of cocaine produced sensitization and a kindling-like phenomenon, described by Goddard in the 1960s (Goddard 1967; Post 1975). In the late 1970s, in collaboration with James Ballanger, he replicated Okuma’s findings about the effectiveness of carbamazepine in manic-depressive illness (Ballanger and Post 1978, 1980; Kuma, Kishomoto, Inoue et al. 1973). In the mid-1980s Post reported on sensitization and kindling-like phenomena in bipolar disorder (Post, Rubinow and Ballanger 1986). Post contributed to the clinical development of nimodipine, gabapentine and lamotrigine for the treatment of bipolar disease (Frye, Ketter, Kimrell et al. 2000; Pazzaglia, Post, Ketter et al. 1993; Post, Speer, Obrucea and Leverich 2002; Post, Weiss, Leverich et al. 2001).

           Interviewees included in Volume 4 entered the field at different stages in the development of neuropsychopharmacology. Hence, the transcripts cover 50 years of history, including the generation of hypotheses about the pathophysiology of depression, the mode of action of tricyclic antidepressants, the generation of hypotheses about the pathophysiology of bipolar disorder and the mode of action of anticonvulsants.

           Samuel Gershon, the editor of this volume, is one of the pioneers of neuropsychopharmacology.  His Introduction and Dramatis Personae that complement the volume are personal notes on the interviewees.




Avissar S, Schreiber G, Danon A, Belmaker RH. Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature. 1988; 331: 440-2.

Ballanger JC, Post RM. Therapeutic effect of carbamazepine in affective illness. A preliminary report. Commun Psychopharmacol 1978; 2: 159-75.

Ballanger JC, Post RM. Carbamazepine in manic-depressive illness. A new treatment. Am J Psychiatry 1980; 137: 782 - 90.

Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder II: Adjuvant treatment of refractory rapid cycling with high dose thyroxine. Arch Gen Psychiatry. 1990; 47: 435-40.

Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder, I. Association with Grade I hypothyroidism: Arch Gen Psychiatry. 1990; 47: 427-32

Biederman J, Lerer Y, Belmaker RH. Combination of Lithium carbonate and haloperidol in schizoaffective disorder Archives of General Psychiatry 1979; 7: 327-33.

Brown WA. Treatment response in melancholia. Acta Psychiatria Scandinavica 2007; 115: 125-9.

Brown WA, Arato M, Shrivastava R. Pituitary-adrenocortical hyperfunction and intolerance to fluvoxamine, a selective serotonin uptake inhibitor. Am J Psychiatry 1986; 143: 88 - 90.

Caldwell JD, Prange AJJr, Pedersen CA. Oxytocin facilitates the sexual receptivity of estrogen-treated female rats. Neuropeptides 1986; 7: 175–89.

Carroll BJ, Curtis GC. Neuroendocrine identification of depressed patients. Aust NZJ Psychiat 1976; 10: 13-20.

Carroll BJ, Curtis GC, Mendels J. Neuroendocrine regulation  in depression. I. Limbic system-adrenocortical dysfunction. Arch Gen Psychiatry 1976; 33: 1039-33.

Carroll BJ, Feinberg M, Souse PE, Rawson SG, Greden JF. The Carroll Rating Scale for Depression. I. Development, reliability and validation. Brit J Psychiatry 1981; 138: 194-200.

Carroll BJ, Martin FI, Davies B. Resistance to suppression by dexamethasone of plasma 11-OHCS levels in severe depressive illness. Brit Med J 1958; 3: 285-7.

Ebstein RP, Belmaker RH, Grunhaus L, Rimon R. Lithium inhibition of adrenaline sensitive adenylate cyclase in human. Nature 1976; 259: 41-3.

Feinberg M, Carroll BJ. The Carroll Rating Scale for Depression. In: Sartorius N, Ban TA, editors. Assessment of Depression. Berlin: Springer-Verlag; 1986. p. 188-200’

Frye MA, Ketter TA, Kimrell TA, Dunn RT, Speer AM, Osuch EA, Luckenbaugh  DA, Cora-Locatelli G, Leverich GS, Post RM. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. Journal of Clinical Psychopharmacology 2000; 20: 607-14.

Goddard GV. Development of epileptic seizures through brain stimulation at low intensity. Nature 197; 214: 1020 – 1.

Goodwin FK, Ebert M. Lithium in mania: Clinical trials and controlled studies. In: Gershon S, Shopsin B, editors. Lithium: Its Role in Psychiatric Research and Treatment. New York: Plenum Press; 1973. p. 237-52.

Goodwin FK, Murphy DL, Bunney WE. Lithium carbonate treatment in depression and mania: a longitudinal double-blind study. Arch Gen Psychiatry1969; 21: 486-96.

Goodwin FK, Sack RL. Central dopamine function in affective illness. Evidence from precursors, enzyme inhibitors, and studies of central dopamine turnover. In Usdin E, editor.The Neuropsychopharmacology of Monoamines and Their Regulatory Enzymes. New York: Raven Press; 1974. p. 261-79.

Greden JF, Albala AA, Smokler IA, Gardner R, Carroll BJ. Speech-pause time: A marker of psychomotor retardation among endogenous depressives. Biol Psychiatry 1981; 16: 851-9.

Greden JF, De Vigne JP, Albala AA, Tarika J, Buttenheim M, Eiser A, Carroll BJ. Serial dexamethasone suppression tests among rapidly cycling bipolar patients. Biol Psychiatry 1982; 17: 455-62. 

Grunhaus L, Tiongco D, Roehrich A, Eiser A, Feinberg M, Greden JF. Serial monitoring of antidepressant response to electroconvulsivetherapy with sleep EEG recordings and dexamethasone suppression tests. Biol Psychiatry 1985; 20: 805-8

Gyulai L, Bauer M, Bauer MS, Garcia-Espana F, Cnaan A, Whybrow PC. Thyroid hypofunction in patients with rapid cycling bipolar disorder and lithium challenge.  Biol Psychiatry 2003; 53: 899-905.

Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol versus placebo and haloperidol in excited psychoses: A controlled study. Arch Gen Psychiatry. 1984; 41: 165-170.

Lerer B, Ebstein RP, Belmaker RH. Subsensitivity of human β-adrenergic adenylate cyclase after salbutamol  treatment of depression. Psychopharmacology 1981; 75: 169-72.

Lewy AJ, Ahmad S, Jackson JML, Sack RL, Melatonin shifts circadian rhythm according to a phase response curve. Chronobiol 1992; 9: 390-92.

Lewy, AJ, Bauer, V K., Cutler N, Sack RL. Melatonin treatment of winter depression: A pilot study. Psychiatry Res. 1998; 77, 57-61

Lewy AJ, Emens J, Jackman A, Yuhas K. Circadian uses of melatonin in human. Chronobiology International 2006; 23: 403-12.

Lewy, AJ, Kern HA, Rosenthal NE, Wehr TA. Bright artificial light treatment of a manic-depressive patient with a seasonal mood cycle. Am J Psychiatry 1982; 139: 1496-8.

Lewy AJ, Markey SP. Analysis of melatonin in human plasma by gas chromatography. Science 1978; 201: 741-3.

Lewy AJ, Sack RL, Singer CM. Treating phase typed chronobiologic sleep and mood disorders using appropriately timed  artificial bright light  Psychopharmacology Bulletin  1985; 21: 368-72.

Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP. Light suppresses melatonin secretion in human. Science 1980; 210: 1257-9.

McLeod WR, Carroll BJ, Davies B. Hypothalamic dysfunction and antidepressant drugs. Brit Med J 1970; 2: 480-21.

Okuma T, Kishomoto A, Inoue K, Matsumoto T, Nakao T, Ogura C, Antimanic and prophylactic effects if carbamazepine  (Tegretol) in manic depressive psychosis. A preliminary report. Folia Psychiatr Neurol Jpn 1973; 27: 283-97.

Pazzaglia PJ, Post RM, Ketter TA, George MS, Marangell LB.Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation.Psychiatry Res. 1993;49:257-72.

Pedersen CA, Prange A Jr. Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin. Proc Natl Acad Sci USA 1979; 76: 666 -75.

Post RM. Cocaine psychoses: a continuum model. Am J Psychiatry. 1975; 32: 225-31.

Post RM, Rubinow DR, Ballanger JC. Conditioning and sensitization in the longitudinal course of affective illness. Br J Psychiatry 1986; 149: 191-201.

Post RM, Speer AM, Obrocea G, Leverich GS. Acute and prophylactic effects of anticonvulsants in bipolar depression. Clin Neurosci Res. 2002; 2: 228-51.

Post RM, Weiss SRB, Leverich GS, Smith M, Li-Xin Z. Sensitization and kindling-like phenomena in bipolar disorder: implications for psychopharmacology. Clinical Neuroscience 2001; 1: 69-78.

Prange AJ Jr. The pharmacology and biochemistry of depression. Dis Nerv Syst 1964; 25: 217-21.

Prange AJ Jr. The manifold actions of neurotensin: A first synthesis. Ann NY Acad Sci 1982; 400: 368-76.

Prange AJ Jr. The manifold actions of neurotensin, a trophotropic agent. In: Nemeroff C, editor. Neurobiology of Neurotensin. Ann N Y Acad Sci. 1992; 668: 298-336.

Prange AJ Jr, Lipton MA. Enhancement of imipramine mortality in hyperthyroid mice. Nature.1962; 196: 588–9.

Prange AJ Jr, Lipton MA, Love GN. Diminution of imipramine mortality in hypothyroid mice. Nature.1963;197: 1212–3.

Prange AJ Jr, Lipton MA, Love GN. Effect of altered thyroid status on desmethylimipramine mortality in mice   Nature.1964; 204: 1204–5.

Prange AJ Jr, Wilson IC, Lara PP, Alltop LB, Breese GR. Effects of thyrotropin releasing hormone in depression. Lancet. 1972; 2: 999-1002.

Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry. 1969; 126: 457-69.

Rosenthal NE, Sack, DA, Gillin, JC, Lewy AJ, Goodwin, FK, Davenport, Y; Mueller, PS; Newsome, DA; Wehr, TA. Seasonal Affective Disorder: Adescription of the syndrome and preliminary findings with light therapy. Archives of General Psychiatry 1984; 41: 72-80

Whybrow PC, Coppen A, Prange AJ, Noguera R, Bailey JE. Thyroid function and the response to diiodothyronine in depression. Arch Gen Psychiatry. 1972; 26: 242-5.

Whybrow PC, Prange AJ, Treadway CW. Mental changes accompanying thyroid gland dysfunction. Arch Gen Psychiatry. 1969; 20: 48-53.


January 17, 2019