Dehydroepiandrosterone and pregnenolone alterations in schizophrenia

Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment

Volumn , Issue , 2008, Pages 251-297

  Ritsner, Michael S ^a   Gibel, Anatoly ^a   Ratner, Yael ^a   Weizman, Abraham ^b  

^a SHA'AR MENASHE MENTAL HEALTH CENTER   (Israel)

^b GEHA MENTAL HEALTH CENTER   (Israel)

Author keywords

anxiety; dehydroepiandrosterone; dehydroepiandrosterone sulfate; metabolism; mode of action; mood and cognitive impairment; Pregnenolone; pregnenolone sulfate; schizophrenia; symptoms

Indexed keywords

EID: 74549211364     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-4020-6854-6_14     Document Type: Chapter

References (241)

1. Baulieu EE, Robel P. Dehydroepiandrosterone and dehydroepiandrosterone sulfate as neuroactive neurosteroids. J Endocrinol 1996;150(Suppl):221-239.
2. Mao X, Barger SW. Neuroprotection by dehydroepiandrosterone-sulfate: role of an NFkappaB-like factor. Neuroreport 1998;9:759-763.
3. Friess E, Schiffelholz T, Steckler T, Steiger A. Dehydroepiandrosterone - a neurosteroid. Eur J Clin Invest 2000;30(Suppl 3):46-50.
4. Wen S, Dong K, et al. Treatment with dehydroepiandrosterone sulfate increases NMDA receptors in hippocampus and cortex. Eur J Pharmacol 2001;430:373-374.
5. Johnson M, Bebb R, Sirrs S. Uses of DHEA in aging and other disease states. Ageing Res Rev 2002;1:29-41.
6. Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu EE. Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci USA 1981;78:4704-4707.
7. Baulieu EE. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 1997;52:1-32.
8. Epperson CN, Wisner KL, Yamamoto B. Gonadal steroids in the treatment of mood disorders. Psychosom Med 1999;61:676-697.
9. Sundstrom Poromaa I, Smith S, Gulinello M. GABA receptors, progesterone and premenstrual dysphoric disorder. Arch Women Ment Health 2003;6:23-41.
10. Eser D, Schule C, Baghai TC, et al. Neuroactive steroids in depression and anxiety disorders: clinical studies. Neuroendocrinology 2006;84:244-254.
11. Compagnone NA, Mellon SH. Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol 2000;21:1-56.
12. Stoffel-Wagner B. Neurosteroid metabolism in the human brain. Eur J Endocrinol 2001;145:669-679.
13. Stoffel-Wagner B. Neurosteroid biosynthesis in the human brain and its clinical implications. Ann NY Acad Sci 2003;1007:64-78.
14. Labrie F, Luu-The V, Belanger A, et al. Is dehydroepiandrosterone a hormone? J Endocrinol 2005;187:169-196.
15. Le Goascogne C, Jo DH, Corpéchot C. Neurosteroids: biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain. J Steroid Biochem 1991;40:71-81.
16. Rupprecht R. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003;28:139-168.
17. Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology 1998;23:963-987.
18. Zwain IH, Yen SS. Dehydroepiandrosterone: biosynthesis and metabolism in the brain. Endocrinology 1999;140:880-887.
19. Falany CN, Comer KA, Dooley TP, Glatt H. Human dehydroepiandrosterone sulfotransferase. Purification, molecular cloning, and characterization. Ann NY Acad Sci 1995;774:59-72.
20. Rainey WE, Carr BR, Sasano H, Suzuki T, Mason JI. Dissecting human adrenal androgen production. Trends Endocrinol Metab 2002;13:234-239.
21. Regelson W, Kalimi M. Dehydroepiandrosterone (DHEA) - the multifunctional steroid. II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other effects. Mechanism of action? Ann NY Acad Sci 1994;719:564-575.
22. King DS, Sharp RL, Vukovich MD, et al. Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men: a randomized controlled trial. JAMA 1999;281:2020-2028.
23. Broeder CE, Quindry J, Brittingham K, et al. The Andro Project: physiological and hormonal influences of androstenedione supplementation in men 35 to 65 years old participating in a high-intensity resistance training program. Arch Intern Med 2000;160:3093-3104.
24. Bird CE, Masters V, Clark AF. Dehydroepiandrosterone sulfate: kinetics of metabolism in normal young men and women. Clin Invest Med 1984;7:119-122.
25. Longcope C. Dehydroepiandrosterone metabolism. J Endocrinol 1996 (Suppl); 150:125-127.
26. Kroboth PD, Salek FS, Pittenger AL, et al. DHEA and DHEA-S: a review. J Clin Pharmacol 1999;39:327-348.
27. Rupprecht R. The neuropsychopharmacological potential of neuroactive steroids. J Psychiatr Res 1997;31:297-314.
28. Mellon SH, Griffin LD, Compagnone NA. Biosynthesis and action of neurosteroids. Brain Res Rev 2001;37:3-12.
29. Labrie F, Belanger A, Van LT, et al. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids 1998;63:322-328.
30. Morissette M, Dicko A, Pezolet M, et al. Effect of dehydroepiandrosterone and its sulfate and fatty acid ester derivatives on rat brain membranes. Steroids 1999;64:796-803.
31. Peng W, Hoidal JR, Farrukh IS. Role of a novel KCa opener in regulating K channels of hypoxic human pulmonary vascular cells. Am J Respir Cell Mol Biol 1999;20:737-745.
32. Gordon G, Mackow MC, Levy HR. On the mechanism of interaction of steroids with human glucose 6-phosphate dehydrogenase. Arch Biochem Biophys 1995;318:25-29.
33. Widstrom RL, Dillon JS. Adrenal androgens in human physiology. Bruce RC (editor in chief); William ER, Bruce RC (guest editors) Semin Reprod Med 2004;22:289-298.
34. Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABA-A receptor. Mechanism of action and physiological significance. Prog Neurobiol 1992;38:379-395.
35. A receptors. J Neuroendocrinol 1995;7:171-177.
36. Majewska MD, Demigören S, Spivak CE, London ED. The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor. Brain Res 1990;526:143-146.
37. Demirgoren S, Majewska MD, Spivak CE, London ED. Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor. Neuroscience 1991;45:127-135.
38. Debonnel G, Bergeron R, De Montigny C. Potentiation by dehydroepiandrosterone of the neuronal response to N-methyl-D-aspartate in the CA3 region of the rat dorsal hippocampus: an effect mediated via sigma receptors. J Endocrinol 1996 (Suppl) 150:33-42.
39. Marx CE, Jarskog LF, Lauder JM, et al. Neurosteroid modulation of embryonic neuronal survival in vitro following anoxia. Brain Res 2000;871:104-112.
40. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992;6:2311-2322.
41. A receptor function. Trends Pharmacol Sci 1995;16:295-303.
42. Do-Rego JL, Mensah-Nyagan GA, Beaujean D, Vaudry D, et al. gamma-Aminobutyric acid, acting through gamma-aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus. Proc Natl Acad Sci USA 2000;97:13925-13930.
43. Nechmad A, Maayan R, Ramadan E, et al. Clozapine decreases rat brain dehydroepiandrosterone and dehydroepiandrosterone sulfate levels. Eur Neuropsychopharmacol 2003;13:29-31.
44. Fahey JM, Lindquist DG, Pritchard GA, Miller LG. Pregnenolone sulfate potentiation of NMDA-mediated increases in intracellular calcium in cultured chick cortical neurons. Brain Res 1995;669:183-188.
45. 3H]norepinephrine release evoked by N-methyl-d-aspartate in the rat hippocampus. Proc Natl Acad Sci USA 1995;92:3774-3778.
46. Sun JL, Dong YL, Fu YM, et al. Neurosteroid pregnenolone sulfate inhibits stimulus-evoked EPSC via presynaptic inhibition of protein kinase A in rat prelimbic cortical neurons. Neuropharmacology 2005;49:389-399.
47. Horak M, Vlcek K, Chodounska H, Vyklicky L, Jr. Subtype-dependence of N-methyl-Daspartate receptor modulation by pregnenolone sulfate. Neuroscience 2006;137:93-102.
48. Hige T, Fujiyoshi Y, Takahashi T. Neurosteroid pregnenolone sulfate enhances glutamatergic synaptic transmission by facilitating presynaptic calcium currents at the calyx of Held of immature rats. Eur J Neurosci 2006;24:1955-1966.
49. Bergeron R, De Montigny C, et al. Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors. J Neurosci 1996;16:1193-1202.
50. Schiess AR, Partridge LD. Pregnenolone sulfate acts through a G-protein-coupled sigma1-like receptor to enhance short term facilitation in adult hippocampal neurons. Eur J Pharmacol 2005;518:22-29.
51. 1) receptor mediated antidepressant-like effects of neurosteroids in the Porsolt forced swim test. Neuroreport 1998;9:3069-3073.
52. Melchior CL, Ritzmann RF. Dehydroepiandrosterone is an anxiolytic in mice on the plus maze. Pharmacol Biochem Behav 1994;47:437-444.
53. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the GABA (A) receptor. Nat Rev Neurosci 2005;6:565-575.
54. Morrow AL, Devaud LL, Purdy RH, Paul SM. Neuractive steroid modulators of the stress response. In: Chrousos GP, McCarty R, Pacák K, Cizza G, Sternberg E, Gold PW, Kvetnansky R (eds). Stress: basic mechanisms and clinical implications. New York: The New York Academy of Sciences, 1995, 257-272.
55. Dong E, Matsumoto K, Uzunova V, et al. Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci USA 2001;98:2849-2854.
56. Wolkowitz OM, Epel ES, et al. Stress hormone-related psychopathology: pathophysiological and treatment implications. World J Biol Psychiatry 2001;2:115-143.
57. Hu Y, Cardounel A, et al. Anti-stress effects of dehydroepiandrosterone: protection of rats against repeated immobilization stress-induced weight loss, glucocorticoid receptor production, and lipid peroxidation. Biochem Pharmacol 2000;59:753-762.
58. Boudarene M, Legros JJ, et al. Study of the stress response: role of anxiety, cortisol and DHEAs. Encephale 2002;28:139-146.
59. Rasmusson AM, Vythilingam M, Morgan CA 3rd. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectr 2003;8:651-566, 665-667.
60. Rasmusson AM, Vasek J, Lipschitz DS, et al. An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology 2004;29:1546-1557.
61. Obut TA, Ovsyukova MV, Cherkasova OP. Prolonged decrease in stress reactivity caused by dehydroepiandrosterone sulfate. Bull Exp Biol Med 2006;141:571-573.
62. Kalimi M, Shafagoj Y, Loria R. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol Cell Biochem 1994;131:99-104.
63. Kimonides VG, Spillantini MG, et al. Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience 1999;89:429-436.
64. Karishma KK, Herbert J. Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosteroneinduced suppression. Eur J Neurosci 2002;16:445-453.
65. Parker LN, Levin ER, Lifrak ET. Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab 1985;60:947-952.
66. Parker L, Eugene J, Farber D, et al. Dissociation of adrenal androgen and cortisol levels in acute stress. Horm Metab Res 1985;17:209-212.
67. Hechter O, Grossman A, Chatterton RT. Relationship of dehydroepiandrosterone and cortisol in disease. Med Hypotheses 1997;49:85-91.
68. Goodyer IM, Herbert J, Altham PM. Adrenal steroid secretion and major depression in 8-to 16-year-olds. III. Influence of cortisol/DHEA ratio at presentation on subsequent rates of disappointing life events and persistent major depression. Psychol Med 1998;28:265-273.
69. Goodyer IM, Park RJ, Netherton CM, Herbert J. Possible role of cortisol and dehydroepiandrosterone in human development and psychopathology. Br J Psychiatry 2001;179:243-249.
70. Kroboth PD, Amico JA, Stone RA, et al. Influence of DHEA administration on 24-hour cortisol concentrations. J Clin Psychopharmacol 2003;23:96-99.
71. Van Broekhoven F, Verkes RJ. Neurosteroids in depression: a review. Psychopharmacology (Berl) 2003;165:97-110.
72. Basta-Kaim A, Budziszewska B, Jaworska-Feil L, et al. Effects of neurosteroids on glucocorticoid receptor-mediated gene transcription in LMCAT cells - A possible interaction with psychotropic drugs. Eur Neuropsychopharmacol 2007;17:37-45.
73. Roberts E, Bologa L, Flood JF, Smith GE. Effects of dehydroepiandrosterone and its sulfate on brain tissue in culture and on memory in mice. Brain Res 1987;406:357-362.
74. Bologa L, Sharma J, et al. Dehydroepiandrosterone and its sulfated derivative reduce neuronal death and enhance astrocytic differentiation in brain cell cultures. J Neurosci Res 1987;17:225-234.
75. Schumacher M, Robel P, Baulieu EE. Development and regeneration of the nervous system: a role for neurosteroids. Dev Neurosci 1996;18:6-21.
76. Schumacher M, Guennoun R, Robel P, Baulieu EE. Neurosteroids in the Hippocampus. Neuronal Plasticity and Memory 1997;2:65-78.
77. Compagnone NA, Mellon SH. Dehydroepiandrosterone: a potential signalling molecule for neocortical organization during development. Proc Natl Acad Sci USA 1998;95:4678-4683.
78. Gursoy E, Cardounel A, et al. Pregnenolone protects mouse hippocampal (HT-22) cells against glutamate and amyloid beta protein toxicity. Neurochem Res 2001;26:15-21.
79. Shirakawa H, Katsuki H, Kume T, et al. Pregnenolone sulphate attenuates AMPA cytotoxicity on rat cortical neurons. Eur J Neurosci 2005;21:2329-2335.
80. Veiga S, Garcia-Segura LM, et al. Neuroprotection by the steroids pregnenolone and dehydroepiandrosterone is mediated by the enzyme aromatase. J Neurobiol 2003;56:398-406.
81. Charalampopoulos I, Alexaki VI, Tsatsanis C, et al. Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging. Ann NY Acad Sci 2006;1088:139-152.
82. Campbell B. Adrenarche and the evolution of human life history. Am J Hum Biol 2006;18:569-589.
83. Flood JF, Morley JE, Roberts E. Memory-enhancing effects in male mice of pregnenolone and of steroids metabolically derived from it. Proc Natl Acad Sci USA 1992;89:1567-1571.
84. Flood J., et al. Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures. Proc Nat Acad Sci USA 1995;92:10806-108010.
85. Robel P, Young J, Corpechot C, et al. Biosynthesis and assay of neurosteroids in rats and mice: functional correlates. J Steroid Biochem Mol Biol 1995;53:355-360.
86. Mayo W, Dellu F, Robel P, et al. Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processes in the rat. Brain Res 1993;607:324-328.
87. Isaacson RL, Varner JA, Baars J-M, De Wied D. The effects of pregnenolone sulfate and ethylestrenol on retention of a passive avoidance task. Brain Res 1995;689:79-84.
88. Mathis C, Paul SM, Crawley JN. The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced deficits in a passive avoidance memory task. Psychopharmacology (Berl) 1994;116:201-206.
89. Cheney DL, Uzunov D, Guidotti A. Pregnenolone sulfate antagonizes dizocilpine amnesia: role for allopregnanolone. Neuroreport 1995;6:1697-1700.
90. Melchior CL, Ritzmann RF. Neurosteroids block the memory-impairing effects of ethanol in mice. Pharmacol Biochem Behav 1996;53:51-56.
91. Bowlby MR. Pregnenolone sulfate potentiation of N-methyl-d-aspartate receptor channels in hippocampal neurons. Mol Pharmacol 1993;43:813-819.
92. Mathis C, Vogel E, Cagniard B, et al. The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice. Neuropharmacology 1996;35:1057-1064.
93. Markowski M, Ungeheuer M, Bitran D, Locurto C. Memory-enhancing effects of DHEAS in aged mice on a win-shift water escape task. Physiol Behav 2001;72:521-525.
94. Vallee M, Mayo W, Le Moal M. Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging. Brain Res Brain Res Rev 2001;37:301-312.
95. Rhodes ME, Li PK, et al. Enhancement of hippocampal acetylcholine release by the neurosteroid dehydroepiandrosterone sulfate: an in vivo microdialysis study. Brain Res 1996;733:284-286.
96. Rhodes ME, Li PK, et al. Enhanced plasma DHEAS, brain acetylcholine and memory mediated by steroid sulfatase inhibition. Brain Res 1997;773:28-32.
97. Johnson DA, Rhodes ME, et al. Chronic steroid sulfatase inhibition by (p-O-sulfamoyl)-Ntetradecanoyl tyramine increases dehydroepiandrosterone sulfate in whole brain. Life Sci 1997;61:355-359.
98. Li PK, Rhodes ME, et al. Memory enhancement mediated by the steroid sulfatase inhibitor (p-O-sulfamoyl)-N-tetradecanoyl tyramine. Life Sci 1997;60:45-51.
99. Lupien SJ, Fiocco A, Wan N, et al. Stress hormones and human memory function across the lifespan. Psychoneuroendocrinology 2005;30:225-242.
100. Roozendaal B, McGaugh JL. Amygdaloid nuclei lesions differentially affect glucocorticoidinduced memory enhancement in an inhibitory avoidance task. Neurobiol Learn Mem 1996;65:1-8.
101. El-Etr M, Akwa Y, Baulieu EE, Schumacher M. The neuroactive steroid pregnenolone sulfate stimulates the release of gonadotropin-releasing hormone from GT1-7 hypothalamic neurons, through N-methyl-D-aspartate receptors. Endocrinology 2006;147:2737-2743.
102. Diamond DM, Branch BJ, et al. The neurosteroid dehydroepiandrosterone sulfate (DHEAS) enhances hippocampal primed burst, but not long-term, potentiation. Neurosci Lett 1996;202:204-208.
103. Wolf OT, Kirschbaum C. Actions of dehydroepiandrosterone and its sulfate in the central nervous system: effects on cognition and emotion in animals and humans. Brain Res Rev 1999;30:264-288.
104. Labrie C, Flamand M, Belanger A, Labrie F. High bioavailability of dehydroepiandrosterone administered percutaneously in the rat. J Endocrinol 1996;150(Suppl):107-118.
105. Mo Q, Lu SF, et al. Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity. J Steroid Biochem Mol Biol 2006;99:50-58.
106. Roberts E, Fitten LJ. Serum steroid levels in two old men with Alzheimer's disease (AD) before and after oral administration of dehydroepiandrosterone (DHEA). Pregnenolone synthesis may be rate limiting in aging. In: Kalimi M, Regelson W (eds). The biological role of dehydroepiandrosterone (DHEA). Berlin: de Gruyter, 1990, pp. 43-63.
107. Morley JE, Kaiser F, et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci USA 1997;94:7537-7542.
108. Orentreich N, Brind JL, Vogelman JH, et al. Long-term longitudinal measurements of plasma dehydro-epiandrosterone sulfate in normal men. J Clin Endocrinol Metab 2002;75:1002-1004.
109. Labrie F, Belanger A, Cusan L, et al. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 1997;82:2396-2402.
110. Nafziger AN, Bowlin SJ, et al. Longitudinal changes in dehydroepiandrosterone concentrations in men and women. J Lab Clin Med 1998;131:316-323.
111. Carlström K, Brody S, Lunell N-O, et al. Dehydroepiandrosterone sulphate and dehydroepiandrosterone in serum: differences related to age and sex. Maturitas 1988;10:297-306.
112. Orentreich N, Brind JL, Rizer RL, et al. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551-555.
113. Zumoff B, Bradlow HL. Sex difference in the metabolism of dehydroisoandrosterone sulfate. J Clin Endocrinol Metab 1980;51:334-336.
114. Glei DA, Goldman N, Weinstein M, Liu IW. Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ by sex? Exp Gerontol 2004;39:321-331.
115. Migeon CJ, Plager JE. Identification and isolation of dehydroisoandrosterone from peripheral human plasma. J Biol Chem 1954;209:767-772.
116. Guazzo EP, Kirkpatrick PJ, et al. Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age. J Clin Endocrinol Metab 1996;81:3951-3960.
117. Yildiz BO, Goodarzi MO, et al. Heritability of dehydroepiandrosterone sulfate in women with polycystic ovary syndrome and their sisters. Fertil Steril 2006;86:1688-1693.
118. Feldman HA, Johannes CB, et al. Low dehydroepiandrosterone sulfate and heart disease in middle-aged men: cross-sectional results from the Massachusetts Male Aging Study. Ann Epidemiol 1998;8:217-228.
119. Feldman HA, Johannes CB, et al. Low dehydroepiandrosterone and ischemic heart disease in middle-aged men: prospective results from the Massachusetts male aging study. Am J Epidemiol 2001;153:79-89.
120. Van Niekerk JK, Huppert FA, et al. Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation. Psychoneuroendocrinology 2001;26:591-612.
121. Barrett-Connor E, Ferrara A. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study. J Clin Endocrinol Metab 1996;81:59-64.
122. Tellez N, Comabella M, et al. Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone. Mult Scler 2006;12:487-494.
123. Narvaez J, Bernad B, et al. Low serum levels of DHEAS in untreated polymyalgia rheumatica/giant cell arteritis. J Rheumatol 2006;33:1293-1298.
124. Yamakita N, Murai T, Kokubo Y, et al. Dehydroepiandrosterone sulphate is increased and dehydroepiandrosterone-response to corticotrophin-releasing hormone is decreased in the hyperthyroid state compared with the euthyroid state. Clin Endocrinol (Oxf) 2001;55:797-803.
125. Oberbeck R, Benschop RJ, Jacobs R, et al. Endocrine mechanisms of stress-induced DHEAsecretion. J Endocrinol Invest 1998;21:148-153.
126. Morgan CA 3rd, Southwick S, Hazlett G, et al. Relationships among plasma dehydroepiandrosterone sulfate and cortisol levels, symptoms of dissociation, and objective performance in humans exposed to acute stress. Arch Gen Psychiatry 2004;61:819-825.
127. Spivak B, Maayan R, Kotler M, et al. Elevated circulatory level of GABA (A) - antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol Med 2000;30:1227-1231.
128. Monteleone P, Luisi M, Colurcio B, et al. Plasma levels of neuroactive steroids are increased in untreated women with anorexia nervosa or bulimia nervosa. Psychosom Med 2001;63:62-68.
129. Yehuda R, Brand SR, Golier JA, Yang RK. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr Scand 2006;114:187-193.
130. Jogems-Kosterman BJ, De Knijff DW, Kusters R, Van Hoof JJ. Basal cortisol and DHEA levels in women with borderline personality disorder. J Psychiatr Res 2006 [epub ahead of print].
131. Monteleone P, Luisi M, Martiadis V, et al. Impaired reduction of enhanced levels of dehydroepiandrosterone by oral dexamethasone in anorexia nervosa. Psychoneuroendocrinology 2006;31:537-542.
132. Cleare AJ, O'Keane V, et al. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology 2004;29:724-732.
133. George MS, Guidotti A, Rubinow D, et al. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psychiatry 1994;35:775-780.
134. Bicikova M, Tallova J, Hill M, et al. Serum concentrations of some neuroactive steroids in women suffering from mixed anxiety-depressive disorder. Neurochem Res 2000;25:1623-1627.
135. Semeniuk T, Jhangri GS, Le Melledo JM. Neuroactive steroid levels in patients with generalized anxiety disorder. J Neuropsychiatry Clin Neurosci 2001;13:396-398.
136. Heydari B, Le Melledo JM. Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med 2002;32:929-933.
137. Tagawa N, Tamanaka J, et al. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and pregnenolone sulfate concentrations in patients with hyperthyroidism and hypothyroidism. Clin Chem 2000;46:523-528.
138. Hill M, Popov P, et al. Altered profiles of serum neuroactive steroids in premenopausal women treated for alcohol addiction. Steroids 2005;70:515-524.
139. Takebayashi M, Kagaya A, Uchitomi Y, et al. Plasma dehydroepiandrosterone sulfate in unipolar major depression. Short communication. J Neural Transm 1998;105:537-542.
140. Heuser I, Deuschle M, Luppa P, et al. Increased diurnal plasma concentrations of dehydroepiandrosterone in depressed patients. J Clin Endocrinol Metab 1998;83:3130-3133.
141. Maayan R, Yagorowski Y, Grupper D, et al. Basal plasma dehydroepiandrosterone sulfate level: a possible predictor for response to electroconvulsive therapy in depressed psychotic inpatients. Biol Psychiatry 2000;48:693-701.
142. Michael A, Jenaway A, Paykel ES, Herbert J. Altered salivary dehydroepiandrosterone levels in major depression in adults. Biol Psychiatry 2000;48:989-995.
143. Grillon C, Pine DS, Baas JM, et al. Cortisol and DHEA-S are associated with startle potentiation during aversive conditioning in humans. Psychopharmacology (Berl.) 2006;186:434-441.
144. Cruess DG, Antoni MH, Kumar M, et al. Cognitive-behavioral stress management buffers decreases in dehydroepiandrosterone sulfate (DHEA-S) and increases in the cortisol/DHEAS ratio and reduces mood disturbance and perceived stress among HIV-seropositive men. Psychoneuroendocrinology 1999;24:537-549.
145. Pajer K, Tabbah R, Gardner W, et al. Adrenal androgen and gonadal hormone levels in adolescent girls with conduct disorder. Psychoneuroendocrinology 2006;31:1245-1256.
146. Osran H, Reist C, Chen CC, et al. Adrenal androgens and cortisol in major depression. Am J Psychiatry 1993;150:806-809.
147. Scott LV, Salahuddin F, Cooney J, et al. Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health. J Affect Disord 1999;54:129-137.
148. Reus VI, Wolkowitz OM, Frederick S. Antiglucocorticoid treatments in psychiatry. Psychoneuroendocrinology 1997;22(Suppl 1):121-124.
149. Fabian TJ, Dew MA, Pollock BG, et al. Endogenous concentrations of DHEA and DHEA-S decrease with remission of depression in older adults. Biol Psychiatry 2001;50:767-774.
150. Goodyer IM, Herbert J, et al. Adrenal secretion during major depression in 8-to 16-yearolds. I. Altered diurnal rhythms in salivary cortisol and dehydroepiandrosterone (DHEA) at presentation. Psychol Med 1996;26:245-256.
151. Young AH, Gallagher P, Porter RJ. Elevation of the cortisol- dehydroepiandrosterone ratio in drug-free depressed patients. Am J Psychiatry 2002;159:1237-1239.
152. Goodyer IM, Herbert J, Tamplin A. Psychoendocrine antecedents of persistent first-episode major depression in adolescents: a community-based longitudinal enquiry. Psychol Med 2003;33:601-610.
153. Ferrari E, Mirani M, et al. Cognitive and affective disorders in the elderly: a neuroendocrine study. Arch Gerontol Geriatr 2004 (Suppl 9):171-182.
154. Gallagher P, Young A. Cortisol/DHEA ratios in depression. Neuropsychopharmacology 2002;26:410.
155. Kahl KG, Bens S, Ziegler K, et al. Cortisol, the cortisol- dehydroepiandrosterone ratio, and pro-inflammatory cytokines in patients with current major depressive disorder comorbid with borderline personality disorder. Biol Psychiatry 2006;59:667-671.
156. De Bruin VM, Vieira MC, Rocha MN, Viana GS. Cortisol and dehydroepiandosterone sulfate plasma levels and their relationship to aging, cognitive function, and dementia. Brain Cogn 2002;50:316-323.
157. Christeff N, Nunez EA, Gougeon ML. Changes in cortisol/DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy. Ann NY Acad Sci 2000;917:962-970.
158. Brophy MH, Rush AJ, Crowley G. Cortisol, estradiol, and androgens in acutely ill paranoid schizophrenics. Biol Psychiatry 1983;18:583-590.
159. Harris DS, Wolkowitz OM, Reus VI. Movement disorder, memory, psychiatric symptoms and serum DHEA levels in schizophrenic and schizoaffective patients. World J Biol Psychiatry 2001;2:99-102.
160. Goyal RO, Sagar R, Ammini AC, et al. Negative correlation between negative symptoms of schizophrenia and testosterone levels. Ann NY Acad Sci 2004;1032:291-294.
161. Ritsner M, Maayan R, Gibel A, et al. Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur Neuropsychopharmacol 2004;14:267-273.
162. Yilmaz N, Herken H, Cicek HK, et al. Increased levels of nitric oxide, cortisol and adrenomedullin in patients with chronic schizophrenia. Med Princ Pract 2007;16:137-141.
163. Tourney G, Hatfield L. Plasma androgens in male schizophrenics. Arch Gen Psychiatry 1972;27:753-755.
164. Oertel GW, Benes P, Schirazi M, et al. Interaction between dehydroepiandrosterone, cyclic adenosine-3', 5'-monophosphate and glucose-6-phosphate-dehydrogenase in normal and diseased subjects. Experientia 1974;30:872-873.
165. Oades RD, Schepker R. Serum gonadal steroid hormones in young schizophrenic patients. Psychoneuroendocrinology 1994;19:373-385.
166. Strous RD, Maayan R, Lapidus R, et al. Increased circulatory dehydroepiandrosterone and dehydroepiandrosterone-sulphate in first-episode schizophrenia: relationship to gender, aggression and symptomatology. Schizophr Res 2004;71:427-434.
167. Di Michele F, Caltagirone C, Bonaviri G, et al. Plasma dehydroepiandrosterone levels are strongly increased in schizophrenia. J Psychiatr Res 2005;39:267-273.
168. Ritsner M, Gibel A, Ram E, et al. Alterations in DHEA metabolism in schizophrenia: twomonth case-control study. Eur Neuropsychopharmacol 2006;16:137-146.
169. Gallagher P, Watson S, Smith MS, et al. Plasma cortisol- dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder. Schizophr Res 2007;90:258-265.
170. Tourney G, Erb JL. Temporal variations in androgens and stress hormones in control and schizophrenic subjects. Biol Psychiatry 1979;14:395-404.
171. Erb JL, Kadane JB, Tourney G, et al. Discrimination between schizophrenic and control subjects by means of plasma dehydroepiandrosterone measurements. J Clin Endocrinol Metab 1981;52:181-186.
172. Ritsner M, Gibel A, Maayan R, et al. State and trait related predictors of serum cortisol to DHEA (S) molar ratios and hormone concentrations in schizophrenia patients. Eur Neuropsychopharmacol 2007;17:257-264.
173. Ceskova E, Drybcak P, Hrobar P, et al. The changes of biological markers and treatment efficacy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:323-335.
174. Ceskova E, Kasparek T, Zourkova A, Prikryl R. Dexamethasone suppression test in firstepisode schizophrenia. Neuro Endocrinol Lett 2006;27:433-437.
175. Zhang XY, Zhou DF, Cao LY, et al. Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology 2005;30:1532-1538.
176. Kaneda Y, Fujii A, Ohmori T. The hypothalamic-pituitary-adrenal axis in chronic schizophrenic patients long-term treated with neuroleptics. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:935-938.
177. Taherianfard M, Shariaty M. Evaluation of serum steroid hormones in schizophrenic patients. Indian J Med Sci 2004;58:3-9.
178. Heinz A, Weingartner H, George D, et al. Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations. Psychiatry Res 1999;89:97-106.
179. Shirayama Y, Hashimoto K, Suzuki Y, Higuchi T. Correlation of plasma neurosteroid levels to the severity of negative symptoms in male patients with schizophrenia. Schizophr Res 2002;58:69-74.
180. Hsiao CC. Positive correlation between anxiety severity and plasma levels of dehydroepiandrosterone sulfate in medication-free patients experiencing a major episode of depression. Psychiatry Clin Neurosci 2006;60:746-750.
181. Strous RD, Maayan R, Lapidus R, et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 2003;60:133-141.
182. Strous RD, Stryjer R, Maayan R, et al. Analysis of clinical symptomatology, extrapyramidal symptoms and neurocognitive dysfunction following
183. Ritsner MS, Gibel A, Ratner Y, et al. Improvement of sustained attention and visual and movement skills, but not clinical symptoms, after dehydroepiandrosterone augmentation in schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychopharmacol 2006;26:495-499.
184. Ritsner M, Maayan R, Gibel A, Weizman A. Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol 2007;17:358-365.
185. Censits DM, Ragland JD, Gur RC, Gur RE. Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: a longitudinal study. Schizophr Res 1997;24:289-298.
186. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol 2005;60:229-242.
187. Hutton SB, Puri BK, Duncan LJ, et al. Executive function in first-episode schizophrenia. Psychol Med 1998;28:463-473.
188. Brewer WJ, Pantelis C, Anderson V, et al. Stability of olfactory identification deficits in neurolepticnaive patients with first-episode psychosis. Am J Psychiatry 2001;158:107-115.
189. Rund BR. A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull 1998;24:425-435.
190. Hoff AL, Svetina C, Shields G, et al. Ten year longitudinal study of neuropsychological functioning subsequent to a first episode of schizophrenia. Schizophr Res 2005;78:27-34.
191. Lewis DA, Moghaddam B. Cognitive dysfunction in schizophrenia: convergence of gammaaminobutyric acid and glutamate alterations. Arch Neurol 2006;63:1372-1376.
192. Ko YH, Joe SH, Cho W, et al. Estrogen, cognitive function and negative symptoms in female schizophrenia. Neuropsychobiology 2006;53:169-175.
193. Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 1998;83:3487-3492.
194. Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone (DHEA) replacement in elderly men on event related potentials (ERPs), memory and wellbeing. J Gerontol A Biol Sci Med Sci 1998;53:385-390.
195. Wolf OT, Kudielka BM, Hellhammer DH, et al. Opposing effects of DHEA replacement in elderly subjects on declarative memory and attention after exposure to a laboratory stressor. Psychoneuroendocrinology 1998;23:617-629.
196. Huppert FA, Van Niekerk JK. Dehydroepiandrosterone (DHEA) supplementation for cognitive function (Cochrane Review). Oxford: The Cochrane Library (Issue 2), Update Software 2000.
197. Moffat SD, Zonderman AB, Harman SM, et al. The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 2000;160:2193-2198.
198. Fonda SJ, Bertrand R, O'Donnell A, et al. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005;60:385-390.
199. Murialdo G, Barreca A, Nobili F, et al. Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia. J Endocrinol Invest 2001;24:139-146.
200. Armanini D, Vecchio F, Basso A, et al. Alzheimer's disease: pathophysiological implications of measurement of plasma cortisol, plasma dehydroepiandrosterone sulfate, and lymphocytic corticosteroid receptors. Endocrine 2003;22:113-118.
201. Genedani S, Rasio G, Cortelli P, et al. Studies on homocysteine and dehydroepiandrosterone sulphate plasma levels in Alzheimer's disease patients and in Parkinson's disease patients. Neurotox Res 2004;6:327-332.
202. Yanase T, Fukahori M, Taniguchi S, et al. Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) in Alzheimer's disease and in cerebrovascular dementia. Endocr J 1996;43:119-123.
203. Morrison MF, Redei E, Ten Have T, et al. Dehydroepiandrosterone sulfate and psychiatric measures in a frail, elderly residential care population. Biol Psychiatry 2000;47:144-1450.
204. CANTAB, Cambridge Automated Neuropsychological Test Battery. http://www.cantab.com/cantab/site/home.acds).
205. Heaton RK, Wisconsin Card Sorting Test Manual. Revised and expanded. Odessa, FL: Psychological Assessment Resources, 1993.
206. Jacquy J, Wilmotte J, et al. Cerebral blood flow patterns studied by rheoencephalography in schizophrenia. Neuropsychobiology 1976;2:94-103.
207. Weinberger DR, Berman KF. Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci 1996;351:1495-1503.
208. Hill K, Mann L, et al. Hypofrontality in schizophrenia: a meta-analysis of functional imaging studies. Acta Psychiatr Scand 2004;110:243-256.
209. Paulman RG, Devous MD, Sr, et al. Hypofrontality and cognitive impairment in schizophrenia: dynamic single-photon tomography and neuropsychological assessment of schizophrenic brain function. Biol Psychiatry 1990;27:377-399.
210. Davidson LL, Heinrichs RW. Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Psychiatry Res 2003;122:69-87.
211. Riehemann S, Volz HP, et al. Hypofrontality in neuroleptic-naive schizophrenic patients during the Wisconsin Card Sorting Test - a fMRI study. Eur Arch Psychiatry Clin Neurosci 2001;251:66-71.
212. Moreno-Iniguez M, Ortuno F, et al. Regional cerebral blood flow SPECT study, at rest and during Wisconsin Card Sorting Test (WCST) performance, in schizophrenia naive patients or treated with atypical neuroleptics. Actas Esp Psiquiatr 2005;33:343-351.
213. Ortuno F, Moreno-Iniguez M, et al. Cortical blood flow during rest and Wisconsin Card Sorting Test performance in schizophrenia. Wien Med Wochenschr 2006;156:179-184.
214. Hazlett EA, Buchsbaum MS, et al. Hypofrontality in unmedicated schizophrenia patients studied with PET during performance of a serial verbal learning task. Schizophr Res 2000;43:33-46.
215. Lammers CH, Garcia-Borreguero D, Schmider J, et al. Combined dexamethasone/corticotropinreleasing hormone test in patients with schizophrenia and in normal controls. II. Biol Psychiatry 1995;38:803-807.
216. Marx CE, Shampine LJ, et al. Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy? Pharmacol Biochem Behav 2006;84:598-608.
217. Marx CE, Shampine LJ, et al. Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions. Pharmacol Biochem Behav 2006;84:609-617.
218. Oseko F, Morikawa K, Nakano A, et al. Effect of chronic hyperprolactinemia induced by sulpiride on plasma dehydroepiandrosterone (DHA) in normal men. Andrologia 1986;18:523-528.
219. Ritsner M, Gibel A, Maayan R, et al. Cortisol/dehydroepiandrosterone ratio and responses to antipsychotic treatment in schizophrenia. Neuropsychopharmacology 2005;30:1913-1922.
220. Jakovljevic M, Muck-Seler D, Pivac N, Crncevic Z. Platelet 5-HT and plasma cortisol concentrations after dexamethasone suppression test in patients with different time course of schizophrenia. Neuropsychobiology 1998;37:142-145.
221. Walker EF, Diforio D. Schizophrenia: a neural diathesis-stress model. Psychology Review 1997;104:667-685.
222. Bradlow HL, Murphy J, Byrne JJ. Immunological properties of dehydroepiandrosterone, its conjugates, and metabolites. Ann NY Acad Sci 1999;876:91-101.
223. Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 1999;22:410-416.
224. Le Melledo JM, Baker GB. Neuroactive steroids and anxiety disorders. J Psychiatry Neurosci 2002;27:161-165.
225. Marx CE, Stevens RD, et al. Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology 2006;31:1249-1263.
226. Sawa A, Snyder SH. Schizophrenia: diverse approaches to a complex disease. Science 2002;296:692-695.
227. Anderson JE, O'Donnell BF, McCarley RW, Shenton ME. Progressive changes in schizophrenia: do they exist and what do they mean? Restor Neurol Neurosci 1998;12:175-184.
228. Sabeti J, Nelson TE, Purdy RH, Gruol DL. Steroid pregnenolone sulfate enhances NMDAreceptorindependent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors. Hippocampus 2007 [epub ahead of print].
229. Maurice T, Phan VL, Urani A, et al. Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1) receptor: pharmacological evidence and therapeutic opportunities. Jpn J Pharmacol 1999;81:125-155.
230. Maurice T, Urani A, Phan VL, Romieu P. The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev 2001;37:116-132.
231. Boccuzzi G, Aragno M, Seccia M, et al. Protective effect of dehydroepiandrosterone against copper-induced lipid peroxidation in the rat. Free Radic Biol Med 1997;22:1289-1294.
232. Aragno M, Brignardello E, Tamagno E, et al. Dehydroepiandrosterone administration prevents the oxidative damage induced by acute hyperglycemia in rats. J Endocrinol 1997;155:233-240.
233. Kimonides VG, Khatibi NH, et al. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci USA 1998;95:1852-1857.
234. Cardounel A, Regelson W, et al. Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell death: mechanism of action. Proc Soc Exp Biol Med 1999;222:145-149.
235. Bastianetto S, Ramassamy C, et al. Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Brain Res Mol Brain Res 1999;66:35-41.
236. Charalampopoulos I, Tsatsanis C, et al. Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins. Proc Natl Acad Sci USA 2004;101:8209-8214.
237. Majewska MD. Neuronal actions of dehydroepiandrosterone. Possible roles in brain development, aging, memory, and affect. Ann NY Acad Sci 1995;774:111-120.
238. Morin C, Zini R, Simon N, Tillement JP. Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses. Neuroscience 2002;115:415-424.
239. Suzuki M, Wright LS, Marwah P, et al. Mitotic and neurogenic effects of dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex. Proc Natl Acad Sci USA. 2004;101:3202-3207.
240. Takahashi H, Nakajima A, et al. Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) inhibit the apoptosis in human peripheral blood lymphocytes. J Steroid Biochem Mol Biol 2004;88:261-264.
241. Kurata K, Takebayashi M, et al. Beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms. J Pharmacol Exp Ther 2004;311:237-245.