Hostname: page-component-76d6cb85b7-jhrpq Total loading time: 0 Render date: 2026-07-27T04:25:11.445Z Has data issue: false hasContentIssue false
  • English
  • Français

Importance of folate in human nutrition

Published online by Cambridge University Press:  09 March 2007

Kamala Krishnaswamy  and
K. Madhavan Nair
Kamala Krishnaswamy*
Affiliation:
National Institute of Nutrition, Jamai-Osmania, Hyderabad-500007, India
K. Madhavan Nair
Affiliation:
National Institute of Nutrition, Jamai-Osmania, Hyderabad-500007, India
*
*Corresponding author: Dr Kamala Krishnaswamy, fax +91 40 7019074, email icmrnin@ren.nic.in, nin@ap.ap.nic.in
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the 'Save PDF' action button.

From a public health perspective, some of the new insights into folic acid nutrition are of significance. Folate intake recommendations vary under different conditions. Intake of 350 μg is required to maintain plasma homocysteine levels, 650 μg for those with elevated plasma homocysteine, about 400 μg for women planning to become pregnant and 4000 μg for those with history of neural tube defect affected pregnancy. This raises the question whether the folate intake is adequate for the general population, particularly in the vulnerable groups or whether there is a need for scientists to take a fresh view of the requirements, recommended dietary intakes, and consider intervention measures which will have impact on the folate nutritional status. The recommendations should provide a margin of safety to allow for decreased intake, increased requirements, individual variability and bioavailability of natural food folates. The folate intake and nutriture in relation to India and other developing countries needs careful consideration to reduce anemia, neural tube defects and possibly impact on the high incidence of cardiovascular diseases.

Keywords

FolateHomocysteineHealth and diseaseRDAIndia

Information

Type
Research Article
Information
British Journal of Nutrition , Volume 85 , Issue S2 , May 2001 , pp. S115 - S124
Copyright
Copyright © The Nutrition Society 2001

References

Abramsky, L, Blotting, B, Chapple, J & Stone, D (1999) Has advice on periconceptional folate supplementation reduced neural tube defects? Lancet 354, 998–999.CrossRefGoogle ScholarPubMed
Agarwal, SS, Singh, U, Singh, PS, Singh, SS, Das, V, Sharma, A, Mehra, P, Chandravathi, , Malik, GK & Misra, PK (1991) Prevalence and spectrum of congenital malformations in a prospective study at teaching hospital. Indian Journal of Medical Research 94, 413–419.Google Scholar
Agarwal, SS (1998) Folic acid for prevention of neural tube defects. Bulletin of the Nutrition Foundation of India 19, 5–8.Google Scholar
Ahmed, F, Bamji, MS & Iyengar, L (1975) Effect of oral contraceptive agents on vitamin nutrition status. American Journal of Clinical Nutrition 28, 606–615.CrossRefGoogle ScholarPubMed
Babu, S & Srikantia, SG (1976) Availability of folates from some foods. American Journal of Clinical Nutrition 29, 376–379.CrossRefGoogle ScholarPubMed
Babu, S (1976 a) Effect of germination on folic acid content of Bengal gram and ragi. Indian Journal of Nutrition and Dietetics 13, 139–141.Google Scholar
Babu, S (1976 b) Studies on folic acid. PhD Thesis, Osmania University, Hyderabad, India.Google Scholar
Bailey, LB (1998) Dietary reference intakes for folate: the debut of dietary folate equivalents. Nutrition Reviews 56, 294–299.CrossRefGoogle ScholarPubMed
Berry, RJ, Li, MPHTMZ, Erickson, DJ, Li, S, Moare, CA, Wang, H, Mulinare, J, Zhao, P, Wong, LYC, Gindler, J, Hong, SX & Correa, A (1999) Prevention of neural tube defects with folic acid in China. New England Journal of Medicine 341, 1485–1490.CrossRefGoogle ScholarPubMed
Blount, BC, Mack, MM, Wehr, CM, MacGregor, JT, Hiatt, RA, Wang, G, Wickramasinghe, SN, Everson, RB & Ames, BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breaking: Implications for cancer and neuronal damage. Proceedings of the National Academy of Sciences, USA 94, 3290–3295.CrossRefGoogle ScholarPubMed
Bonnette, RE, Caudill, MA & Bailey, LB (1998) Plasma homocysteine response to controlled folate intake in pregnant woman. Obstetrics and Gynecology 92, 167–170.Google Scholar
Boushey, CJ, Beresford, SAA, Omenn, GS & Motulsky, AG (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Journal of the American Medical Association 274, 1049–1057.CrossRefGoogle ScholarPubMed
Butterworth, CE, Baugh, CM & Krumdieck, CL (1969) A study of folate absorption in non-utilizing carbon-14-labeled polyglutamate synthesized by the solid phase method. Journal of Clinical Investigation 48, 1131–1142.CrossRefGoogle Scholar
Butterworth, CE, Hateh, KD, Gore, H, Muller, H & Krumdieck, CL (1982) Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. American Journal of Clinical Nutrition 35, 73–82.CrossRefGoogle ScholarPubMed
Caudill, MA, Cruz, AC, Gregory, JF, Hutson, AD & Bailey, LB (1997) Folate status response to controlled folate intake in pregnant women. Journal of Nutrition 127, 2362–2370.CrossRefGoogle ScholarPubMed
Caudill, MA, Gregory, JF, Hutson, AD & Bailey, LB (1998) Folate catabolism in pregnant and non-pregnant women with controlled folate intakes. Journal of Nutrition 128, 204–208.CrossRefGoogle Scholar
Chacko, KA (1998) Plasma homocysteine levels in-patients with coronary heart disease. Indian Heart Journal 50, 295–299.Google ScholarPubMed
Chambers, K, Popkin, J, Arnold, W, Irwin, B & Hall, JG (1994) Neural tube defects in British Columbia. Lancet 343, 489–490.CrossRefGoogle Scholar
Chandler, CJ, Wang, TT & Halsted, CH (1986) Pteroylpolyglutamate hydrolase from human jejunal brush borders: Purification and characterization. Journal of Biological Chemistry 261, 928–933.CrossRefGoogle ScholarPubMed
Choi, SW, Lathrop, Stem L, Dzia, lo HM, Dolnikowski, GG, Selhub, J & Mason, JB (1999) A common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene decreases genomic, DNA methylation, but does not reduce DNA strand breaks, p53 methylation or uracil misincorporation: implication for colorectal carcinogenesis. Gastroenterology 116, 303.Google Scholar
Choi, SW & Mason, JB (2000) Folate and carcinogenesis: an integrated scheme. Journal of Nutrition 130, 129–132.CrossRefGoogle ScholarPubMed
Collins, CS, Bailey, LB, Hillier, S, Cerda, JJ & Wilder, BJ (1988) Red blood cell uptake of supplemental folate in patients on anticonvulsant drug therapy. American Journal of Clinical Nutrition 48, 1445–1450.CrossRefGoogle ScholarPubMed
Cossins, EA (1984) Folates in biological materials. In Folates and Pterins Vol. 1, 1–60 [Blakley, RL & Benkovic, SJ, editors]. New York: John Wiley and Sons Inc.Google Scholar
Cuskelly, GJ, McNulty, H & Scott, JM (1996) Effect of increasing dietary folate on red cell folate: implications for prevention of neural tube defects. Lancet 347, 657–659.CrossRefGoogle ScholarPubMed
Daly, S, Mills, JL, Molloy, AM, Conley, M, Lee, YJ, Kirke, PN, Weir, DG & Scott, JM (1997) Minimum effective dose of folic acid for food fortification to prevent neural tube defect. Lancet 350, 1666–1669.CrossRefGoogle Scholar
Dawson, DN & Waters, HM (1994) Malnutrition: folate and cobalamine deficiency. British Journal of Biomedical Science 51, 221–227.Google Scholar
de Bree, A, Dusseldorp, MV, Brouwer, IA, Hof, van het KH & Theunissen, RPM (1997) Folate intake in Europe: recommended, actual and desired intake. European Journal of Clinical Nutrition 51, 643–660.CrossRefGoogle ScholarPubMed
Dierkes, J, Kroesen, M & Pietrzik, K (1998) Folic acid and vitamin B6 supplementation and plasma homocysteine concentrations in healthy young women. International Journal of Vitamin Nutrition Research 68, 98–103.Google ScholarPubMed
Dolk, H, BeWals, P, Gillerot, Y, Lechat, MF, Ayme, S, Cornel, M, Cuschieri, A, Garne, E, Goujard, J & Laurence, KM (1991) Heterogeniety of neural tube defects in Europe: The significance of site of defect and presence of other major anomalies in relation to geographic differences in prevalence. Teratology 44, 547–559.CrossRefGoogle Scholar
Elsborg, L (1974) Inhibition of intestinal absorption of folate by phenytoin. Acta Haematologica 52, 24–28.CrossRefGoogle ScholarPubMed
Emery, AE (1986) Methods in Medical Genetics, An introduction to statistical methods. 2nd edition. Edinburgh: Churchill/Livingstone.Google Scholar
Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Mathews, RG, Boers, GJ, denHeijer, M, Kluijtmans, LA, Vanden, Heuvel LP & Rozen, R (1995) A candidate genetic risk factor for vascular disease; a common mutation in methylene — tetrahydrofolate reductase. Nature Genetics 10, 111–113.CrossRefGoogle Scholar
Gheye, S, Lakshmi, AV, Krishna, TP & Krishnaswamy, K (1999) Fibrinogen and homocysteine in coronary artery disease. Indian Heart Journal 51, 499–502.Google ScholarPubMed
Giovannucci, E, Stampfer, M, Colditz, G, Rimm, E, Trichopolous, D, Rosner, B, Speizer, F & Willett, W (1993) Folate, methionine and alcohol intake and risk of colorectal adenoma. Journal of National Cancer Institute 85, 875–884.CrossRefGoogle ScholarPubMed
Gopalan, C, Ramasastry, BV, Balasubramanyam, SC, Narasinga Rao, BS, Deosthale, YG & Pant, KC (1989) Nutritive Value of Indian Foods. Hyderabad: National Institute of Nutrition, ICMR.Google Scholar
Gopalan, C (1994) Late effects of foetal undernutrition. The Bulletin of Nutrition Foundation of India 15, 1–4.Google Scholar
Graham, IM, Daly, LE, Refsum, HM, Robinson, K, Brattstrom, LE, Ueland, PM, Palma-Reis, RJ, Boers, GH, Sheahan, RG, Israelsson, B, Uiterwaal, CS, Meleady, R, McMaster, D, Verhoef, P, Witteman, J, Rubba, P, Bellet, H, Wautrecht, JC, de Valk, HW, Sales, Luis AC, Parrot-Rouland, FM, Tan, KS, Higgins, I, Garcon, D & Andria, G (1997) Plasma homocysteine as a risk factor for vascular disease. Journal of the American Medical Association 277, 1775–1781.CrossRefGoogle ScholarPubMed
Green, R, Jacobsen, DW & LB, Baily (1995) Clinical implications of hyperhomocysteinemia Folate in Health and Disease 195–235 [Baily, LB, editor]. New York: Marcel Dekker.Google Scholar
Gregory, JF (1997) Bioavailability of folate. European Journal of Clinical Nutrition 51, S54-S59.Google ScholarPubMed
Gregory, JF, Williamson, J, Liao, J-F, Bailey, LB & Toth, JP (1998) Kinetic model of folate metabolism in non-pregnant women consuming [2H2] folic acid: isotopic labelling of urinary folate and the catabolite PABG indicates slow intake-dependent turnover of folate pools. Journal of Nutrition 128, 1896–1906.CrossRefGoogle Scholar
Heinburger, DC, Alexander, CB, Birch, R, Batterworth, CE, Bailey, WC & Bumdieck, K (1988) Improvement of bronchial metaplasia in smokers treated with folate and vitamin B12 (report of a preliminary randomized, double-blind intervention trial). Journal of the American Medical Association 259, 1525–1530.CrossRefGoogle Scholar
Homocysteine Lowering Trialists' Collaboration (1998) Lowering blood homocysteine with folic acid based supplements; meta-analysis of randomized trials. British Medical Journal 316, 894–898.CrossRefGoogle Scholar
Indian Council of Medical Research (1989) Evaluation of National Nutritional Anaemia Prophylaxis Programme. New Delhi A report of a Task Force Study, ICMR.Google Scholar
Indian Council of Medical Research (1990) Nutrient Requirements and Dietary Allowances for Indians. Hyderabad, IndiaNational Institute of Nutrition, ICMR.Google Scholar
Indian Council of Medical Research 1992 Field supplementation trial in pregnant women with 60 mg, 120 mg and 180 mg of iron with 500 μg of folic acidA Report of a Task Force Study, ICMR.Google Scholar
Iyengar, L (1971) Folic acid requirements in Indian pregnant women. American Journal of Obstetrics and Gynecology 111, 13–16.CrossRefGoogle ScholarPubMed
Iyengar, L & Apte, SV (1972) Nutrient stores in human foetal liver. British Journal of Nutrition 27, 313–317.CrossRefGoogle Scholar
Iyengar, L & Babu, S (1975) Folic acid absorption in pregnancy. British Journal of Obstetrics and Gynaecology 82, 20–23.CrossRefGoogle ScholarPubMed
Iyengar, L & Rajalakshmi, K (1975) Effect of folic acid supplement on birth weights of infants. American Journal of Obstetrics and Gynecology 122, 332–336.CrossRefGoogle ScholarPubMed
Jacob, RA, Wu, MM, Henning, SM & Swendseid, ME (1994) Homocysteine increase as folate decreases in plasma of healthy men during short term dietary folate and methyl group restriction. Journal of Nutrition 124, 1072–1080.CrossRefGoogle ScholarPubMed
Jacob, RA, Gretz, DM, Taylor, PC, James, JS, Pogribny, PI, Miller, BJ, Henning, SM & Swendseid, ME (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. Journal of Nutrition 128, 1204–1212.CrossRefGoogle ScholarPubMed
Jacobsen, DW (1996) Determinants of hyperhomocysteinemia. A matter of nature and nurture. American Journal of Clinical Nutrition 64, 641–642.CrossRefGoogle ScholarPubMed
Kang, SS, Wong, PWK & Norusis, M (1987) Homocysteinemia due to folate deficiency. Metabolism 36, 458–462.CrossRefGoogle ScholarPubMed
Kang, SS, Wong, PW, Zhou, JM, Sora, J, Lessick, M, Ruggie, N & Grcevich, G (1988) Thermolabile methylene tetrahydrofolate reductase in patients with coronary artery disease. Metabolism 37, 611–613.CrossRefGoogle ScholarPubMed
Kulkarni, ML, Mathew, MA & Reddy, V (1989) The range of neural tube defects in South India. Archives of Disease in Childhood 64, 201–204.CrossRefGoogle Scholar
Kulkarni, ML & Jose, S (1997) Folic acid prevents neural tube defects in high prevalence area. Indian Pediatrics 34, 561–562.Google ScholarPubMed
Laurence, KM, James, N, Miller, MH, Tennant, GB & Campbell, H (1981) Double blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. British Medical Journal 282, 1509–1511.CrossRefGoogle ScholarPubMed
Lemire, RJ (1988) Neural tube defects. Journal of the American Medical Association 259, 558–562.CrossRefGoogle ScholarPubMed
Locksmith, GJ & Duff, P (1998) Preventing neural tube defects: the importance of periconceptional folic acid supplements. Obstetrics and Gynaecology (United States) 91, 1027–1034.Google ScholarPubMed
Ma, J, Stampfer, MJ, Giovannucci, E, Arigas, C, Hunter, DJ, Fuchs, C, Willett, WC, Selhub, J, Hennekens, CH & Rozen, RC (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions and risk of colorectal cancer. Cancer Research 57, 1098–1102.Google ScholarPubMed
Malinow, MR, Duell, PB, Hess, DL, Anderson, PH, Kruger, WD, Phillipson, BE, Gluckman, RA, Block, PC & Upson, BM (1998) Reduction of plasma homocysteine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. New England Journal of Medicine 338, 1009–1015.CrossRefGoogle ScholarPubMed
Ministry, of Health & Family, Welfare (1970) Prophylaxis against nutritional anaemia among mothers and children. Technical information MCH No. 1, Government of India, New Delhi.Google Scholar
MRC Vitamin Study Group (1991) Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 338, 131–137.CrossRefGoogle Scholar
National Academy of Sciences (1989) Recommended Dietary allowances. Food and Nutrition Board, 10th edition. Washington DC: National Academy Press.Google Scholar
National Academy of Sciences 1998 Dietary References Intakes: thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, patothenic acid, biotin and choline. A report of the Standing Committee on the Scientific evaluation of dietary reference intakes and its Panel on folate, other B-vitamins and choline and Sub-Committee on upper reference levels in nutrients: 196–305Food and Nutrition Board, Institute of Medicine National Academy Press.Google Scholar
NNMB (1999) National Nutrition Monitoring Bureau — Report of second repeat survey — rural (1996–97), National Institute of Nutrition, Indian Council of Medical Research, Hyderabad.Google Scholar
Neela, J & Raman, L (1997) The relationship between maternal nutritional status and spontaneous abortion. National Medical Journal of India 10, 15–16.Google ScholarPubMed
Neuhouser, ML, Beresford, SA, Hickok, DE & Mosen, ER (1998) Absorption of dietary and supplemental folate in women with prior pregnancies with neural tube defects and controls. Journal of American College of Nutrition 17, 625–630.CrossRefGoogle ScholarPubMed
Nygard, O, Nordrehang, JE, Refsum, HM, Ueland, PM, Farstad, M & Vollsett, SE (1997) Plasma homocysteine levels and mortality in patients with coronary heart disease. New England Journal of Medicine 337, 230–236.CrossRefGoogle Scholar
O'Broin, JD, Temperley, IJ, Brown, JP & Scott, JM (1975) Nutritional stability of various naturally occurring monoglutamate derivatives of folic acid. American Journal of Clinical Nutrition 28, 438–444.CrossRefGoogle ScholarPubMed
O'Keefe, CA, Bailey, LB, Thomas, EA, Hofler, SA, Davis, BA, Cerda, JJ & Gregory, JF (1995) Controlled dietary folate affects folate status in non-pregnant women. Journal of Nutrition 125, 2717–2725.Google Scholar
Pfeiffer, CM, Rogers, LM, Bailey, LB & Gregory, JF (1997) Absorption of folate from fortified cereal-grain products and of supplemental folate consumed with or without food determined by using a dual stable isotope protocol. American Journal of Clinical Nutrition 66, 1388–1397.CrossRefGoogle ScholarPubMed
Prinz-Langenohl, R, Bronstrup, A, Thorand, B, Hages, M & Pietrzik, K (1999) Availability of food folate in humans. Journal of Nutrition 129, 913–916.CrossRefGoogle ScholarPubMed
Raman, L, Subbalaxmi, PV, Vasumathi, N, Rawal, A, Vasanthi, G, Parvathi, CH, Adinarayana, K, Pawashe, AB & Rao, KV (1989) Iron and folic acid nutritional status of women in slum. Nutrition Reports International 39, 73–80.Google Scholar
Ramasastry, BVC (1965) Folate activity in human milk. British Journal of Nutrition 19, 581–586.CrossRefGoogle Scholar
Rimm, EB, Willett, WC, Hu, FB, Sampson, L, Colditz, GA, Manson, JE, Hennekens, C & Stampfer, MJ (1998) Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. Journal of the American Medical Association 279, 359–364.CrossRefGoogle ScholarPubMed
Sauberlich, HE, Kretsch, MJ, Skala, JH, Johnson, HL & Taylor, PC (1987) Folate requirement and metabolism in non-pregnant women. American Journal of Clinical Nutrition 46, 1016–1028.CrossRefGoogle Scholar
Scott, JM, Kirke, P, Molloy, A, Daly, L & Weir, D (1994) The role of folate in the prevention of neural tube defects. Proceedings of the Nutrition Society of India 53, 631–638.CrossRefGoogle ScholarPubMed
Scott, JM, Kirke, PM, Wei, DG (1995) Folate and neural tube defects. In Folate in Health and Disease, 329–360 [Bailey, LB, editor]. New York: Marcel Dekker.Google Scholar
Selhub, J, Jacques, PF, Wilson, PW, Rush, D & Rosenberg, IH (1993) Vitamin status and primary determinants of homocysteinaemia in an elderly population. Journal of the American Medical Association 270, 2693–2698.CrossRefGoogle Scholar
Seyoum, E & Selhub, J (1998) Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action. Journal of Nutrition 128, 1956–1960.CrossRefGoogle ScholarPubMed
Sharma, JB & Gulati, N (1992) Potential relationship between dengue fever and neural tube defects in a northern district of India. International Journal of Obstetrics and Gynecology 39, 291.CrossRefGoogle Scholar
Shaw, GN, Velie, EM & Schatter, DM (1997) Is dietary intake of methionine associated with a reduction in risk for neural tube defect - affected pregnancies? Teratology 56, 295–299.3.0.CO;2-X>CrossRefGoogle ScholarPubMed
Stevenson, AC, Johnston, HA, Stewart, MJP & Golding, DR (1966) Malformation of structure developed from the neural tube. Bulletin of the World Health Organization 34 (Suppl 9), 25–34.Google Scholar
Tamura, T & Stokstad, ELR (1973) The availability of food folate in man. British Journal of Haematology 25, 513–532.CrossRefGoogle ScholarPubMed
Tamura, T (1998) Determination of food folate. Journal of Nutrition 9, 285–293.Google Scholar
Tucker, KL, Selhub, J, Wilson, PF & Rosenberg, IH (1996) Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. Journal of Nutrition 126, 3025–3031.CrossRefGoogle ScholarPubMed
Ueland, PM & Refsum, H (1989) Plasma homocysteine, a risk factor for vascular disease; plasma levels in health, disease and drug therapy. Journal of Clinical and Laboratory Medicine 114, 473–501.Google ScholarPubMed
vanhet Hof, KH, Tijburg, LB, Pietrzik, K & Weststrate, JA (1999) Influence of feeding different vegetables on plasma levels of carotenoids, folate and vitamin C. Effect of disruption of the vegetable matrix. British Journal of Nutrition 82, 203–212.CrossRefGoogle Scholar
Vijayaraghavan, K, Brahmam, GNV, Nair, KM, Akbar, D & Prahlad, Rao N (1990) Evaluation of National Nutritional Anaemia Prophylaxis Programme. Indian Journal of Pediatrics 57, 183–190.CrossRefGoogle Scholar
Wagner, C (1996) Symposium on the subcellular compartmentation of folate metabolism. Journal of Nutrition 126, 1228S-1234S.CrossRefGoogle ScholarPubMed
Wald, NJ, Watt, HC, Law, MR, Weir, DG, McPartlin, J & Scott, JM (1998) Homocysteine and ischemic heart dsease. Archives of Internal Medicine 158, 862–867.CrossRefGoogle Scholar
Wang, TTY, Chandler, CJ & Halstead, CH (1986) Intracellular pteroylpolyglutamate hydrolase from human jejunal mucosa: isolation and characterization. Journal of Biological Chemistry 261, 13551–13555.CrossRefGoogle ScholarPubMed
Welch, GN & Loscalzo, J (1998) Homocysteine and atherosclerosis. The New England Journal of Medicine 338, 1042–1050.CrossRefGoogle Scholar
Wouters, MG, Moorrees, MT, van der, Mooren MJ, Blom, HJ, Boers, GH, Schellekens, LA, Thomas, CM & Eskes, TK (1995) Plasma homocysteine and menopausal status. European Journal of Clinical Investigation 25, 801–805.CrossRefGoogle ScholarPubMed
Young, SN & Ghadirian, AM (1989) Folic acid and psychopathology. Progress in Neuropsychopharmacology and Biological Psychiatry 13, 841–863.CrossRefGoogle ScholarPubMed