Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-23T12:49:01.793Z Has data issue: false hasContentIssue false
  • English
  • Français

Metabolic dysregulation and late-life depression: a prospective study

Published online by Cambridge University Press:  12 December 2016

R. M. Marijnissen ,
N. Vogelzangs ,
M. E. Mulder ,
R. H. S. van den Brink ,
H. C. Comijs  and
R. C. Oude Voshaar
R. M. Marijnissen*
Affiliation:
Department of Old Age Psychiatry, ProPersona, Arnhem/Wolfheze, The Netherlands University Center of Psychiatry & Interdisciplinary Center for Psychopathology of Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
N. Vogelzangs
Affiliation:
Department of Epidemiology, Cardiovascular Research Institute Maastricht (CARIM) & Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands
M. E. Mulder
Affiliation:
Department of Old Age Psychiatry, ProPersona, Arnhem/Wolfheze, The Netherlands
R. H. S. van den Brink
Affiliation:
University Center of Psychiatry & Interdisciplinary Center for Psychopathology of Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
H. C. Comijs
Affiliation:
Department Psychiatry, EMGO Institute for Health and Care Research VU University Medical Center/GGZinGeest, Amsterdam, The Netherlands
R. C. Oude Voshaar
Affiliation:
University Center of Psychiatry & Interdisciplinary Center for Psychopathology of Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
*
*Address for correspondence: R. M. Marijnissen, MD, Ph.D., Department of Old Age Psychiatry, ProPersona, Wolfheze 2, 6874 BE Wolfheze, The Netherlands. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Depression is associated with the metabolic syndrome (MS). We examined whether metabolic dysregulation predicted the 2-year course of clinical depression.

Method

A total of 285 older persons (⩾60 years) suffering from depressive disorder according to DSM-IV-TR criteria was followed up for 2 years. Severity of depression was assessed with the Inventory of Depressive Symptomatology (IDS) at 6-month intervals. Metabolic syndrome was defined according the National Cholesterol Education Programme (NCEP-ATP III). We applied logistic regression and linear mixed models adjusted for age, sex, years of education, smoking, alcohol use, physical activity, somatic co-morbidity, cognitive functioning and drug use (antidepressants, anti-inflammatory drugs) and severity of depression at baseline.

Results

MS predicted non-remission at 2 years (odds ratioper component = 1.26, 95% confidence interval 1.00–1.58), p = 0.047), which was driven by the waist circumference and HDL cholesterol. MS was not associated with IDS sum score. Subsequent analyses on its subscales, however, identified an association with the somatic symptom subscale score over time (interaction time × somatic subscale, p = 0.005), driven by higher waist circumference and elevated fasting glucose level.

Conclusions

Metabolic dysregulation predicts a poor course of late-life depression. This finding supports the concept of ‘metabolic depression’, recently proposed on population-based findings of a protracted course of depressive symptoms in the presence of metabolic dysregulation. Our findings seem to be driven by abdominal obesity (as indicated by the waist circumference) and HDL cholesterol dysregulation.

Keywords

Abdominal obesitydepressionelderlymetabolic syndromewaist circumference
Type
Original Articles
Information
Psychological Medicine , Volume 47 , Issue 6 , April 2017 , pp. 1041 - 1052
Copyright
Copyright © Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Akbaraly, TN, Kivimäki, M, Brunner, EJ, Chandola, T, Marmot, MG, Singh-Manoux, A, Ferrie, JE (2009). Association between metabolic syndrome and depressive symptoms in middle-aged adults: results from the Whitehall II study. Diabetes Care 32, 499–504.CrossRefGoogle ScholarPubMed
Andrew, MK, Rockwood, K (2007). Psychiatric illness in relation to frailty in community-dwelling elderly people without dementia: a report from the Canadian Study of Health and Aging. Canadian Journal on Aging 26, 33–38.CrossRefGoogle ScholarPubMed
Babor, TF, Kranzler, HR, Lauerman, RJ (1989). Early detection of harmful alcohol consumption: comparison of clinical, laboratory, and self-report screening procedures. Addictive Behaviors 14, 139–157.CrossRefGoogle ScholarPubMed
Blackwell, E, Mendes de Leon, CF, Miller, GE (2006). Applying mixed regression models to the analyses of repeated-measures data in psychosomatic medicine. Psychosomatic Medicine 68, 870–878.CrossRefGoogle Scholar
Capuron, L, Su, S, Miller, AH, Bremner, JD, Goldberg, J, Vogt, GJ, Maisano, C, Jones, L, Murrah, NV, Vaccarino, V (2008). Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biological Psychiatry 64, 896–900.CrossRefGoogle ScholarPubMed
Collard, RM, Comijs, HC, Naarding, P, Oude Voshaar, RC (2014). Physical frailty: vulnerability of patients suffering from late-life depression. Aging Mental Health 18, 570–578.CrossRefGoogle ScholarPubMed
Comijs, HC, Nieuwesteeg, J, Kok, R, van Marwijk, HW, van der Mast, RC, Naarding, P, Voshaar, RC, Verhaak, P, de Waal, MW, Stek, ML (2015). The two-year course of late-life depression; results from the Netherlands study of depression in older persons. BMC Psychiatry 12, 15–20.Google Scholar
Comijs, HC, van Marwijk, HW, van der Mast, RC, Naarding, P, Oude Voshaar, RC, Beekman, AT, Boshuisen, M, Dekker, J, Kok, R, de Waal, MW, Penninx, BW, Stek, ML, Smit, JH (2011). The Netherlands study of depression in older persons (NESDO); a prospective cohort study. BMC Research Notes 4, 524.CrossRefGoogle ScholarPubMed
Craig, CL, Marshall, AL, Sjöström, M, Bauman, AE, Booth, ML, Ainsworth, BE, Pratt, M, Elelund, U, Yngve, A, Sallis, JF, Oja, P (2003). International physical activity questionnaire: 12-country reliability and validity. Medicine and Science in Sports and Exercise 35, 1381–1395.CrossRefGoogle ScholarPubMed
Deliopoulou, K, Konsta, A, Penna, S, Papakostas, P, Kotzampassi, K (2013). The impact of weight loss on depression status in obese individuals subjected to intragastric balloon treatment. Obesity Surgery 23, 669–675.CrossRefGoogle ScholarPubMed
Do Nascimento, KK, Pereira, KS, Firmo, JO, Lima-Costa, MF, Diniz, BS, Castro-Costa, E (2015). Predictors of incidence of clinically significant depressive symptoms in the elderly: 10-year follow-up study of the Bambui cohort study of aging. International Journal of Geriatric Psychiatry 30, 1171–1176.CrossRefGoogle ScholarPubMed
Folstein, MF, Folstein, SE, McHugh, PR (1975). ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189–198.CrossRefGoogle Scholar
Foster-Dingley, JC, Moonen, JE, van den Berg-Huijsmans, AA, de Craan, AJ, de Ruijter, W, van der Grond, J, van der Mast, RC (2015). Lower blood pressure and gray matter integrity loss in older persons. Journal of Clinical Hypertension 17, 630–637.CrossRefGoogle ScholarPubMed
Garcia-Toro, M, Gili, M, Ibarra, O, Monzon, S, Vives, M, Garcia-Campayo, J (2014). Metabolic syndrome improvement in depression six months after prescribing simple hygienic-dietary recommendations. BMC Research Notes 7, 339–442.CrossRefGoogle ScholarPubMed
Giltay, EJ, van Reedt Dortland, AK, Nissinen, A, Giampaoli, S, van Veen, T, Zitman, FG, Bots, S, Kromhout, D (2009). Serum cholesterol, apolipoprotein E genotype and depressive symptoms in elderly European men: the FINE study. Journal of Affective Disorders 115, 471–477.CrossRefGoogle ScholarPubMed
Grundy, SM, Brewer, HB Jr., Cleeman, JI, Smith, SC Jr., Lenfant, C (2004). American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109, 433–438.CrossRefGoogle ScholarPubMed
Hamer, M, Bay, GD, Kivimaki, M (2015). Sarcopenic obesity and risk of new onset depressive symptoms in older adults: English longitudinal study of ageing. International Journal of Obesity 39, 1717–1720.CrossRefGoogle ScholarPubMed
Hasler, G, Pine, DS, Gamma, A, Milos, G, Ajdacic, V, Eich, D, Rossler, W, Angst, J (2004). The associations between psychopathology and being overweight: a 20-year prospective study. Psychological Medicine 34, 1047–1057.CrossRefGoogle ScholarPubMed
Hegeman, JM, Wardenaar, KJ, Comijs, HC, de Waal, MW, Kok, RM, van der Mast, RC (2012). The subscale structure of the Inventory of Depressive Symptomatology Self Report (IDS-SR) in older persons. Journal of Psychiatric Research 46, 1383–1388.CrossRefGoogle ScholarPubMed
Kessler, RC, Birnbaum, H, Bromet, E, Hwang, I, Sampson, N, Shahly, V (2010). Age differences in major depression: results from the National Comorbidity Survey Replication (NCS-R). Psychological Medicine 40, 225–237.CrossRefGoogle ScholarPubMed
Khan, AY, Carrithers, J, Preskorn, SH, Lear, R, Wisniewski, SR, John Rush, A, Stegman, D, Kelley, C, Kreiner, K, Nierenberg, AA, Fava, M (2006). Clinical and demographic factors associated with DSM-IV melancholic depression. Annals of Clinical Psychiatry 18, 91–98.CrossRefGoogle ScholarPubMed
Kloiber, S, Ising, M, Reppermund, S, Horstmann, S, Dose, T, Majer, M, Zihl, J, Pfister, H, Unschuld, PG, Holsboer, F, Lucae, S (2007). Overweight and obesity affect treatment response in major depression. Biological Psychiatry 62, 321–326.CrossRefGoogle ScholarPubMed
Koponen, H, Jokelainen, J, Keinänen-Kiukaanniemi, S, Kumpusalo, E, Vanhala, M (2008). Metabolic syndrome predisposes to depressive symptoms: a population-based 7-year follow-up study. Journal of Clinical Psychiatry 69, 178–182.CrossRefGoogle ScholarPubMed
Kriegsman, DM, Penninx, BW, van Eijk, JT, Boeke, AJ, Deeg, DJ (1996). Self-reports and general practitioner information on the presence of chronic diseases in community dwelling elderly. A study on the accuracy of patients’ self-reports and on determinants of inaccuracy. Journal of Clinical Epidemiology 49, 1407–1417.CrossRefGoogle Scholar
Lamers, F, de Jonge, P, Nolen, WA, Smit, JH, Zitman, FG, Beekman, AT, Penninx, BW (2010). Identifying depressive subtypes in a large cohort study: results from the Netherlands Study of Depression and Anxiety (NESDA). Journal of Clinical Psychiatry 71, 1582–1589.CrossRefGoogle Scholar
Lamers, F, Vogelzangs, N, Merikangas, KR, de Jonge, P, Beekman, AT, Penninx, BW (2013). Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Molecular Psychiatry 18, 692–699.CrossRefGoogle ScholarPubMed
Levitan, RD, Davis, C, Kaplan, AS, Arenovich, T, Phillips, DI, Ravindran, AV (2012). Obesity comorbidity in unipolar major depressive disorder: refining the core phenotype. Journal of Clinical Psychiatry 73, 1119–1124.CrossRefGoogle ScholarPubMed
Licht, CM, de Geus, EJ, Seldenrijk, A, van Hout, HP, Zitman, FG, van Dyck, R, Penninx, BW (2009). Depression is associated with decreased blood pressure, but antidepressant useincreases the risk for hypertension. Hypertension 53, 631–638.CrossRefGoogle ScholarPubMed
Licht-Strunk, E, van der Windt, DA, van Marwijk, HW, de Haan, M, Beekman, AT (2007). The prognosis of depression in older patients in general practice and the community. A systematic review. Family Practice 24, 168–180.CrossRefGoogle ScholarPubMed
Liu, CS, Carvalho, AF, McIntyre, RS (2014). Towards a ‘metabolic’ subtype of major depressive disorder: shared pathophysiological mechanisms may contribute to cognitive dysfunction. CNS and Neurological Disorders Drug Targets 13, 1693–1707.CrossRefGoogle ScholarPubMed
Mansur, RB, Brietzke, E, McIntyre, RS (2015). Is there a ‘metabolic-mood syndrome’? A review of the relationship between obesity and mood disorders. Neuroscience and Biobehaval Reviews 52, 89–104.CrossRefGoogle Scholar
Marijnissen, RM, Bus, BA, Holewijn, S, Franke, B, Purandare, N, de Graaf, J, den Heijer, M, Buitelaar, JK, Oude Voshaar, RC (2011). Depressive symptom clusters are differentially associated with general and visceral obesity. Journal of the American Geriatrics Society 59, 67–72.CrossRefGoogle ScholarPubMed
Marijnissen, RM, Naudé, PJ, Comijs, HC, Schoevers, RA, Oude Voshaar, RC (2014). Waist circumference and neutrophil gelatinase-associated lipocalin in late-life depression. Brain, Behavior, and Immunity 37, 231–239.CrossRefGoogle ScholarPubMed
Marijnissen, RM, Smits, JE, Schoevers, RA, van den Brink, RH, Holewijn, S, Franke, B, de Graaf, J, Oude Voshaar, RC (2013). Association between metabolic syndrome and depressive symptom profiles–sex-specific? Joural of Affective Disorders 151, 1138–1142.CrossRefGoogle ScholarPubMed
Mast, BT, Miles, T, Penninx, BW, Yaffe, K, Rosano, C, Satterfield, S, Ayonayon, HN, Harris, T, Simonsick, EM (2008). Vascular disease and future risk of depressive symptomatology in older adults: findings from the Health, Aging, and Body Composition study. Biological Psychiatry 64, 320–326.CrossRefGoogle ScholarPubMed
Mather, AS, Rodriguez, C, Guthrie, MF, McHarg, AM, Reid, IC, McMurdo, ME (2002). Effects of exercise on depressive symptoms in older adults with poorly responsive depressive disorder: randomised controlled trial. British Journal of Psychiatry 180, 411.CrossRefGoogle ScholarPubMed
Mead, GE, Morley, W, Campbell, P, Greig, CA, McMurdo, M, Lawlor, DA (2009). Exercise for depression. Cochrane Database of Systemic Reviews, 11(7): CD004366.Google Scholar
Milaneschi, Y, Simonsick, EM, Vogelzangs, N, Strotmeyer, ES, Yaffe, K, Harris, TB, Tolea, MI, Ferrucci, L, Panninx, BW (2012). Health, aging, and body composition study. Leptin, abdominal obesity, and onset of depression in older men and women. Journal of Clinical Psychiatry 73, 1205–1211.CrossRefGoogle ScholarPubMed
Mitchell, JE, King, WC, Chen, JY, Devlin, M, Flum, D, Garcia, L, Inabet, W, Pender, JR, Kalarchian, MA, Khandelwal, S, Marcus, MD, Schrope, B, Strain, G, Wolfe, B, Yanovski, S (2014). Course of depressive symptoms and treatment in the Longitudinal Assessment of Bariatric Surgery (LABS-2) Study. Obesity 22, 1700–1806.CrossRefGoogle ScholarPubMed
Needham, BL, Epel, ES, Adler, NE, Kiefe, C (2010). Trajectories of change in obesity and symptoms of depression: the CARDIA study. American Journal of Public Health 100, 1040–1046.CrossRefGoogle ScholarPubMed
Novick, JS, Stewart, JW, Wisniewski, SR, Cook, IA, Manev, R, Nierenberg, AA, Rosenbaum, JF, Shores-Wilson, K, Balascubramani, GK, Biggs, MM, Zisook, S, Rush, AJ; STAR*D investigators (2005). Clinical and demographic features of atypical depression in outpatients with major depressive disorder: preliminary findings from STAR*D. Journal of Clinical Psychiatry 66, 1002–1011.CrossRefGoogle ScholarPubMed
Opel, N, Redlich, R, Grotegerd, D, Dohm, K, Heindel, W, Kugel, H, Arolt, V, Dannlowski, U (2015). Obesity and major depression: body-mass index (BMI) is associated with a severe course of disease and specific neurostructural alterations. Psychoneuroendocrinology 51, 219–226.CrossRefGoogle ScholarPubMed
Pan, A, Keum, N, Okereke, OI, Sun, Q, Kivimaki, M, Rubin, RR, Hu, FB (2012). Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care 35, 1171–1180.CrossRefGoogle ScholarPubMed
Papakostas, GI, Petersen, T, Iosifescu, DV, Burns, AM, Nierenberg, AA, Alpert, JE, Rosenbaum, JF, Fava, M (2005). Obesity among outpatients with major depressive disorder. International Journal of Neuropsychopharmacology 8, 59–63.CrossRefGoogle ScholarPubMed
Penninx, BW, Milaneschi, Y, Lamers, F, Vogelzangs, N (2013). Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Medicine 15, 129.CrossRefGoogle Scholar
Penninx, BW, Nolen, WA, Lamers, F, Zitman, FG, Smit, JH, Spinhoven, P, Cuijpers, P, de Jong, PJ, van Marwijk, HW, van der Meer, K, Verhaak, P, Laurant, MG, de Graaf, R, Hoogendijk, WJ, van der Wee, N, Ormel, J, van Dyck, R, Beekman, AT (2011). Two-year course of depressive and anxiety disorders: results from the Netherlands Study of Depression and Anxiety (NESDA). Journal of Affective Disorders 133, 76–85.CrossRefGoogle ScholarPubMed
Remigio-Baker, RA, Diez Roux, AV, Szklo, M, Crum, RM, Leoutsakos, JM, Franco, M, Schreiner, PJ, Carnethon, MR, Nettleton, JA, Mujahid, MS, Michos, ED, Gary-Webb, TL, Golden, SH (2014) Physical environment may modify the association between depressive symptoms and change in waist circumference: the multi-ethnic study of atherosclerosis. Psychosomatics 55, 144–154.CrossRefGoogle ScholarPubMed
Rethorst, CD, Bernstein, I, Trivedi, MH (2014). Inflammation, obesity, and metabolic syndrome in depression: analysis of the 2009–2010 National Health and Nutrition Examination Survey (NHANES). Journal of Clinical Psychiatry 75, 1428–1432.CrossRefGoogle ScholarPubMed
Rethorst, CD, Wipfli, BM, Landers, DM (2009). The antidepressive effects of exercise: a meta-analysis of randomized trials. Sports Medicine 39, 21.CrossRefGoogle ScholarPubMed
Rush, AJ, Gullion, CM, Basco, MR, Jarrett, RB, Trivedi, MH (1996). The inventory of depressive symptomatology (IDS): psychometric properties. Psychological Medicine 26, 477–486.CrossRefGoogle ScholarPubMed
Sagud, M, Mihaljevic-Peles, A, Uzun, S, Cusa, BV, Kozumplik, O, Kudlek-Mikulic, S, Mustapic, M, Barisic, I, Muck-Seler, D, Pivac, N (2013). The lack of association between components of metabolic syndrome and treatment resistance in depression. Psychopharmacology 230, 15–21.CrossRefGoogle ScholarPubMed
Spijker, J, de Graaf, R, Bijl, RV, Beekman, AT, Ormel, J, Nolen, WA (2002). Duration of major depressive episodes in the general population: results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). British Journal of Psychiatry 181, 208–213.CrossRefGoogle ScholarPubMed
Stunkard, AJ, Faith, MS, Allison, KC (2003). Depression and obesity. Biological Psychiatry 54, 330–337.CrossRefGoogle ScholarPubMed
Sullivan, PF, Kessler, RC, Kendler, KS (1998). Latent class analysis of lifetime depressive symptoms in the national comorbidity survey. American Journal of Psychiatry 155, 1398–1406.CrossRefGoogle ScholarPubMed
Takeuchi, T, Nakao, M, Kachi, Y, Yano, E (2013). Association of metabolic syndrome with atypical features of depression in Japanese people. Psychiatry and Clinical Neurosciences 67, 532–539.CrossRefGoogle ScholarPubMed
Thombs, BD, Ziegelstein, RC, Pilote, L, Dozois, DJA, Beck, AT, Dobson, KS, Fuss, S, de Jonge, P, Grace, SL, Stewart, DE, Ormel, J, Abbey, SE (2010). Somatic symptom overlap in Beck Depression Inventory-II scores following myocardial infarction. British Journal of Psychiatry 197, 61–66.CrossRefGoogle ScholarPubMed
Van Reedt Dortland, AK, Vreeburg, SA, Giltay, EJ, Licht, CM, Vogelzangs, N, van Veen, T, de Geus, EJ, Penninx, BW, Zitman, FG (2013). The impact of stress systems and lifestyle on dyslipidemia and obesity in anxiety and depression. Psychoneuroendocrinology 38, 209–218.CrossRefGoogle ScholarPubMed
Viinamäki, H, Heiskanen, T, Lehto, SM, Niskanen, L, Koivumaa-Honkanen, H, Tolmunen, T, Honkalampi, K, Saharinen, T, Haatainen, K, Hintikka, J (2009). Association of depressive symptoms and metabolic syndrome in men. Acta Psychiatrica Scandinavica 120, 23–29.CrossRefGoogle ScholarPubMed
Vogelzangs, N, Beekman, AT, Boelhouwer, IG, Bandinelli, S, Milaneschi, Y, Ferrucci, L, Penninx, BW (2011). Metabolic depression: a chronic depressive subtype? Findings from the InCHIANTI study of older persons. Journal of Clinical Psychiatry 72, 598–604.CrossRefGoogle ScholarPubMed
Vogelzangs, N, Beekman, ATF, van Reedt Dortland, AKB, Schoevers, RA, Giltay, EJ, de Jonge, P, Penninx, BWJH (2014 b). Inflammatory and metabolic dysregulation and the 2-year course of depressive disorders in antidepressant users. Neuropsychopharmacology 39, 1624–1634.CrossRefGoogle ScholarPubMed
Vogelzangs, N, Comijs, HC, Oude Voshaar, RC, Stek, ML, Penninx, BWJH (2014 a) Late-life depression symptom profiles are differentially associated with immunometabolic functioning. Brain, Behavior, and Immunity 41, 109–115.CrossRefGoogle ScholarPubMed
Vogelzangs, N, Kritchevsky, SB, Beekman, AT, Brenes, GA, Newman, AB, Satterfield, S, Yaffe, K, Harris, TB, Penninx, BW (2010). Health ABC Study. Obesity and onset of significant depressive symptoms: results from a prospective community-based cohort study of older men and women. Journal of Clinical Psychiatry 71, 391–399.CrossRefGoogle ScholarPubMed
Wensveen, FM, Valentic, S, Sestan, M, Turk Wensveen, T, Polic, B (2015). The ‘Big Bang’ in obese fat: events initiating obesity-induced adipose tissue inflammation. European Journal of Immunology 45, 2446–2456.CrossRefGoogle Scholar
Wittchen, HU, Robins, LN, Cottler, LB, Sartorius, N, Burke, JD, Regier, D (1991/1992) Cross-cultural feasibility, reliability and sources of variance of the Composite International Diagnostic Interview (CIDI). The Multicentre WHO/ADAMHA Field Trials. Br J Psychiatry 159, 645–653, 658. Erratum in: The British Journal of Psychiatry 160, 136.CrossRefGoogle ScholarPubMed
You, T, Nicklas, BJ (2008). Effects of exercise on adipokines and the metabolic syndrome. Current Diabetes Reports 8, 7–11.CrossRefGoogle ScholarPubMed
Zhou, JX, Li, HC, Bai, XJ, Chang, BC, Li, CJ, Sun, P, Chen, LM (2013). Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects. Behavioral and Brain Functions 22, 9–34.Google Scholar