Abstract
Rationale and objective
Schizophrenia displays sex differences in many aspects. Decreased brain-derived neurotrophic factor (BDNF) levels have been reported to be associated with high body weight or obesity as well as other psychopathological aspects in schizophrenia patients. This study aimed to explore sex differences in the relationship between serum BDNF levels and obesity in patients with chronic schizophrenia.
Methods
We recruited 132 Chinese patients with chronic schizophrenia (98 males and 34 females) and compared sex differences in the body mass index (BMI), obesity, serum BDNF levels, and their associations. Psychopathology symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). A regression model with various demographic and clinical variables was applied to predict the serum levels of BDNF.
Results
Female patients had a higher rate of obesity and higher BMI, but lower BDNF levels than male schizophrenia patients. A significantly negative correlation was observed between BMI and BDNF levels only in female patients but not in male patients. The multiple regression model with demographic and clinical variables significantly predicted BDNF levels only in female patients, with a medium size effect. And only in female patients, BMI made a significant contribution to this prediction.
Conclusion
Our results indicate significant sex differences in the obesity, BMI, BDNF levels, and their association in chronic patients with schizophrenia, showing a significant inverse correlation between BMI and BDNF levels only in female patients. Thus, sex needs to be considered when assessing the relationship between BDNF and metabolic syndromes in schizophrenia.
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References
Adachi N, Numakawa T, Richards M, Nakajima S, Kunugi H (2014) New insight in expression, transport, and secretion of brain-derived neurotrophic factor: implications in brain-related diseases. World J Biol Chem 5:409–428. https://doi.org/10.4331/wjbc.v5.i4.409
Allison DB, Newcomer JW, Dunn AL, Blumenthal JA, Fabricatore AN, Daumit GL, Cope MB, Riley WT, Vreeland B, Hibbeln JR, Alpert JE (2009) Obesity among those with mental disorders. A National Institute of Mental Health Meeting Report. Am J Prev Med 36:341–350. https://doi.org/10.1016/j.amepre.2008.11.020
Beauchet O (2006) Testosterone and cognitive function: current clinical evidence of a relationship. Eur J Endocrinol 155:773–781
Begliuomini S, Casarosa E, Pluchino N, Lenzi E, Centofanti M, Freschi L, Pieri M, Genazzani AD, Luisi S, Genazzani AR (2007) Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor. Hum Reprod 22:995–1002. https://doi.org/10.1093/humrep/del479
Bonaccorso S, Sodhi M, Li J, Bobo WV, Chen Y, Tumuklu M, Theleritis C, Jayathilake K, Meltzer HY (2015) The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia. Bipolar Disord 17:528–535. https://doi.org/10.1111/bdi.12294
Brown S (1997) Excess mortality of schizophrenia. A meta-analysis. Br J Psychiatry 171:502–508
Chen H, Feng Y, Shu H, Lu TM, Zhu HM, Yang BL, Xiong M (2010) Survey on menopausal age and menstruation span in women in Pudong district of Shanghai (Article in Chinese). Zhonghua Fu Chan Ke Za Zhi 45:415–419
Cohen, J., Cohen, P., West, S. G., Aiken LS (2003) Applied multiple regression/correlation analysis for the behavioral sciences (3rd ed.). Lawrence Erlbaum Associates., Mahwah, NJ
Coppola V, Tessarollo L (2004) Control of hyperphagia prevents obesity in BDNF heterozygous mice. Neuroreport 15:2665–2668
Correll CU (2007) Balancing efficacy and safety in treatment with antipsychotics. CNS Spectr 12:12–20
Duan W, Guo Z, Jiang H, Ware M, Mattson MP (2003) Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology 144:2446–2453
Eriksson J, Haring R, Grarup N, Vandenput L, Wallaschofski H, Lorentzen E, Hansen T, Mellström D, Pedersen O, Nauck M, Lorentzon M, Nystrup Husemoen LL, Völzke H, Karlsson M, Baumeister SE, Linneberg A, Ohlsson C (2017) Causal relationship between obesity and serum testosterone status in men: a bi-directional Mendelian randomization analysis. PLoS One 12:1–16. https://doi.org/10.1371/journal.pone.0176277
Fang H, Zhen YF, Liu XY, Xu G, Soares JC, Zhao J, Zhang XY (2016) Association of the BDNF Val66Met polymorphism with BMI in chronic schizophrenic patients and healthy controls. Int Clin Psychopharmacol 31:353–357. https://doi.org/10.1097/YIC.0000000000000142
Faul F, Erdfelder E, Buchner A, Lang AG (2009) Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods 41:1149–1160. https://doi.org/10.3758/BRM.41.4.1149
Fernandes BS, Steiner J, Berk M, Molendijk ML, Gonzalez-Pinto A, Turck CW, Nardin P, Gonçalves CA (2015) Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol Psychiatry 20:1108–1119. https://doi.org/10.1038/mp.2014.117
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502. https://doi.org/10.1177/107424840501000106
Gray AH, Wright J, Bruce L, Oakley J (2015) Clinical pharmacy pocket companion, Second Edi. Pharmaceutical Press, London
Green MJ, Matheson SL, Shepherd a Shepherd A, Weickert CS, Carr VJ (2011) Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 16:960–972. doi: https://doi.org/10.1038/mp.2010.88
Gunstad J, Schofield P, Paul RH, Spitznagel MB, Cohen RA, Williams LM, Kohn M, Gordon E (2006) BDNF Val66Met polymorphism is associated with body mass index in healthy adults. Neuropsychobiology 53:153–156. https://doi.org/10.1159/000093341
Hou C-L, Ma X-R, Zang Y, Jia FJ, Lin YQ, Chiu HFK, Ungvari GS, Ng CH, Zhong BL, Cao XL, Li Y, Cai MY, Xiang YT (2016) Antipsychotic polypharmacy and quality of life in patients with schizophrenia treated in primary care in China. Int J Clin Pharmacol Ther 54:36–42
Issa G, Wilson C, Terry AV, Pillai A (2010) An inverse relationship between cortisol and BDNF levels in schizophrenia: data from human postmortem and animal studies. Neurobiol Dis 39:327–333. https://doi.org/10.1016/j.nbd.2010.04.017
Kay SR, Fiszbein AOL (1987) The Positive and Negative Syndrome Scale for schizophrenia. Schizophr Bull 13:261–276. https://doi.org/10.1093/schbul/13.2.261
Kernie SG (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19:1290–1300. https://doi.org/10.1093/emboj/19.6.1290
Kim S-W, Lee J-Y, Kang H-J, Kim SY, Bae KY, Kim JM, Shin IS, Yoon JS (2016) Gender-specific associations of the brain-derived neurotrophic factor Val66Met polymorphism with neurocognitive and clinical features in schizophrenia. Clin Psychopharmacol Neurosci 14:270–278. https://doi.org/10.9758/cpn.2016.14.3.270
Komulainen P, Pedersen M, Hänninen T, Bruunsgaard H, Lakka TA, Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R (2008) BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA study. Neurobiol Learn Mem 90:596–603
Kuo FC, Lee CH, Hsieh CH, Kuo P, Chen YC, Hung YJ (2013) Lifestyle modification and behavior therapy effectively reduce body weight and increase serum level of brain-derived neurotrophic factor in obese non-diabetic patients with schizophrenia. Psychiatry Res 209:150–154. https://doi.org/10.1016/j.psychres.2012.11.020
Lebrun B, Bariohay B, Moyse E, Jean A (2006) Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview. Auton Neurosci 126–127:30–38. https://doi.org/10.1016/j.autneu.2006.02.027
Lee J (2012) A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. 10:61–70. https://doi.org/10.9758/cpn.2012.10.2.61
Lee J, Nurjono M, Lee T-S (2016) Levels of serum brain-derived neurotrophic factor in schizophrenia. J Nerv Ment Dis 204:636–639. https://doi.org/10.1097/NMD.0000000000000463
Li J, Ye F, Xiao W, Tang X, Sha W, Zhang X, Wang J (2016a) Increased serum brain-derived neurotrophic factor levels following electroconvulsive therapy or antipsychotic treatment in patients with schizophrenia. Eur Psychiatry 36:23–28. https://doi.org/10.1016/j.eurpsy.2016.03.005
Li Q, Chen D, Liu T, Walss-Bass C, de Quevedo JL, Soares JC, Zhao J, Zhang XY (2016b) Sex differences in body mass index and obesity in Chinese patients with chronic schizophrenia. J Clin Psychopharmacol 36:643–648. https://doi.org/10.1097/JCP.0000000000000594
Lin C, Hung Y, Tsai M, Huang T (2017) Increased serum brain-derived neurotrophic factor in male schizophrenic patients with metabolic syndrome. Medicine (Baltimore) 96:e7089. https://doi.org/10.1097/MD.0000000000007089
Liu X, Zhu Z, Kalyani M, Janik JM, Shi H (2014) Effects of energy status and diet on Bdnf expression in the ventromedial hypothalamus of male and female rats. Physiol Behav 130:99–107. https://doi.org/10.1016/j.physbeh.2014.03.028
Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, Virchow JC (2005) The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 26:115–123. https://doi.org/10.1016/j.neurobiolaging.2004.03.002
Lovejoy JC (2003) The menopause and obesity. Prim Care—Clin Off Pract 30:317–325. https://doi.org/10.1016/S0095-4543(03)00012-5
Luine V, Frankfurt M (2013) Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience 239:34–45. https://doi.org/10.1016/j.neuroscience.2012.10.019
Lyons W, Mamounas L, Ricaurte G et al (1999) Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 96:15239–15244
Millward DJ, Truby H, Fox KR, Livingstone MBE, Macdonald IA, Tothill P (2014) Sex differences in the composition of weight gain and loss in overweight and obese adults. Br J Nutr 111:933–943. https://doi.org/10.1017/S0007114513003103
Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, de Hert M (2013) Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull 39:306–318. https://doi.org/10.1093/schbul/sbr148
Newcomer JW (2007) Metabolic syndrome and mental illness. Am J Manag Care 13:S170–S177
Numakawa T, Adachi N, Richards M, Chiba S, Kunugi H (2013) Brain-derived neurotrophic factor and glucocorticoids: reciprocal influence on the central nervous system. Neuroscience 239:157–172. https://doi.org/10.1016/j.neuroscience.2012.09.073
Ösby U, Correia N, Brandt L, et al (2000) Time trends in schizophrenia mortality in Stockholm County, Sweden: cohort study. Rapid diagnosis of falciparum malaria by using the Para Sight F test in travellers returning to the United Kingdom: prospective study 321:483–484
Pandya CD, Hoda MN, Kutiyanawalla A, Buckley PF, Pillai A (2013) Differential effects upon brain and serum BDNF levels in rats as response to continuous and intermittent administration strategies of two second generation antipsychotics. Schizophr Res 151:287–288. https://doi.org/10.1016/j.schres.2013.09.027
Pomponi M, Di Gioia A, Bria P, Pomponi M (2008) Fatty aspirin: a new perspective in the prevention of dementia of Alzheimer’s type? Curr Alzheimer Res 5:422–431
Qin XY, Wu HT, Cao C, Loh YP, Cheng Y (2017) A meta-analysis of peripheral blood nerve growth factor levels in patients with schizophrenia. Mol Psychiatry 22(9):1306–1312
Rao JS, Kim HW, Harry GJ, Rapoport SI, Reese EA (2013) Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr Res 147:24–31. https://doi.org/10.1016/j.schres.2013.02.017
Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, Lechan RM, Jaenisch R (2001) Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 15:1748–1757
Rosas-Vargas H, Martínez-Ezquerro JD, Bienvenu T (2011) Brain-derived neurotrophic factor, food intake regulation, and obesity. Arch Med Res 42:482–494. https://doi.org/10.1016/j.arcmed.2011.09.005
Ryan MCM, Collins P, Thakore J (2003) Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 160:284–289
Scharfman HE, MacLusky NJ (2008) Estrogen–growth factor interactions and their contributions to neurological disorders. Headache 48:S77–S89. https://doi.org/10.1111/j.1526-4610.2008.01200.x.Estrogen
Scharfman HE, MacLusky NJ (2006) Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS. Front Neuroendocrinol 27:415–435. https://doi.org/10.1016/j.yfrne.2006.09.004
Shugart YY, Chen L, Day INM, Lewis SJ, Timpson NJ, Yuan W, Abdollahi MR, Ring SM, Ebrahim S, Golding J, Lawlor DA, Davey-Smith G (2009) Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI. Eur J Hum Genet 17:1050–1055. https://doi.org/10.1038/ejhg.2008.272
Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777 doi: 20024066
Sohrabji F, Lewis DK (2006) Estrogen-BDNF interactions: implications for neurodegenerative diseases. Front Neuroendocrinol 27:404–414. https://doi.org/10.1016/j.yfrne.2006.09.003
Spratt E, Granholm A-C, Carpenter LA, Boger H, Papa C, Logan S, Chaudhary H, Boatwright SW, Brady K (2015) Pilot study and review: physiological differences in BDNF, a potential biomarker in males and females with autistic disorder. Int Neuropsychiatr Dis J 3:19–26. https://doi.org/10.1016/B978-0-12-420118-7.00008-1.Dopamine
Tsai A, Liou YJ, Hong CJ, Wu CL, Tsai SJ, Bai YM (2011) Association study of brain-derived neurotrophic factor gene polymorphisms and body weight change in schizophrenic patients under long-term atypical antipsychotic treatment. NeuroMolecular Med 13:328–333. https://doi.org/10.1007/s12017-011-8159-5
Venkatasubramanian G, Chittiprol S, Neelakantachar N et al (2007) Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. Am J Psychiatry 164:1557–1560
Vinogradov S, Fisher M, Holland C, Shelly W, Wolkowitz O, Mellon SH (2009) Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biol Psychiatry 66:549–553. https://doi.org/10.1016/j.biopsych.2009.02.017.Is
Xiu MH, Hui L, Dang YF, de Hou T, Zhang CX, Zheng YL, Chen DC, Kosten TR, Zhang XY (2009) Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. Prog Neuro-Psychopharmacology Biol Psychiatry 33:1508–1512. https://doi.org/10.1016/j.pnpbp.2009.08.011
Zai GCM, Zai CCH, Chowdhury NI, Tiwari AK, Souza RP, Lieberman JA, Meltzer HY, Potkin SG, Müller DJ, Kennedy JL (2012) The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. Prog Neuro-Psychopharmacology Biol Psychiatry 39:96–101. https://doi.org/10.1016/j.pnpbp.2012.05.014
Zhang X, Chen D, Xiu M et al (2012a) Gender differences in never-medicated first-episode schizophrenia and medicated chronic schizophrenia patients. J Clin Psychiatry 73:1025–1033
Zhang X, Chen D, Xiu M, et al (2012b) Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum Genet 131:1187–1195. doi: https://doi.org/10.1007/s00439-012-1150-x.Cognitive
Zhang XY, Chen DC, Tan YL, Tan SP, Wang ZR, Yang FD, Xiu MH, Hui L, Lv MH, Zunta-Soares GB, Soares JC (2014) Gender difference in association of cognition with BDNF in chronic schizophrenia. Psychoneuroendocrinology 48:136–146. https://doi.org/10.1016/j.psyneuen.2014.06.004
Zhang XY, Xiu MH, Chen DC, de Yang F, Wu GY, Lu L, Kosten TA, Kosten TR (2010) Nicotine dependence and serum BDNF levels in male patients with schizophrenia. Psychopharmacology 212:301–307. https://doi.org/10.1007/s00213-010-1956-y
Zhang XY, Zhou DF, Wu GY, Cao LY, Tan YL, Haile CN, Li J, Lu L, Kosten TA, Kosten TR (2008) BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology 33:2200–2205. https://doi.org/10.1038/sj.npp.1301619
Zhang Y, Fang X, Fan W, Tang W, Cai J, Song L, Zhang C (2018) Brain-derived neurotrophic factor as a biomarker for cognitive recovery in acute schizophrenia: 12-week results from a prospective longitudinal study. Psychopharmacol 235:1191–1198
Zhou B, China CM-AG of the WG on O in (2002) Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults—study on optimal cut-off points of body mass index and waist circumference in Chinese adults. Biomed Env Sci 15:83–96
Funding
Funding for this study was provided by grants from the National Natural Science Foundation of China (81371477), Suzhou Key Medical Center for Psychiatric Diseases (Szzx201509), and Suzhou Key laboratory for Biological Psychiatry (SZS201722). These sources had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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The research protocol was approved by the Institutional Review Board, Beijing Hui-Long-Guan hospital (BHLGH). A psychiatrist explained the research protocol and procedures to the potential subject using language appropriate to the subject’s level of comprehension and emotional readiness. All subjects gave written informed consent to participate in the study.
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Yang, F., Wang, K., Du, X. et al. Sex difference in the association of body mass index and BDNF levels in Chinese patients with chronic schizophrenia. Psychopharmacology 236, 753–762 (2019). https://doi.org/10.1007/s00213-018-5107-1
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DOI: https://doi.org/10.1007/s00213-018-5107-1