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Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders

  • G. Mezquida (a1), R. Penadés (a1) (a2) (a3) (a4), B. Cabrera (a1) (a4), G. Savulich (a5), A. Lobo (a4) (a6), A. González-Pinto (a4) (a7) (a8), M.J. Penzol (a4) (a9), I. Corripio (a4) (a10) (a11), E. Fernandez-Egea (a4) (a12), P. Gassó (a3) (a13), M.J. Cuesta (a14) (a15), M. Bernardo (a1) (a2) (a3) (a4) and PEPs group...

Abstract

Objective

A functional polymorphism of the brain-derived neurotrophic factor gene (BDNF) Val66Met has been associated with cognitive function and symptom severity in patients with schizophrenia. It has been suggested that the Val66Met polymorphism has a role as a modulator in a range of clinical features of the illness, including symptoms severity, therapeutic responsiveness, age of onset, brain morphology and cognitive function. However, little work has been done in first-episode schizophrenia (FES) spectrum disorders. The objective of this study is to investigate the association of the BDNF Val66Met polymorphism on cognitive function and clinical symptomatology in FES patients.

Methods

Using a cross-sectional design in a cohort of 204 patients with FES or a schizophrenia spectrum disorder and 204 healthy matched controls, we performed BDNF Val66Met genotyping and tested its relationship with cognitive testing (attention, working memory, learning/verbal memory and reasoning/problem-solving) and assessment of clinical symptom severity.

Results

There was no significant influence of the BDNF allele frequency on cognitive factor scores in either patients or controls. An augmented severity of negative symptoms was found in FES patients that carried the Met allele.

Conclusions

The results of this study suggest that in patients with a first-episode of schizophrenia or a schizophrenia spectrum disorder, the BDNF Val66Met polymorphism does not exert an influence on cognitive functioning, but is associated with negative symptoms severity. BDNF may serve as suitable marker of negative symptomatology severity in FES patients within the schizophrenia spectrum.

Copyright

Corresponding author

*Corresponding author. Barcelona clinic schizophrenia unit, hospital clinic of Barcelona, 170, Villarroel, 08036 Barcelona, Spain. Tel.: +34932275400x3142; fax: +34932275548. E-mail address:bernardo@clinic.ub.es(M. Bernardo).

Footnotes

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1

M. Bioque, C. García-Rizo, M. Parellada, C. Llorente, A. Alonso, M. Rabella, M. Martinez-Cengotitabengoa, I. Gonzalez-Ortega, F. Barcones, S. del Olmo, E.J. Aguilar, M.J. Escartí, D. Bergé, R. Cortizo, E. Vieta, C. Torrent, J. Castro-Fornieles, I. Baeza, F. Contreras, A. Albacete, J. Bobes, P. Portilla, A. Zabala, R. Segarra, I. Morales-Muñoz, R. Rodriguez-Jimenez, A. Butjosa, J. Usall, S. Sarró, R. Landín-Romero, Á. Ibáñez, A. Sánchez-Torres, V. Balanzá-Martínez.

Footnotes

References

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[1]Schizophrenia working group of the psychiatric genomics consortium Nature 2014;511:421427
[2]Sullivan, PFKendler, KSNeale, MCSchizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:11871192
[3]Kheirollahi, MKazemi, EAshouri, SBrain-derived neurotrophic factor gene Val66Met polymorphism and risk of schizophrenia: a meta-analysis of case-control studies. Cell Mol Neurobiol. 2016;36:110
[4]Bernardo, MBioque, MSchizophrenia: from neurobiology to nosology of mental disorders. Actas Esp Psiquiatr. 2010;38(3): 1517
[5]Andreasen, NCWilcox, MAHo, BCEpping, EZiebell, SZeien, Eet al.Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes. Mol Psychiatry. 2012;17(11): 10931102
[6]Ursini, GCavalleri, TFazio, LAngrisano, TIacovelli, LPorcelli, Aet al.BDNF rs6265 methylation and genotype interact on risk for schizophrenia. Epigenetics. 2016;11(1): 1123
[7]Ohi, KHashimoto, RIkeda, MYamamori, HYasuda, YFujimoto, Met al.Glutamate networks implicate cognitive impairments in schizophrenia: genome-wide association studies of 52 cognitive phenotypes. Schizophr Bull. 2015;41:909918
[8]Insel, TRRethinking schizophrenia. Nature. 2010;468:187193
[9]Bernardo, MMezquida, GBioque, MNuevos planteamientos clínicos en esquizofrenia: los síntomas negativos. Madrid: Ediveramerica; 2014
[10]Chue, PLalonde, JKAddressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options. Neuropsychiatr Dis Treat. 2014;10:777789
[11]Bernardo, MFernadez-Egea, ETorras, AGutierrez, FAhuir, MArango, CAdaptación y validación en castellano del Inventario para la Esquizofrenia Deficitaria. Med Clin (Barc). 2007;129(3): 9193
[12]Buchanan, RWPersistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33:10131022
[13]Kirkpatrick, BBuchanan, RWMcKenney, PDAlphs, LDCarpenter, WT Jr.The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 1989;30:119123
[14]Kirkpatrick, BGalderisi, SDeficit schizophrenia: an update. World Psychiatry. 2008;7:143147
[15]Bernardo, MMezquida, GDisease burden. Schizophrenia: a costly illness. Insights in the management of schizophrenia. 2014 www.hospitalpharmacyeurope.com
[16]Kirkpatrick, BMiller, BGarcia-Rizo, CFernandez-Egea, ESchizophrenia: a systemic disorder. Clin Schizophr Relat Psychoses. 2014;8:7379
[17]Tsapakis, EMDimopoulou, TTarazi, FIClinical management of negative symptoms of schizophrenia: an update. Pharmacol Ther. 2015;153:135147
[18]American psychiatric association Diagnostic and statistical manual of mental disorders (DSM5). 5th ed.Washington, DC:American Psychiatric Press; 2013
[19]Bernardo, MBioque, MDSM-5 ¿quo vadis?. Madrid: Evideramerica; 2013
[20]Green, MFKern, RSHeaton, RKLongitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72:4151
[21]Keefe, RSFenton, WSHow should DSM-V criteria for schizophrenia include cognitive impairment?. Schizophr Bull. 2007;33:912920
[22]Harvey, PDAssessment of everyday functioning in schizophrenia: implications for treatments aimed at negative symptoms. Schizophr Res. 2013;150:353355
[23]Penades, RGasto, CBoget, TCatalan, RSalamero, MDeficit in schizophrenia: the relationship between negative symptoms and neurocognition. Compr Psychiatry. 2001;42:6469
[24]Vilalta-Gil, VVilaplana, MOchoa, SHaro, JMDolz, MUsall, Jet al.Neurocognitive performance and negative symptoms: are they equal in explaining disability in schizophrenia outpatients?. Schizophr Res. 2006;87:246253
[25]Dominguez, MDWichers, MLieb, RWittchen, HUvan Os, JEvidence that onset of clinical psychosis is an outcome of progressively more persistent subclinical psychotic experiences: an 8-year cohort study. Schizophr Bull. 2009;37:8493
[26]Pickard, BSSchizophrenia biomarkers: translating the descriptive into the diagnostic. J Psychopharmacol. 2015;29:138143
[27]Galderisi, SMerlotti, EMucci, ANeurobiological background of negative symptoms. Eur Arch Psychiatry Clin Neurosci. 2015;265:543558
[28]Kremeyer, BGarcia, JKymalainen, HWratten, NRestrepo, GPalacio, Cet al.Evidence for a role of the NOS1AP (CAPON) gene in schizophrenia and its clinical dimensions: an association study in a South American population isolate. Hum Hered. 2009;67:163173
[29]Notaras, MHill, Rvan den Buuse, MA role for the BDNF gene Val66Met polymorphism in schizophrenia?. A comprehensive review. Neurosci Biobehav Rev. 2015;51:1530
[30]Penadés, RGarcia-Rizo, CBioque, MGonzález-Rodríguez, ACabrera, BMezquida, Get al.The search for new biomarkers for cognition in schizophrenia. Schizophr Res Cogn. 2015;2:172178
[31]Bueller, JAAftab, MSen, SGomez-Hassan, DBurmeister, MZubieta, JKBDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry. 2006;59:812815
[32]Ibarra, PAlemany, SFatjo-Vilas, MCordova-Palomera, AGoldberg, XArias, Bet al.The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study. Eur Psychiatry. 2014;29:293300
[33]Buckley, PFPillai, AHowell, KRBrain-derived neurotrophic factor: findings in schizophrenia. Curr Opin Psychiatry. 2011;24:122127
[34]Gratacos, MGonzalez, JRMercader, JMde Cid, RUrretavizcaya, MEstivill, XBrain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61:911922
[35]Rybakowski, JKBorkowska, ACzerski, PMSkibinska, MHauser, JPolymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord. 2003;5:468472
[36]Martinowich, KLu, BInteraction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008;33:7383
[37]Zhai, JYu, QChen, MGao, YZhang, QLi, Jet al.Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. Int J Clin Exp Pathol. 2013;6:16171623
[38]Kanazawa, TGlatt, SJKia-Keating, BYoneda, HTsuang, MTMeta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder. Psychiatr Genet. 2007;17:165170
[39]Ahmed, AOMantini, AMFridberg, DJBuckley, PFBrain-derived neurotrophic factor (BDNF) and neurocognitive deficits in people with schizophrenia: a meta-analysis. Psychiatry Res. 2015;226:113
[40]Chang, HALu, RBShy, MJChang, CCLee, MSHuang, SYBrain-derived neurotrophic factor Val66Met polymorphism: association with psychopathological symptoms of schizophrenia?. J Neuropsychiatry Clin Neurosci. 2009;21:3037
[41]Zhang, XYChen da, CXiu, MHHaile, CNLuo, XXu, Ket al.Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum Genet. 2012;131:11871195
[42]Miyajima, FOllier, WMayes, AJackson, AThacker, NRabbitt, Pet al.Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav. 2008;7:411417
[43]Martinho, E Jr.Michelon, LAyres, AMScazufca, MMenezes, PRSchaufelberger, MSet al.BDNF gene polymorphism, cognition and symptom severity in a Brazilian population-based sample of first-episode psychosis subjects. Rev Bras Psiquiatr. 2012;34(2): 219225
[44]Papaleo, FLipska, BKWeinberger, DRMouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology. 2012;62(3): 12041220
[45]Buchanan, RWWeiner, EKelly, DLGold, JMKeller, WRWaltz, JAet al.Rasagiline in the treatment of the persistent negative symptoms of schizophrenia. Schizophr Bull. 2015;41:900908
[46]Bernardo, MBioque, MParellada, MSaiz Ruiz, JCuesta, MJLlerena, Aet al.Assessing clinical and functional outcomes in a gene-environment interaction study in first episode of psychosis (PEPs). Rev Psiquiatr Salud Ment. 2013;6:416
[47]Williams, JBGibbon, MFirst, MBSpitzer, RLDavies, MBorus, Jet al.The structured clinical interview for DSM-III-R (SCID). II. Multisite test-retest reliability. Arch Gen Psychiatry. 1992;49:630636
[48]American psychiatric association DSM-IV: diagnostic and statistical manual of mental disorders. 4th ed.Washington;American psychiatric association:1994.
[49]Hollingshead, ABRedlich, FC.Class and mental illness.. 1955/09/01 ed. New York 1958.
[50]Kay, SRFiszbein, AOpler, LAThe positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261276
[51]Peralta, VCuesta, MJValidación de la escala de los síndromes positivo y negativo (PANSS) en una muestra de esquizofrénicos españoles. Actas Luso-Español Neurol Psiquiatría. 1994;22:171177
[52]Marder, SRDavis, JMChouinard, GThe effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997;58:538546
[53]Cuesta, MJSanchez-Torres, AMCabrera, BBioque, MMerchan-Naranjo, JCorripio, Iet al.Premorbid adjustment and clinical correlates of cognitive impairment in first-episode psychosis. The PEPsCog study. Schizophr Res. 2015;164:6573
[54]Conners, CConner’s continuous performance test II: computer program for Windows. Technical guide and software manual. Systems MH: North Tonawanda. 2000
[55]Wechsler, DWAIS-III: Escala de inteligencia de Wechsler para Adultos. Tercera versión (WAIS-III: Wechsler Adult Intelligence Scale. Third Version). Madrid: TEA, SA; 1999
[56]Heaton, RKWisconsin card sorting test manuel. Odessa (FL): Psychological Assessment Resource Inc; 1981
[57]Benedet, MJTest de Aprendizaje Verbal España-Complutense (TAVEC). Madrid 1988
[58]Baron, RKenny, DThe moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;51:11731182
[59]Govindarajan, ARao, BSNair, DTrinh, MMawjee, NTonegawa, Set al.Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc Natl Acad Sci U S A. 2006;103(35): 1320813213
[60]Kawashima, KIkeda, MKishi, TKitajima, TYamanouchi, YKinoshita, Yet al.BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. Schizophr Res. 2009;112(1–3):7279
[61]Nanko, SKunugi, HHirasawa, HKato, NNabika, TKobayashi, SBrain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr Res. 2003;62:281283
[62]Niitsu, TIshima, TYoshida, THashimoto, TMatsuzawa, DShirayama, Yet al.A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia. Psychiatry Res. 2014;215:268273
[63]Nurjono, MLee, JChong, SAA review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci. 2012;10:6170
[64]Dincheva, IGlatt, CELee, FSImpact of the BDNF Val66Met polymorphism on cognition: implications for behavioral genetics. Neuroscientist. 2012;18:439451
[65]Ho, BCMilev, PO’Leary, DSLibrant, AAndreasen, NCWassink, THCognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry. 2006;63:731740
[66]Egan, MFKojima, MCallicott, JHGoldberg, TEKolachana, BSBertolino, Aet al.The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257269
[67]Dempster, EToulopoulou, TMcDonald, CBramon, EWalshe, MFilbey, Fet al.Association between BDNF val66 met genotype and episodic memory. Am J Med Genet B Neuropsychiatr Genet.134B 2005 7375
[68]Tabares-Seisdedos, RBalanza-Martinez, VSanchez-Moreno, JMartinez-Aran, ASalazar-Fraile, JSelva-Vera, Get al.Neurocognitive and clinical predictors of functional outcome in patients with schizophrenia and bipolar I disorder at 1-year follow-up. J Affect Disord. 2008;109:286299
[69]Lu, WZhang, CYi, ZLi, ZWu, ZFang, YAssociation between BDNF Val66Met polymorphism and cognitive performance in antipsychotic-naive patients with schizophrenia. J Mol Neurosci. 2012;47:505510
[70]Marques-Iturria, IGarolera, MPueyo, RSegura, BHernan, IGarcia-Garcia, Iet al.The interaction effect between BDNF val66met polymorphism and obesity on executive functions and frontal structure. Am J Med Genet B Neuropsychiatr Genet.165B 2014 245253
[71]Rybakowski, JKBorkowska, ASkibinska, MSzczepankiewicz, AKapelski, PLeszczynska-Rodziewicz, Aet al.Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain-derived neurotrophic factor gene. Psychiatry Clin Neurosci. 2006;60:7076
[72]Kirkpatrick, BStrauss, GPNguyen, LFischer, BADaniel, DGCienfuegos, Aet al.The brief negative symptom scale: psychometric properties. Schizophr Bull. 2011;37:300305
[73]Mane, AGarcia-Rizo, CGarcia-Portilla, MPBerge, DSugranyes, GGarcia-Alvarez, Let al.Spanish adaptation and validation of the Brief negative symptoms scale. Compr Psychiatry. 2014;55:17261729
[74]Kring, AMGur, REBlanchard, JJHoran, WPReise, SPThe Clinical assessment interview for negative symptoms (CAINS): final development and validation. Am J Psychiatry. 2013;170:165172
[75]Valiente-Gomez, AMezquida, GRomaguera, AVilardebo, IAndres, HGranados, Bet al.Validation of the Spanish version of the Clinical assessment for negative symptoms (CAINS). Schizophr Res. 2015;166:104109

Keywords

Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders

  • G. Mezquida (a1), R. Penadés (a1) (a2) (a3) (a4), B. Cabrera (a1) (a4), G. Savulich (a5), A. Lobo (a4) (a6), A. González-Pinto (a4) (a7) (a8), M.J. Penzol (a4) (a9), I. Corripio (a4) (a10) (a11), E. Fernandez-Egea (a4) (a12), P. Gassó (a3) (a13), M.J. Cuesta (a14) (a15), M. Bernardo (a1) (a2) (a3) (a4) and PEPs group...

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Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders

  • G. Mezquida (a1), R. Penadés (a1) (a2) (a3) (a4), B. Cabrera (a1) (a4), G. Savulich (a5), A. Lobo (a4) (a6), A. González-Pinto (a4) (a7) (a8), M.J. Penzol (a4) (a9), I. Corripio (a4) (a10) (a11), E. Fernandez-Egea (a4) (a12), P. Gassó (a3) (a13), M.J. Cuesta (a14) (a15), M. Bernardo (a1) (a2) (a3) (a4) and PEPs group...
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