Hostname: page-component-7479d7b7d-m9pkr Total loading time: 0 Render date: 2024-07-10T15:13:33.890Z Has data issue: false hasContentIssue false
  • English
  • Français

BDNF Val66Met and clinical response to antipsychotic drugs: A systematic review and meta-analysis

Published online by Cambridge University Press:  23 March 2020

S. Cargnin ,
A. Massarotti  and
S. Terrazzino
S. Cargnin
Affiliation:
Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100Novara, Italy
A. Massarotti
Affiliation:
Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100Novara, Italy
S. Terrazzino*
Affiliation:
Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100Novara, Italy
*
⁎ Corresponding author. Tel.: +39 3 213 758 27; fax: +39 3 213 758 21. E-mail address:salvatore.terrazzino@uniupo.it (S. Terrazzino).
Get access

Abstract

Background

The polymorphic brain-derived neurotrophic factor (BDNF) gene has been postulated to be involved in inter-individual variability response to antipsychotic drugs.

Purpose

To perform a qualitative and quantitative synthesis of studies evaluating the influence of BDNF genetic variation on clinical response to antipsychotics.

Methods

The review protocol was published in the PROSPERO database (Reg. no CRD42015024614). A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to July 2015. The methodological quality of identified studies was assessed using the MINORS criteria. Publication bias was estimated and potential sources of heterogeneity were investigated via meta-regression, subgroup and sensitivity analyses.

Results

Nine studies including a total of 2461 antipsychotic-treated patients fulfilled inclusion criteria for meta-analysis of BDNF Val66Met. Using the random-effects model, the pooled results showed no significant association with antipsychotic response for the dominant (Met carriers vs Val/Val, OR: 0.93, 95% CI: 0.72–1.19, P = 0.55), codominant (Met/Met vs Val/Val, OR: 0.82, 95% CI: 0.59–1.15, P = 0.25), recessive (Met/Met vs Val carriers, OR: 0.81, 95% CI 0.60–1.10, P = 0.18) or the allelic contrast (Met vs Val, OR: 0.92, 95% CI 0.76–1.10, P = 0.34). Visual inspection of funnel plots and further evaluation with Egger's test did not suggest evidence of publication bias. Despite lack of significant heterogeneity in most comparisons, no evidence of association also emerged in the subgroup and sensitivity analyses conducted.

Conclusion

The present meta-analysis excludes a clinically relevant effect of BDNF Val66Met on antipsychotic drug response per se. Nevertheless, further investigation is still needed to clarify in well-designed, large sample-based studies, the impact of BDNF haplotypes containing the Val66Met polymorphism.

Keywords

Schizophrenia and psychosisGeneticsAntipsychoticsMeta-analysisBDNF brain-derived neurotrophic factorBPRS Brief Psychiatric Rating ScaleCGI Clinical Global Impression ScaleGAS Global Assessment ScaleHWE Hardy–Weinberg EquilibriumMAF minor allele frequencyPANNS Positive and Negative Syndrome ScaleOR odds ratioSAD schizoaffective disorderSCZ schizophrenia
Type
Review
Information
European Psychiatry , Volume 33 , Issue 1 , March 2016 , pp. 45 - 53
Copyright
Copyright © European Psychiatric Association 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

Carpenter, W.T. Jr.Buchanan, R.W.Schizophrenia. N Engl J Med 1994; 330: 681–690CrossRefGoogle ScholarPubMed
Sinclair, D.Adams, C.E.Treatment-resistant schizophrenia: a comprehensive survey of randomised controlled trials. BMC Psychiatry 2014; 14:253CrossRefGoogle ScholarPubMed
Caspi, A.Reichenberg, A.Weiser, M.Rabinowitz, J.Shmushkevich, M.Lubin, G., et al.Premorbid behavioral and intellectual functioning in schizophrenia patients with poor response to treatment with antipsychotic drugs. Schizophr Res 2007; 94: 45–49CrossRefGoogle ScholarPubMed
Huber, G.Gross, G.Schüttler, R.Linz, M.Longitudinal studies of schizophrenic patients. Schizophr Bull 1980; 6: 592–605CrossRefGoogle ScholarPubMed
Meltzer, H.Y.Treatment-resistant schizophrenia – the role of clozapine. Curr Med Res Opin 1997; 14: 1–20CrossRefGoogle ScholarPubMed
Modinos, G.Iyegbe, C.Prata, D.Rivera, M.Kempton, M.J.Valmaggia, L.R., et al.Molecular genetic gene–environment studies using candidate genes in schizophrenia: a systematic review. Schizophr Res 2013; 150: 356–365CrossRefGoogle ScholarPubMed
Pouget, J.G.Müller, D.J.Pharmacogenetics of antipsychotic treatment in schizophrenia. Methods Mol Biol 2014; 1175: 557–587CrossRefGoogle Scholar
Arnold, S.E.Neurodevelopmental abnormalities in schizophrenia: insights from neuropathology. Dev Psychopathol 1999; 11: 439–456CrossRefGoogle ScholarPubMed
Fatemi, S.H.Folsom, T.D.The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 2009; 35: 528–548CrossRefGoogle ScholarPubMed
Binder, D.K.Scharfman, H.E.Brain-derived neurotrophic factor. Growth Factors 2004; 22: 123–131CrossRefGoogle ScholarPubMed
Durany, N.Michel, T.Zochling, R.Boissl, K.W.Cruz-Sanchez, F.F.Riederer, P., et al.Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 2001; 52: 79–86CrossRefGoogle ScholarPubMed
Takahashi, M.Shirakawa, O.Toyooka, K.Kitamura, N.Hashimoto, T.Maeda, K., et al.Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000; 5: 293–300CrossRefGoogle ScholarPubMed
Thome, J.Foley, P.Riederer, P.Neurotrophic factors and the maldevelopmental hypothesis of schizophrenic psychoses. Review article. J Neural Transm 1998; 105: 85–100CrossRefGoogle ScholarPubMed
Fernandes, B.S.Steiner, J.Berk, M.Molendijk, M.L.Gonzalez-Pinto, A.Turck, C.W., et al.Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol Psychiatry 2015; 20: 1108–1119CrossRefGoogle ScholarPubMed
Lee, J.G.Cho, H.Y.Park, S.W.Seo, M.K.Kim, Y.H.Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 1001–1006CrossRefGoogle ScholarPubMed
Chen, Z.Y.Patel, P.D.Sant, G.Meng, C.X.Teng, K.K.Hempstead, B.L., et al.Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 2004; 24: 4401–4411CrossRefGoogle ScholarPubMed
Egan, M.F.Kojima, M.Callicott, J.H.Goldberg, T.E.Kolachana, B.S.Bertolino, A., et al.The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269CrossRefGoogle ScholarPubMed
Petryshen, T.L.Sabeti, P.C.Aldinger, K.A.Fry, B.Fan, J.B.Schaffner, S.F., et al.Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry 2010; 15: 810–815CrossRefGoogle ScholarPubMed
Notaras, M.Hill, R.van den Buuse, M.The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatry 2015; 20: 916–930CrossRefGoogle ScholarPubMed
Zai, G.C.Zai, C.C.Chowdhury, N.I.Tiwari, A.K.Souza, R.P.Lieberman, J.A., et al.The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39: 96–101CrossRefGoogle ScholarPubMed
Mitjans, M.Catalán, R.Vázquez, M.González-Rodríguez, A.Penadés, R.Pons, A., et al.Hypothalamic-pituitary-adrenal system, neurotrophic factors and clozapine response: association with FKBP5 and NTRK2 genes. Pharmacogenet Genomics 2015; 25: 274–277CrossRefGoogle ScholarPubMed
Terzić, T.Kastelic, M.Dolžan, V.Plesničar, B.K.Genetic variability testing of neurodevelopmental genes in schizophrenic patients. J Mol Neurosci 2015; 56: 205–211CrossRefGoogle ScholarPubMed
Munafo, M.R.Flint, J.Meta-analysis of genetic association studies. Trends Genet 2004; 20: 439–444CrossRefGoogle ScholarPubMed
Salvatore, Terrazzino.Sarah, Cargnin.BDNF genetic variation and clinical response to antipsychotic drugs: a systematic review and meta-analysis. PROSPERO 2015 http://www.crd.york.ac.uk/PROSPERO_REBRANDING/display_record.asp?ID=CRD42015024614 [CRD42015024614]Google Scholar
Kaur, H.Jajodia, A.Grover, S.Baghel, R.Gupta, M.Jain, S., et al.Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients. PLoS One 2014; 9:e102556CrossRefGoogle ScholarPubMed
Nikolac Perkovic, M.Nedic Erjavec, G.Zivkovic, M.Sagud, M.Uzun, S.Mihaljevic-Peles, A., et al.Association between the brain-derived neurotrophic factor Val66Met polymorphism and therapeutic response to olanzapine in schizophrenia patients. Psychopharmacology (Berl) 2014; 231: 3757–3764CrossRefGoogle ScholarPubMed
Yoshimura, R.Hori, H.Ikenouchi-Sugita, A.Umene-Nakano, W.Katsuki, A.Hayashi, K., et al.Aripiprazole altered plasma levels of brain-derived neurotrophic factor and catecholamine metabolites in first-episode untreated Japanese schizophrenia patients. Hum Psychopharmacol 2012; 27: 33–38CrossRefGoogle ScholarPubMed
Slim, K.Nini, E.Forestier, D.Kwiatkowski, F.Panis, Y.Chipponi, J.Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg 2003; 73: 712–716CrossRefGoogle ScholarPubMed
Furukawa, T.A.Guyatt, G.H.Griffith, L.E.Can we individualize the “number needed to treat”? An empirical study of summary effect measures in meta-analyses. Int J Epidemiol 2002; 31: 72–76CrossRefGoogle ScholarPubMed
Zintzaras, E.Lau, J.Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol 2008; 61: 634–645CrossRefGoogle ScholarPubMed
Lau, J.Ioannidis, J.P.Schmid, C.H.Quantitative synthesis in systematic reviews. Ann Intern Med 1997; 127: 820–826CrossRefGoogle ScholarPubMed
Higgins, J.P.Thompson, S.G.Deeks, J.J.Altman, D.G.Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560CrossRefGoogle ScholarPubMed
Egger, M.Davey Smith, G.Schneider, M.Minder, C.Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 629–634CrossRefGoogle ScholarPubMed
Hong, C.J.Yu, Y.W.Lin, C.H.Tsai, S.J.An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett 2003; 349: 206–208CrossRefGoogle ScholarPubMed
Xu, M.Li, S.Xing, Q.Gao, R.Feng, G.Lin, Z., et al.Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. Eur J Hum Genet 2010; 18: 707–712CrossRefGoogle ScholarPubMed
Xu, M.Q.St Clair, D.Feng, G.Y.Lin, Z.G.He, G.Li, X., et al.BDNF gene is a genetic risk factor for schizophrenia and is related to the chlorpromazine-induced extrapyramidal syndrome in the Chinese population. Pharmacogenet Genomics 2008; 18: 449–457CrossRefGoogle ScholarPubMed
Nanko, S.Kunugi, H.Hirasawa, H.Kato, N.Nabika, T.Kobayashi, S.Brain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr Res 2003; 62: 281–283Google ScholarPubMed
Notaras, M.Hill, R.van den Buuse, M.A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev 2015; 51: 15–30CrossRefGoogle ScholarPubMed
Rybakowski, J.K.BDNF gene: functional Val66Met polymorphism in mood disorders and schizophrenia. Pharmacogenomics 2008; 9: 1589–1593CrossRefGoogle Scholar
Bakker, P.R.Bakker, E.Amin, N.van Duijn, C.M.van Os, J.van Harten, P.N.Candidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study. PLoS One 2012; 7:e36561CrossRefGoogle ScholarPubMed
Wang, Y.Wang, J.D.Wu, H.R.Zhang, B.S.Fang, H.Ma, Q.M., et al.The Val66Met polymorphism of the brain-derived neurotrophic factor gene is not associated with risk for schizophrenia and tardive dyskinesia in Han Chinese population. Schizophr Res 2010; 120: 240–242CrossRefGoogle Scholar
Zhao, X.Huang, Y.Chen, K.Li, D.Han, C.Kan, Q.The brain-derived neurotrophic factor Val66Met polymorphism is not associated with schizophrenia: an updated meta-analysis of 11,480 schizophrenia cases and 13,490 controls. Psychiatry Res 2015; 225: 217–220CrossRefGoogle Scholar
Miura, I.Zhang, J.P.Nitta, M.Lencz, T.Kane, J.M.Malhotra, A.K., et al.BDNF Val66Met polymorphism and antipsychotic-induced tardive dyskinesia occurrence and severity: a meta-analysis. Schizophr Res 2014; 152: 365–372CrossRefGoogle ScholarPubMed
Supplementary material: File

Cargnin et al. supplementary material

Figure S1

Download Cargnin et al. supplementary material(File)
File 573.4 KB
Submit a response

Comments

No Comments have been published for this article.