Psychopharmacology

, Volume 231, Issue 18, pp 3757–3764

Association between the brain-derived neurotrophic factor Val66Met polymorphism and therapeutic response to olanzapine in schizophrenia patients

  • Matea Nikolac Perkovic
  • Gordana Nedic Erjavec
  • Maja Zivkovic
  • Marina Sagud
  • Suzana Uzun
  • Alma Mihaljevic-Peles
  • Oliver Kozumplik
  • Dorotea Muck-Seler
  • Nela Pivac
Original Investigation

Abstract

Rationale

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a major role in neurogenesis and neuroplasticity, and in the modulation of several neurotransmitter systems including the dopaminergic system. There are mixed reports about the association between the BDNF Val66Met polymorphism, schizophrenia, and treatment response to antipsychotic drugs.

Objectives

The present study evaluated the association of the BDNF Val66Met polymorphism with treatment response to atypical antipsychotic olanzapine in schizophrenia and the possible predictive value of the BDNF Val66Met genotype status in treatment response to antipsychotic medication.

Methods

The study included 590 ethnically homogenous Caucasian patients with schizophrenia (diagnosed using the SCID), 40.2 ± 12.0 years old, treated with olanzapine monotherapy (10–20 mg/day), or with other antipsychotics such as risperidone (3–6 mg/day), clozapine (100–500 mg/day), haloperidol (3–115 mg/day), fluphenazine (4–25 mg/day), and quetiapine (50–800 mg/day). Patients were subdivided into responders and non-responders according to a 50 % reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscale scores after 8 weeks of treatment.

Results

The results, corrected for possible effects of gender and age, showed a significant association between the BDNF Val66Met polymorphism and treatment response to olanzapine in patients. The Val/Val genotype was observed more frequently in treatment responders to olanzapine, and this genotype was associated with an improvement in clinical symptoms.

Conclusions

Our results suggest that BDNF Val66Met variants might influence the response to 8 weeks of monotherapy with olanzapine, in a relatively large sample of patients with schizophrenia.

Keywords

Antipsychotics Olanzapine Risperidone Clozapine Haloperidol Fluphenazine Quetiapine BDNF Val66Met polymorphism Schizophrenia Treatment response 

Supplementary material

213_2014_3515_MOESM1_ESM.doc (28 kb)
Supplementary Table S1(DOC 28 kb)
213_2014_3515_MOESM2_ESM.doc (36 kb)
Supplementary Table S2(DOC 36 kb)
213_2014_3515_MOESM3_ESM.doc (44 kb)
Supplementary Table S3(DOC 44 kb)

References

  1. Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 10:345–352PubMedCrossRefGoogle Scholar
  2. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimaki T, Leinonen E (2005) Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. J Neural Transm 112:885–890PubMedCrossRefGoogle Scholar
  3. Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22:123–131PubMedCentralPubMedCrossRefGoogle Scholar
  4. Buckley PF, Mahadik S, Pillai A, Terry A Jr (2007) Neurotrophins and schizophrenia. Schizophr Res 94:1–11PubMedCrossRefGoogle Scholar
  5. Chao MV, Rajagopal R, Lee FS (2006) Neurotrophin signalling in health and disease. Clin Sci (Lond) 110:167–173CrossRefGoogle Scholar
  6. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) 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 24:4401–4411PubMedCrossRefGoogle Scholar
  7. Daniel W (1990) Applied nonparametric statistics. PWS Kent Publishing Company, BostonGoogle Scholar
  8. Dodd S, Maes M, Anderson G, Dean OM, Moylan S, Berk M (2013) Putative neuroprotective agents in neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 42:135–145PubMedCrossRefGoogle Scholar
  9. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269PubMedCrossRefGoogle Scholar
  10. First MB, Spitzer RL, Williams JBW, Gibbons M (1995) Structured clinical interview for DSM-IV-patient edition (SCID-P). American Psychiatric, Washington DCGoogle Scholar
  11. Fritz CO, Morris PE, Richler JJ (2012) Effect size estimates: current use, calculations, and interpretation. J Exp Psychol Gen 141:17Google Scholar
  12. Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X (2007) Brain-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 61:911–922PubMedCrossRefGoogle Scholar
  13. Hong CJ, Liou YJ, Tsai SJ (2011) Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull 86:287–297PubMedCrossRefGoogle Scholar
  14. Hong CJ, Yu YW, Lin CH, Tsai SJ (2003) An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett 349:206–208PubMedCrossRefGoogle Scholar
  15. Jindal RD, Pillai AK, Mahadik SP, Eklund K, Montrose DM, Keshavan MS (2010) Decreased BDNF in patients with antipsychotic naive first episode schizophrenia. Schizophr Res 119:47–51PubMedCentralPubMedCrossRefGoogle Scholar
  16. Kawashima K, Ikeda M, Kishi T, Kitajima T, Yamanouchi Y, Kinoshita Y, Okochi T, Aleksic B, Tomita M, Okada T, Kunugi H, Inada T, Ozaki N, Iwata N (2009) BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. Schizophr Res 112:72–79PubMedCrossRefGoogle Scholar
  17. Lang UE, Hellweg R, Seifert F, Schubert F, Gallinat J (2007) Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity. Biol Psychiat 62:530–535PubMedCrossRefGoogle Scholar
  18. Lee JG, Cho HY, Park SW, Seo MK, Kim YH (2010) Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells. Prog Neuropsychopharmacol Biol Psychiatry 34:1001–1006PubMedCrossRefGoogle Scholar
  19. Leucht S, Davis JM, Engel RR, Kane JM, Wagenpfeil S (2007) Defining ‘response’ in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacology 32:1903–1910PubMedCrossRefGoogle Scholar
  20. McIlwain ME, Harrison J, Wheeler AJ, Russell BR (2011) Pharmacotherapy for treatment-resistant schizophrenia. Neuropsychiatr Dis Treat 7:135–149PubMedCentralPubMedGoogle Scholar
  21. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCentralPubMedCrossRefGoogle Scholar
  22. Nedic G, Perkovic MN, Sviglin KN, Muck-Seler D, Borovecki F, Pivac N (2013) Brain-derived neurotrophic factor Val66Met polymorphism and alcohol-related phenotypes. Prog Neuropsychopharmacol Biol Psychiatry 40:193–198PubMedCrossRefGoogle Scholar
  23. Nieto R, Kukuljan M, Silva H (2013) BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory. Front Psychiatry 4:45PubMedCentralPubMedGoogle Scholar
  24. Nikolac M, Nedic G, Sagud M, Zivkovic M, Muck-Seler D, Pivac N (2012) P616: Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and response to antipsychotic drug therapy. E-journal of the British Pharmacological Society Proceedings of the British Pharmacological Society at http://wwwpA2onlineorg/abstracts/Vol10Issue3abst177PpdfGoogle Scholar
  25. Nurjono M, Lee J, Chong SA (2012) A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci 10:61–70PubMedCentralPubMedCrossRefGoogle Scholar
  26. Obermeier M, Schennach-Wolff R, Meyer S, Moller HJ, Riedel M, Krause D, Seemuller F (2011) Is the PANSS used correctly? A systematic review. Bmc Psychiatry 11Google Scholar
  27. Pae CU, Chiesa A, Porcelli S, Han C, Patkar AA, Lee SJ, Park MH, Serretti A, De Ronchi D (2012) Influence of BDNF variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia. Neuropsychobiology 65:1–11PubMedCrossRefGoogle Scholar
  28. Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner SF, Waggoner SG, Tahl AR, Sklar P (2010) Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry 15:810–815PubMedCentralPubMedCrossRefGoogle Scholar
  29. Pivac N, Kim B, Nedic G, Joo YH, Kozaric-Kovacic D, Hong JP, Muck-Seler D (2009) Ethnic differences in brain-derived neurotrophic factor Val66Met polymorphism in Croatian and Korean healthy participants. Croat Med J 50:43–48PubMedCentralPubMedCrossRefGoogle Scholar
  30. Pivac N, Nikolac M, Nedic G, Mustapic M, Borovecki F, Hajnsek S, Presecki P, Pavlovic M, Mimica N, Muck Seler D (2011) Brain derived neurotrophic factor Val66Met polymorphism and psychotic symptoms in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 35:356–362PubMedCrossRefGoogle Scholar
  31. Russo-Neustadt A (2003) Brain-derived neurotrophic factor, behavior, and new directions for the treatment of mental disorders. Semin Clin Neuropsychiatry 8:109–118PubMedCrossRefGoogle Scholar
  32. Russo SJ, Mazei-Robison MS, Ables JL, Nestler EJ (2009) Neurotrophic factors and structural plasticity in addiction. Neuropharmacology 56(Suppl 1):73–82PubMedCentralPubMedCrossRefGoogle Scholar
  33. Sartorius A, Hellweg R, Litzke J, Vogt M, Dormann C, Vollmayr B, Danker-Hopfe H, Gass P (2009) Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats. Pharmacopsychiatry 42:270–276PubMedCrossRefGoogle Scholar
  34. Spatz C (2011) Basic statistics: tales of distributions. Wadsworth, BelmontGoogle Scholar
  35. Suzuki T, Remington G, Mulsant BH, Uchida H, Rajji TK, Graff-Guerrero A, Mimura M, Mamo DC (2012) Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation. Psychiatry Res 197:1–6PubMedCrossRefGoogle Scholar
  36. Terracciano A, Tanaka T, Sutin AR, Deiana B, Balaci L, Sanna S, Olla N, Maschio A, Uda M, Ferrucci L, Schlessinger D, Costa PT (2010) BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism. Neuropsychopharmacology 35:1083–1089PubMedCentralPubMedCrossRefGoogle Scholar
  37. Thome J, Foley P, Riederer P (1998) Neurotrophic factors and the maldevelopmental hypothesis of schizophrenic psychoses. J Neural Transm 105:85–100PubMedCrossRefGoogle Scholar
  38. Tyler WJ, Perrett SP, Pozzo-Miller LD (2002) The role of neurotrophins in neurotransmitter release. Neuroscientist 8:524–531PubMedCentralPubMedCrossRefGoogle Scholar
  39. Walker E, Hernandez AV, Kattan MW (2008) Meta-analysis: its strengths and limitations. Cleve Clin J Med 75:431–439PubMedCrossRefGoogle Scholar
  40. Xu M, Li S, Xing Q, Gao R, Feng G, Lin Z, St Clair D, He L (2010) Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. Eur J Hum Genet 18:707–712PubMedCentralPubMedCrossRefGoogle Scholar
  41. Xu MQ, St Clair D, Feng GY, Lin ZG, He G, Li XW, He L (2008) BDNF gene is a genetic risk factor for schizophrenia and is related to the chlorpromazine-induced extrapyramidal syndrome in the Chinese population. Pharmacogenet Genom 18:449–457CrossRefGoogle Scholar
  42. Zai GC, Zai CC, Chowdhury NI, Tiwari AK, Souza RP, Lieberman JA, Meltzer HY, Potkin SG, Muller DJ, Kennedy JL (2012) The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 39:96–101PubMedCrossRefGoogle Scholar
  43. Zhang JP, Lencz T, Geisler S, DeRosse P, Bromet EJ, Malhotra AK (2013) Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. Schizophr Res 146:285–288PubMedCentralPubMedCrossRefGoogle Scholar
  44. Zhang JP, Malhotra AK (2011) Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol 7:9–37PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Matea Nikolac Perkovic
    • 1
  • Gordana Nedic Erjavec
    • 1
  • Maja Zivkovic
    • 2
  • Marina Sagud
    • 3
  • Suzana Uzun
    • 2
  • Alma Mihaljevic-Peles
    • 3
  • Oliver Kozumplik
    • 2
  • Dorotea Muck-Seler
    • 1
  • Nela Pivac
    • 1
  1. 1.Division of Molecular MedicineRudjer Boskovic InstituteZagrebCroatia
  2. 2.Department of General PsychiatryClinics for Psychiatry VrapceZagrebCroatia
  3. 3.University Hospital Center ZagrebUniversity of Zagreb School of MedicineZagrebCroatia

Personalised recommendations