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Gene polymorphisms and response to transcranial direct current stimulation for auditory verbal hallucinations in schizophrenia

Published online by Cambridge University Press:  21 March 2018

Harleen Chhabra ,
Venkataram Shivakumar ,
Manjula Subbanna ,
Sunil V. Kalmady ,
Anushree Bose ,
Sri Mahavir Agarwal ,
Vanteemar S. Sreeraj Open the ORCID record for Vanteemar S. Sreeraj [Opens in a new window] ,
Damodharan Dinakaran ,
Janardhanan C. Narayanaswamy  and
Monojit Debnath
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Harleen Chhabra
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Venkataram Shivakumar
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Manjula Subbanna
Affiliation:
Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Sunil V. Kalmady
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Anushree Bose
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Sri Mahavir Agarwal
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Vanteemar S. Sreeraj
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Damodharan Dinakaran
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Janardhanan C. Narayanaswamy
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Monojit Debnath
Affiliation:
Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Ganesan Venkatasubramanian*
Affiliation:
WISER Program, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
*
Author for correspondence: Dr. Ganesan Venkatasubramanian, Professor of Psychiatry, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore 560029, India. Tel: 00 91 80 26995256; E-mail: venkat.nimhans@gmail.com
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Abstract

Objective

Recent observations demonstrate a significant ameliorative effect of add-on transcranial direct current stimulation (tDCS) on auditory verbal hallucinations (AVHs) in schizophrenia. Of the many SNPs, NRG1 rs35753505 and catechol-o-methyl transferase (COMT) rs4680 polymorphisms have shown to have a strong association with neuroplasticity effect in schizophrenia.

Methods

Schizophrenia patients (n=32) with treatment resistant auditory hallucinations were administered with an add-on tDCS. The COMT (rs4680) and NRG1 (rs35753505) genotypes were determined. The COMT genotypes were categorised into Val group (GG; n=15) and Met group (GG/AG; n=17) and NRG1 genotypes were categorised into AA group (n=12) and AG/GG group (n=20).

Results

The reduction in auditory hallucination sub-scale score was significantly affected by COMT-GG genotype [Time×COMT interaction: F(1,28)=10.55, p=0.003, ɳ2=0.27]. Further, COMT-GG effect was epistatically influenced by the co-occurrence of NRG1-AA genotype [Time×COMT×NRG1 interaction: F(1,28)=8.09, p=0.008, ɳ2=0.22]. Irrespective of genotype, females showed better tDCS response than males [Time×Sex interaction: F(1,21)=4.67, p=0.04, ɳ2=0.18].

Conclusion

COMT-GG and NRG1-AA genotypes aid the tDCS-induced improvement in AVHs in schizophrenia patients. Our preliminary observations need replication and further systematic research to understand the neuroplastic gene determinants that modulate the effect of tDCS.

Keywords

hallucinationsgenesschizophreniatDCS
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 30 , Issue 4 , August 2018 , pp. 218 - 225
Copyright
© Scandinavian College of Neuropsychopharmacology 2018 

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References

1. Lewis, DA Moghaddam, B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63, 1372–1376.Google Scholar
2. Tsai, G Coyle, JT (2002) Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42, 165–179.Google Scholar
3. Balu, DT Coyle, JT (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35, 848–870.Google Scholar
4. Voineskos, D, Rogasch, NC, Rajji, TK, Fitzgerald, PB Daskalakis, ZJ (2013) A review of evidence linking disrupted neural plasticity to schizophrenia. Can J Psychiatry 58, 86–92.Google Scholar
5. Bose, A, Shivakumar, V, Narayanaswamy, JC, Nawani, H, Subramaniam, A, Agarwal, SM, Chhabra, H, Kalmady, SV Venkatasubramanian, G (2014) Insight facilitation with add-on tDCS in schizophrenia. Schizophr Res 156, 63–65.Google Scholar
6. Agarwal, SM, Shivakumar, V, Bose, A, Subramaniam, A, Nawani, H, Chhabra, H, Kalmady, SV, Narayanaswamy, JC Venkatasubramanian, G (2013) Transcranial direct current stimulation in schizophrenia – a review. Clin Psychopharmacol Neurosci 11, 118–125.Google Scholar
7. Brunelin, J, Mondino, M, Gassab, L, Haesebaert, F, Gaha, L, Suaud-Chagny, MF, Saoud, M, Mechri, A Poulet, E (2012) Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia. Am J Psychiatry 169, 719–724.Google Scholar
8. Fritsch, B, Reis, J, Martinowich, K, Schambra, HM, Ji, Y, Cohen, LG Lu, B (2010) Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66, 198–204.Google Scholar
9. Bikson, M, Inoue, M, Akiyama, H, Deans, JK, Fox, JE, Miyakawa, H Jefferys, JG (2004) Effects of uniform extracellular DC electric fields on excitability in rat hippocampal slices in vitro. J Physiol 557(Pt 1):175–190.Google Scholar
10. Hasan, A, Nitsche, MA, Rein, B, Schneider-Axmann, T, Guse, B, Gruber, O, Falkai, P Wobrock, T (2011) Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation. Behavioural Brain Research 224, 15–22.Google Scholar
11. Nitsche, M AA, Liebetanz, D, Lang, N, Tergau, F Paulus, W (2007) Induction and modulation of neuroplasticity by transcranial direct current stimulation. In: Marcolin MA and Padberg F editors Transcranial brain stimulation for treatment of psychiatric disorders Adv Biol Psychiatrvol.23 Basel: Kargerp. 172–186.Google Scholar
12. Nitsche, MA Paulus, W (2001) Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57, 1899–1901.Google Scholar
13. Krause, B, Marquez-Ruiz, J Kadosh, RC (2013) The effect of transcranial direct current stimulation: a role for cortical excitation/inhibition balance? Front Hum Neurosci 7, 602.Google Scholar
14. Antal, A, Paulus, W Nitsche, MA (2011) Electrical stimulation and visual network plasticity. Restor Neurol Neurosci. [Review] 29, 365–374.Google Scholar
15. Monte-Silva, K, Kuo, MF, Hessenthaler, S, Fresnoza, S, Liebetanz, D, Paulus, W Nitsche, MA (2013) Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation. Brain Stimul 6, 424–432.Google Scholar
16. Nawani, H, Bose, A, Agarwal, SM, Shivakumar, V, Chhabra, H, Subramaniam, A, Kalmady, S, Narayanaswamy, JC Venkatasubramanian, G (2014) Modulation of corollary discharge dysfunction in schizophrenia by tDCS: preliminary evidence. Brain Stimul 7, 486–488.Google Scholar
17. Kirimoto, H, Ogata, K, Onishi, H, Oyama, M, Goto, Y Tobimatsu, S (2011) Transcranial direct current stimulation over the motor association cortex induces plastic changes in ipsilateral primary motor and somatosensory cortices. Clin Neurophysiol 122, 777–783.Google Scholar
18. Lang, N, Siebner, HR, Ward, NS, Lee, L, Nitsche, MA, Paulus, W, Rothwell, JC, Lemon, RN Frackowiak, RS (2005) How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci 22, 495–504.Google Scholar
19. Venkatakrishnan, A Sandrini, M (2012) Combining transcranial direct current stimulation and neuroimaging: novel insights in understanding neuroplasticity. J Neurophysiol 107, 1–4.Google Scholar
20. Mei, L Xiong, WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9, 437–452.Google Scholar
21. Ho, BC, Wassink, TH, O’Leary, DS, Sheffield, VC Andreasen, NC (2005) Catechol-o-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry 10, 287–298.Google Scholar
22. Bray, NJ, Buckland, PR, Williams, NM, Williams, HJ, Norton, N, Owen, MJ O'Donovan, MC (2003) A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 73, 152–161.Google Scholar
23. Shifman, S, Bronstein, M, Sternfeld, M, Pisante-Shalom, A, Lev-Lehman, E, Weizman, A, Reznik, I, Spivak, B, Grisaru, N, Karp, L, Schiffer, R, Kotler, M, Strous, RD, Swartz-Vanetik, M, Knobler, HY, Shinar, E, Beckmann, JS, Yakir, B, Risch, N, Zak, NB Darvasi, A (2002) A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71, 1296–1302.Google Scholar
24. Akil, M, Kolachana, BS, Rothmond, DA, Hyde, TM, Weinberger, DR Kleinman, JE (2003) Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 23, 2008–2013.Google Scholar
25. Opgen-Rhein, C, Neuhaus, AH, Urbanek, C, Hahn, E, Sander, T Dettling, M (2008) Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test. Schizophr Bull 34, 1231–1239.Google Scholar
26. Quednow, BB, Wagner, M, Mossner, R, Maier, W Kuhn, KU (2010) Sensorimotor gating of schizophrenia patients depends on catechol o-methyltransferase Val158Met polymorphism. Schizophr Bull 36, 341–346.Google Scholar
27. Haraldsson, HM, Ettinger, U, Magnusdottir, BB, Sigmundsson, T, Sigurdsson, E, Ingason, A Petursson, H (2010) Catechol-o-methyltransferase Val 158 Met polymorphism and antisaccade eye movements in schizophrenia. Schizophr Bull 36, 157–164.Google Scholar
28. Witte, AV, Kurten, J, Jansen, S, Schirmacher, A, Brand, E, Sommer, J Floel, A (2012) Interaction of BDNF and COMT polymorphisms on paired-associative stimulation-induced cortical plasticity. J Neurosci 32, 4553–4561.Google Scholar
29. Nieratschker, V, Kiefer, C, Giel, K, Kruger, R Plewnia, C (2015) The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition. Brain Stimul 8, 283–288.Google Scholar
30. Plewnia, C, Zwissler, B, Langst, I, Maurer, B, Giel, K Kruger, R (2013) Effects of transcranial direct current stimulation (tDCS) on executive functions: influence of COMT Val/Met polymorphism. Cortex 49, 1801–1807.Google Scholar
31. Shivakumar, V, Chhabra, H, Subbanna, M, Agarwal, SM, Bose, A, Kalmady, SV, Narayanaswamy, JC, Debnath, M Venkatasubramanian, G (2015) Effect of tDCS on auditory hallucinations in schizophrenia: influence of catechol-o-methyltransferase (COMT) Val158Met polymorphism. Asian J Psychiatr 16, 75–77.Google Scholar
32. Yang, JZ, Si, TM, Ruan, Y, Ling, YS, Han, YH, Wang, XL, Zhou, M, Zhang, HY, Kong, QM, Liu, C, Zhang, DR, Yu, YQ, Liu, SZ, Ju, GZ, Shu, L, Ma, DL Zhang, D (2003) Association study of neuregulin 1 gene with schizophrenia. Mol Psychiatry 8, 706–709.Google Scholar
33. Kukshal, P, Bhatia, T, Bhagwat, AM, Gur, RE, Gur, RC, Deshpande, SN, Nimgaonkar, VL Thelma, BK (2013) Association study of neuregulin-1 gene polymorphisms in a North Indian schizophrenia sample. Schizophr Res 144, 24–30.Google Scholar
34. Kurnianingsih, YA, Kuswanto, CN, McIntyre, RS, Qiu, A, Ho, BC Sim, K (2011) Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder. J Neural Transm 118, 1621–1639.Google Scholar
35. Krug, A, Markov, V, Eggermann, T, Krach, S, Zerres, K, Stocker, T, Shah, NJ, Schneider, F, Nothen, MM, Treutlein, J, Rietschel, M Kircher, T (2008) Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals. Neuroimage 42, 1569–1576.Google Scholar
36. Thirunavukkarasu, P, Vijayakumari, AA, John, JP, Halahalli, HN, Paul, P, Sen, S, Purushottam, M Jain, S (2014) An exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India. Asian J Psychiatr 10, 62–68.Google Scholar
37. Yokley, JL, Prasad, KM, Chowdari, KV, Talkowski, ME, Wood, J, Gur, RC, Gur, RE, Almasy, L, Nimgaonkar, VL Pogue-Geile, MF (2012) Genetic associations between neuregulin-1 SNPs and neurocognitive function in multigenerational, multiplex schizophrenia families. Psychiatr Genet 22, 70–81.Google Scholar
38. Kircher, T, Thienel, R, Wagner, M, Reske, M, Habel, U, Kellermann, T, Frommann, I, Schwab, S, Wolwer, W, von Wilmsdorf, M, Braus, DF, Schmitt, A, Rapp, A, Stocker, T, Shah, NJ, Henn, FA, Sauer, H, Gaebel, W, Maier, W Schneider, F (2009) Neuregulin 1 ICE-single nucleotide polymorphism in first episode schizophrenia correlates with cerebral activation in fronto-temporal areas. Eur Arch Psychiatry Clin Neurosci 259, 72–79.Google Scholar
39. Prata, DP, Breen, G, Osborne, S, Munro, J, Clair, D Collier, DA (2009) An association study of the neuregulin 1 gene, bipolar affective disorder and psychosis. Psychiatr Genet 19, 113–116.Google Scholar
40. Nawaz, R, Asif, H, Khan, A, Ishtiaq, H, Shad, F Siddiqui, S (2014) Drugs Targeting SNPrs35753505 of the NRG1 gene may prevent the association of schizophrenia in a Pakistani population. CNS Neurol Disord Drug Targets 13, 1604–1614.Google Scholar
41. Georgieva, L, Dimitrova, A, Ivanov, D, Nikolov, I, Williams, NM, Grozeva, D, Zaharieva, I, Toncheva, D, Owen, MJ, Kirov, G O'Donovan, MC (2008) Support for neuregulin 1 as a susceptibility gene for bipolar disorder and schizophrenia. Biol Psychiatry 64, 419–427.Google Scholar
42. Nickl-Jockschat, T, Stocker, T, Krug, A, Markov, V, Huang, R, Schneider, F, Habel, U, Eickhoff, SB, Zerres, K, Nothen, MM, Treutlein, J, Rietschel, M, Shah, NJ Kircher, T (2014) A neuregulin-1 schizophrenia susceptibility variant causes perihippocampal fiber tract anomalies in healthy young subjects. Brain Behav 4, 215–226.Google Scholar
43. Yeganeh-Doost, P, Gruber, O, Falkai, P Schmitt, A (2011) The role of the cerebellum in schizophrenia: from cognition to molecular pathways. Clinics (Sao Paulo) 66(Suppl. 1):71–77.Google Scholar
44. Haddock, G, McCarron, J, Tarrier, N Faragher, EB (1999) Scales to measure dimensions of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS). Psychol Med 29, 879–889.Google Scholar
45. Oldfield, RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9(1):97–113.Google Scholar
46. Sheehan, DV, Lecrubier, Y, Sheehan, KH, Amorim, P, Janavs, J, Weiller, E, Hergueta, T, Baker, R Dunbar, GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl. 20):22–33. quiz 4–57.Google Scholar
47. Brunoni, AR, Amadera, J, Berbel, B, Volz, MS, Rizzerio, BG Fregni, F (2011) A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol 14, 1133–1145.Google Scholar
48. Cools, R D’Esposito, M (2011) Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 69, e113–e125.Google Scholar
49. Munafo, MR, Attwood, AS Flint, J (2008) Neuregulin 1 genotype and schizophrenia. Schizophr Bull 34, 9–12.Google Scholar
50. Gong, YG, Wu, CN, Xing, QH, Zhao, XZ, Zhu, J He, L (2009) A two-method meta-analysis of neuregulin 1(NRG1) association and heterogeneity in schizophrenia. Schizophr Res 111, 109–114.Google Scholar
51. Ledonne, A, Nobili, A, Latagliata, EC, Cavallucci, V, Guatteo, E, Puglisi-Allegra, S, D'Amelio, M Mercuri, NB (2015) Neuregulin 1 signalling modulates mGluR1 function in mesencephalic dopaminergic neurons. Mol Psychiatry 20, 959–973.Google Scholar
52. Neddens, J, Vullhorst, D, Paredes, D Buonanno, A (2009) Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity. Commun Integr Biol 2, 261–264.Google Scholar
53. Roy, K, Murtie, JC, El-Khodor, BF, Edgar, N, Sardi, SP, Hooks, BM, Benoit-Marand, M, Chen, C, Moore, H, O'Donnell, P, Brunner, D Corfas, G (2007) Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci USA 104, 8131–8136.Google Scholar
54. Teo, JT, Bentley, G, Lawrence, P, Soltesz, F, Miller, S, Wille, D, McHugh, S, Dodds, C, Lu, B, Croft, RJ, Bullmore, ET Nathan, PJ (2014) Late cortical plasticity in motor and auditory cortex: role of met-allele in BDNF Val66Met polymorphism. Int J Neuropsychopharmacol 17, 705–713.Google Scholar
55. Brunoni, AR, Kemp, AH, Shiozawa, P, Cordeiro, Q, Valiengo, LC, Goulart, AC, Coprerski, B, Lotufo, PA, Brunoni, D, Perez, AB, Fregni, F Bensenor, IM (2013) Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system. Eur Neuropsychopharmacol 23, 1530–1540.Google Scholar
56. Rroji, O, van Kuyck, K, Nuttin, B Wenderoth, N (2015) Anodal tDCS over the primary motor cortex facilitates long-term memory formation reflecting use-dependent plasticity. PLoS One 10, e0127270.Google Scholar
57. Nitsche, MA, Fricke, K, Henschke, U, Schlitterlau, A, Liebetanz, D, Lang, N, Henning, S, Tergau, F Paulus, W (2003) Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol 553(Pt 1):293–301.Google Scholar
58. Polania, R, Paulus, W, Antal, A Nitsche, MA (2011) Introducing graph theory to track for neuroplastic alterations in the resting human brain: a transcranial direct current stimulation study. Neuroimage 54, 2287–2296.Google Scholar
59. Hunter, MA, Coffman, BA, Trumbo, MC Clark, VP (2013) Tracking the neuroplastic changes associated with transcranial direct current stimulation: a push for multimodal imaging. Front Hum Neurosci 7, 495.Google Scholar
60. Pena-Gomez, C, Sala-Lonch, R, Junque, C, Clemente, IC, Vidal, D, Bargallo, N, Falcon, C, Valls-Sole, J, Pascual-Leone, A Bartres-Faz, D (2012) Modulation of large-scale brain networks by transcranial direct current stimulation evidenced by resting-state functional MRI. Brain Stimul 5, 252–263.Google Scholar
61. Kunze, T, Hunold, A, Haueisen, J, Jirsa, V Spiegler, A (2016) Transcranial direct current stimulation changes resting state functional connectivity: a large-scale brain network modeling study. Neuroimage 140, 174–187.Google Scholar
62. Rizos, EN, Michalopoulou, PG, Siafakas, N, Stefanis, N, Douzenis, A, Rontos, I, Laskos, E, Kastania, A, Zoumpourlis, V Lykouras, L (2010) Association of serum brain-derived neurotrophic factor and duration of untreated psychosis in first-episode patients with schizophrenia. Neuropsychobiology 62, 87–90.Google Scholar