Abstract
Symptom improvement in depression due to antidepressant treatment is highly variable and clinically unpredictable. Linking neuronal connectivity and genetic risk factors in predicting antidepressant response has clinical implications. Our investigation assessed whether indices of white matter integrity, serotonin transporter-linked polymorphism (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) val66met polymorphism predicted magnitude of depression symptom change following antidepressant treatment. Fractional anisotropy (FA) was used as an indicator of white matter integrity and was assessed in the uncinate fasciculus and superior longitudinal fasciculus using tract-based spatial statistics (TBSS) and probabilistic tractography. Forty-six medication-free patients with major depressive disorder participated in a diffusion tensor imaging scan prior to completing an 8-week treatment regime with citalopram or quetiapine XR. Indexed improvements in Hamilton Depression Rating Scale score from baseline to 8-week endpoint were used as an indicator of depression improvement. Carriers of the BDNF met allele exhibited lower FA values in the left uncinate fasciculus relative to val/val individuals [F(1, 40) = 7.314, p = 0.009]. Probabilistic tractography identified that higher FA in the left uncinate fasciculus predicted percent change in depression severity, with BDNF moderating this association [F(3, 30) = 3.923, p = 0.018]. An interaction between FA in the right uncinate fasciculus and 5-HTTLPR also predicted percent change in depression severity [F(5, 25) = 5.315, p = 0.002]. Uncorrected TBSS results revealed significantly higher FA in hippocampal portions of the cingulum bundle in responders compared to non-responders (p = 0.016). The predictive value of prefrontal and amygdala/hippocampal WM connectivity on antidepressant treatment response may be influenced by 5-HTTLPR and BDNF polymorphisms in MDD.
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References
Mayberg HS (2003) Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull 65:193–207
Delaveau P, Jabourian M, Lemogne C et al (2011) Brain effects of antidepressants in major depression: a meta-analysis of emotional processing studies. J Affect Disord 130:66–74. doi:10.1016/j.jad.2010.09.032
Mayberg HS, Brannan SK, Tekell JL et al (2000) Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–843
Lamar M, Charlton RA, Ajilore O et al (2013) Prefrontal vulnerabilities and whole brain connectivity in aging and depression. Neuropsychologia 51:1463–1470. doi:10.1016/j.neuropsychologia.2013.05.004
Seminowicz DA, Mayberg HS, McIntosh AR et al (2004) Limbic–frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 22:409–418. doi:10.1016/j.neuroimage.2004.01.015
Gong Q, Wu Q, Scarpazza C et al (2011) Prognostic prediction of therapeutic response in depression using high-field MR imaging. Neuroimage 55:1497–1503. doi:10.1016/j.neuroimage.2010.11.079
Cullen KR, Klimes-Dougan B, Muetzel R et al (2010) Altered white matter microstructure in adolescents with major depression: a preliminary study. J Am Acad Child Adolesc Psychiatry 49(173–83):e1
Zuo N, Fang J, Lv X et al (2012) White matter abnormalities in major depression: a tract-based spatial statistics and rumination study. PLoS One 7:e37561. doi:10.1371/journal.pone.0037561
Murphy ML, Frodl T (2011) Meta-analysis of diffusion tensor imaging studies shows altered fractional anisotropy occurring in distinct brain areas in association with depression. Biol Mood Anxiety Disord 1:3. doi:10.1186/2045-5380-1-3
Dalby RB, Frandsen J, Chakravarty MM et al (2010) Depression severity is correlated to the integrity of white matter fiber tracts in late-onset major depression. Psychiatry Res 184:38–48. doi:10.1016/j.pscychresns.2010.06.008
Alexopoulos GS, Murphy CF, Gunning-Dixon FM et al (2008) Microstructural white matter abnormalities and remission of geriatric depression. Am J Psychiatry 165:238–244. doi:10.1176/appi.ajp.2007.07050744
Alexopoulos GS, Kiosses DN, Choi SJ et al (2002) Frontal white matter microstructure and treatment response of late-life depression: a preliminary study. Am J Psychiatry 159:1929–1932
Delorenzo C, Delaparte L, Thapa-Chhetry B et al (2013) Prediction of selective serotonin reuptake inhibitor response using diffusion-weighted MRI. Front Psychiatry 4:5. doi:10.3389/fpsyt.2013.00005
Schloss P, Williams DC (1998) The serotonin transporter: a primary target for antidepressant drugs. J Psychopharmacol (Oxford) 12:115–121
Hu X, Oroszi G, Chun J et al (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29:8–16
Smeraldi E, Zanardi R, Benedetti F et al (1998) Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 3:508–511
Kraft JB, Peters EJ, Slager SL et al (2007) Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry 61:734–742. doi:10.1016/j.biopsych.2006.07.017
Yoshida K, Ito K, Sato K et al (2002) Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 26:383–386
Serretti A, Kato M, De Ronchi D, Kinoshita T (2007) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 12:247–257. doi:10.1038/sj.mp.4001926
Yu YW-Y, Tsai S-J, Chen T-J et al (2002) Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 7:1115–1119. doi:10.1038/sj.mp.4001141
Sahraian S, Babashams M, Reza-Soltani P et al (2013) Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness in Iranian patients with major depressive disorder. Iran J Psychiatry 8:86–91
Pacheco J, Beevers CG, Benavides C et al (2009) Frontal–limbic white matter pathway associations with the serotonin transporter gene promoter region (5-HTTLPR) polymorphism. J Neurosci 29:6229–6233. doi:10.1523/JNEUROSCI.0896-09.2009
Lu B, Martinowich K (2008) Cell biology of BDNF and its relevance to schizophrenia. Novartis Found Symp 289:119–129 discussion 129–135–193–195
Aydemir C, Yalcin ES, Aksaray S et al (2006) Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 30:1256–1260. doi:10.1016/j.pnpbp.2006.03.025
Brunoni AR, Lopes M, Fregni F (2008) A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 11:1169–1180. doi:10.1017/S1461145708009309
Frodl T, Schüle C, Schmitt G et al (2007) Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 64:410–416. doi:10.1001/archpsyc.64.4.410
Egan MF, Kojima M, Callicott JH et al (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269
Choi M-J, Kang R-H, Lim S-W et al (2006) Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res 1118:176–182. doi:10.1016/j.brainres.2006.08.012
Domschke K, Lawford B, Laje G et al (2010) Brain-derived neurotrophic factor (BDNF) gene: no major impact on antidepressant treatment response. Int J Neuropsychopharmacol 13:93–101. doi:10.1017/S1461145709000030
Tsai S-J, Cheng C-Y, Yu YW-Y et al (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet 123B:19–22. doi:10.1002/ajmg.b.20026
Chiang M-C, Barysheva M, Toga AW et al (2011) BDNF gene effects on brain circuitry replicated in 455 twins. Neuroimage 55:448–454. doi:10.1016/j.neuroimage.2010.12.053
Tost H, Alam T, Geramita M et al (2013) Effects of the BDNF Val66Met polymorphism on white matter microstructure in healthy adults. Neuropsychopharmacology 38:525–532. doi:10.1038/npp.2012.214
Carballedo A, Amico F, Ugwu I et al (2012) Reduced fractional anisotropy in the uncinate fasciculus in patients with major depression carrying the met-allele of the Val66Met brain-derived neurotrophic factor genotype. Am J Med Genet B Neuropsychiatr Genet 159B:537–548. doi:10.1002/ajmg.b.32060
Hyttel J, Arnt J, Sanchez C (1995) The pharmacology of citalopram. Rev Contemp Pharmacother 6:271–285
Stahl SM (2000) Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline. Biol Psychiatry 48:894–901
Baune BT (2008) New developments in the management of major depressive disorder and generalized anxiety disorder: role of quetiapine. Neuropsychiatr Dis Treat 4:1181–1191
Weisler R, Joyce M, McGill L et al (2009) Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study. CNS Spectr 14:299–313
Schmahmann JD, Pandya D (2009) Fiber pathways of the brain. Oxford University Press, New York
de Diego-Adeliño J, Pires P, Gómez-Ansón B et al (2014) Microstructural white-matter abnormalities associated with treatment resistance, severity and duration of illness in major depression. Psychol Med 44:1171–1182. doi:10.1017/S003329171300158X
First MB, Spitzer RL, Gibbon M, Williams JBW (1997) Structured clinical interview for DSM-IV axis I disorders SCID-I. American Psychiatric Pub, Arlington
Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Lesch KP, Bengel D, Heils A et al (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531
Praschak-Rieder N, Kennedy J, Wilson AA et al (2007) Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study. Biol Psychiatry 62:327–331. doi:10.1016/j.biopsych.2006.09.022
Hu X-Z, Lipsky RH, Zhu G et al (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815–826. doi:10.1086/503850
Rybakowski JK, Borkowska A, Czerski PM et al (2003) Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord 5:468–472
Pregelj P, Nedic G, Paska AV et al (2011) The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide. J Affect Disord 128:287–290. doi:10.1016/j.jad.2010.07.001
Liu H, Klomp N, Heynderickx I (2010) A perceptually relevant approach to ringing region detection. IEEE Trans Image Process 19:1414–1426. doi:10.1109/TIP.2010.2041406
MacQueen GM, Yucel K, Taylor VH et al (2008) Posterior hippocampal volumes are associated with remission rates in patients with major depressive disorder. Biol Psychiatry 64:880–883. doi:10.1016/j.biopsych.2008.06.027
Guo W-B, Liu F, Chen J-D et al (2012) Altered white matter integrity of forebrain in treatment-resistant depression: a diffusion tensor imaging study with tract-based spatial statistics. Prog Neuropsychopharmacol Biol Psychiatry 38:201–206. doi:10.1016/j.pnpbp.2012.03.012
Malone DA, Dougherty DD, Rezai AR et al (2009) Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 65:267–275. doi:10.1016/j.biopsych.2008.08.029
Smith SM, Jenkinson M, Johansen-Berg H et al (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487–1505. doi:10.1016/j.neuroimage.2006.02.024
Jenkinson M, Smith S (2001) A global optimisation method for robust affine registration of brain images. Med Image Anal 5:143–156
Rueckert D, Sonoda LI, Hayes C et al (1999) Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 18:712–721. doi:10.1109/42.796284
Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15:1–25. doi:10.1002/hbm.1058
Smith SM, Nichols TE (2009) Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage 44:83–98. doi:10.1016/j.neuroimage.2008.03.061
Hua K, Oishi K, Zhang J et al (2009) Mapping of functional areas in the human cortex based on connectivity through association fibers. Cereb Cortex 19:1889–1895. doi:10.1093/cercor/bhn215
Wakana S, Jiang H, Nagae-Poetscher LM et al (2004) Fiber tract-based atlas of human white matter anatomy. Radiology 230:77–87. doi:10.1148/radiol.2301021640
Fischl B, van der Kouwe A, Destrieux C et al (2004) Automatically parcellating the human cerebral cortex. Cereb Cortex 14:11–22
Stevens JP (2012) Applied multivariate statistics for the social sciences, 5th edn. Routledge, London
Cook RD, Weisberg S (1982) Residuals and influence in regression. Chapman & Hall/CRC, Boca Raton
Catani M, Howard RJ, Pajevic S, Jones DK (2002) Virtual in vivo interactive dissection of white matter fasciculi in the human brain. Neuroimage 17:77–94
Pizzagalli DA (2011) Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 36:183–206. doi:10.1038/npp.2010.166
Carballedo A, Lisiecka D, Fagan A et al (2012) Early life adversity is associated with brain changes in subjects at family risk for depression. World J Biol Psychiatry 13:569–578. doi:10.3109/15622975.2012.661079
Steffens DC, Taylor WD, Denny KL et al (2011) Structural integrity of the uncinate fasciculus and resting state functional connectivity of the ventral prefrontal cortex in late life depression. PLoS One 6:e22697. doi:10.1371/journal.pone.0022697
Svoboda E-M (2007) The functional neuroanatomy of autobiographical memory. ProQuest, Ann Arbor
Schacter DL, Addis DR, Buckner RL (2007) Remembering the past to imagine the future: the prospective brain. Nat Rev Neurosci 8:657–661. doi:10.1038/nrn2213
Ochsner KN, Beer JS, Robertson ER et al (2005) The neural correlates of direct and reflected self-knowledge. Neuroimage 28:797–814. doi:10.1016/j.neuroimage.2005.06.069
Johnson MK, Raye CL, Mitchell KJ et al (2006) Dissociating medial frontal and posterior cingulate activity during self-reflection. Soc Cogn Affect Neurosci 1:56–64. doi:10.1093/scan/nsl004
Foland-Ross LC, Hamilton P, Sacchet MD et al (2014) Activation of the medial prefrontal and posterior cingulate cortex during encoding of negative material predicts symptom worsening in major depression. NeuroReport 25:324–329. doi:10.1097/WNR.0000000000000095
Korgaonkar MS, Williams LM, Song YJ et al (2014) Diffusion tensor imaging predictors of treatment outcomes in major depressive disorder. Br J Psychiatry 205:321–328. doi:10.1192/bjp.bp.113.140376
Acknowledgments
This work was supported by an investigator-initiated grant from Astra Zeneca (Dr. Ramasubbu). The infrastructure for this study was funded through the Hotchkiss Brain Institute for Neuroimaging Research Unit at Seaman Family MRI Research Centre, Foothills Hospital and the Mathison Centre for Mental Health Research and Education, Calgary. We acknowledge the contribution of Gaxiola Ismael, Filomeno Cortese and Brad Goodyear for imaging data acquisition, storage and quality assurance. The authors wish to thank all participants who volunteered their time for this study. The trial is registered at clinical trials.gov (NCT 02132286).
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Tatham, E.L., Hall, G.B.C., Clark, D. et al. The 5-HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression. Eur Arch Psychiatry Clin Neurosci 267, 135–147 (2017). https://doi.org/10.1007/s00406-016-0702-9
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DOI: https://doi.org/10.1007/s00406-016-0702-9