Kynurenine pathway and white matter microstructure in bipolar disorder

  • Sara Poletti
  • Aye Mu Myint
  • Gregor Schüetze
  • Irene Bollettini
  • Elena Mazza
  • Doris Grillitsch
  • Clara Locatelli
  • Markus Schwarz
  • Cristina Colombo
  • Francesco Benedetti
Original Paper


Decreased availability of serotonin in the central nervous system has been suggested to be a central factor in the pathogenesis of depression. Activation of indoleamine 2–3 dioxygenase following a pro-inflammatory state could reduce the amount of tryptophan converted to serotonin and increase the production of tryptophan catabolites such as kynurenic acid, an antagonist of ionotropic excitatory aminoacid receptors, whose levels are reduced in bipolar disorder. Abnormalities in white matter (WM) integrity have been widely reported in BD. We then hypothesized that metabolites involved in serotoninergic turnover in BD could influence DTI measures of WM microstructure. Peripheral levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxy-kynurenine, and 5-HIAA were analysed in 22 patients affected by BD and 15 healthy controls. WM microstructure was evaluated using diffusion tensor imaging and tract-based spatial statistics with threshold-free cluster enhancement only in bipolar patients. We observed that kynurenic acid and 5-HIAA were reduced in BD and associated with DTI measures of WM integrity in several association fibres: inferior and superior longitudinal fasciculus, cingulum bundle, corpus callosum, uncus, anterior thalamic radiation and corona radiata. Our results seem to suggest that higher levels of 5-HIAA, a measure of serotonin levels, and higher levels of kynurenic acid, which protects from glutamate excitotoxicity, could exert a protective effect on WM microstructure. Reduced levels of these metabolites in BD thus seem to confirm a crucial role of serotonin turnover in BD pathophysiology.


IDO Kynurenic acid 5-HIAA Bipolar disorder White matter TBSS 



This study was supported by the European Union EU-FP7-HEALTH-F2-2008-222963 “MOODINFLAME”.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Supplementary material

406_2016_731_MOESM1_ESM.pdf (672 kb)
Supplementary material 1 (PDF 671 kb)


  1. 1.
    Adler CM, Adams J, DelBello MP, Holland SK, Schmithorst V, Levine A, Jarvis K, Strakowski SM (2006) Evidence of white matter pathology in bipolar disorder adolescents experiencing their first episode of mania: a diffusion tensor imaging study. Am J Psychiatry 163:322–324CrossRefPubMedGoogle Scholar
  2. 2.
    Applebaum J, Bersudsky Y, Klein E (2007) Rapid tryptophan depletion as a treatment for acute mania: a double-blind, pilot-controlled study. Bipolar Disord 9:884–887CrossRefPubMedGoogle Scholar
  3. 3.
    Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L (2003) 5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study. J Clin Psychopharmacol 23:563–567CrossRefPubMedGoogle Scholar
  4. 4.
    Asberg M, Traskman L, Thoren P (1976) 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry 33:1193–1197CrossRefPubMedGoogle Scholar
  5. 5.
    Azevedo CJ, Kornak J, Chu P, Sampat M, Okuda DT, Cree BA, Nelson SJ, Hauser SL, Pelletier D (2014) In vivo evidence of glutamate toxicity in multiple sclerosis. Ann Neurol 76:269–278CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bartzokis G (2012) Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments. Front Biosci (Landmark Ed) 16:2695–2733CrossRefGoogle Scholar
  7. 7.
    Bartzokis G, Lu PH, Heydari P, Couvrette A, Lee GJ, Kalashyan G, Freeman F, Grinstead JW, Villablanca P, Finn JP, Mintz J, Alger JR, Altshuler LL (2012) Multimodal magnetic resonance imaging assessment of white matter aging trajectories over the lifespan of healthy individuals. Biol Psychiatry 72:1026–1034CrossRefPubMedGoogle Scholar
  8. 8.
    Basser PJ, Mattiello J, LeBihan D (1994) MR diffusion tensor spectroscopy and imaging. Biophys J 66:259–267CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bearden CE, van Erp TG, Dutton RA, Boyle C, Madsen S, Luders E, Kieseppa T, Tuulio-Henriksson A, Huttunen M, Partonen T, Kaprio J, Lonnqvist J, Thompson PM, Cannon TD (2011) Mapping corpus callosum morphology in twin pairs discordant for bipolar disorder. Cereb Cortex 21:2415–2424CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Benedetti F, Absinta M, Rocca MA, Radaelli D, Poletti S, Bernasconi A, Dallaspezia S, Pagani E, Falini A, Copetti M, Colombo C, Comi G, Smeraldi E, Filippi M (2011) Tract-specific white matter structural disruption in patients with bipolar disorder. Bipolar Disord 13:414–424CrossRefPubMedGoogle Scholar
  11. 11.
    Benedetti F, Bollettini I, Barberi I, Radaelli D, Poletti S, Locatelli C, Pirovano A, Lorenzi C, Falini A, Colombo C, Smeraldi E (2013) Lithium and GSK3-beta promoter gene variants influence white matter microstructure in bipolar disorder. Neuropsychopharmacology 38:313–327CrossRefPubMedGoogle Scholar
  12. 12.
    Benedetti F, Bollettini I, Poletti S, Locatelli C, Lorenzi C, Pirovano A, Smeraldi E, Colombo C (2015) White matter microstructure in bipolar disorder is influenced by the serotonin transporter gene polymorphism 5-HTTLPR. Genes Brain Behav 14:238–250CrossRefPubMedGoogle Scholar
  13. 13.
    Benedetti F, Radaelli D, Poletti S, Locatelli C, Dallaspezia S, Lorenzi C, Pirovano A, Colombo C, Smeraldi E (2011) Association of the C(-1019)G 5-HT1A promoter polymorphism with exposure to stressors preceding hospitalization for bipolar depression. J Affect Disord 132:297–300CrossRefPubMedGoogle Scholar
  14. 14.
    Benedetti F, Riccaboni R, Poletti S, Radaelli D, Locatelli C, Lorenzi C, Pirovano A, Smeraldi E, Colombo C (2014) The serotonin transporter genotype modulates the relationship between early stress and adult suicidality in bipolar disorder. Bipolar Disord 16(8):857–866CrossRefPubMedGoogle Scholar
  15. 15.
    Benedetti F, Yeh PH, Bellani M, Radaelli D, Nicoletti MA, Poletti S, Falini A, Dallaspezia S, Colombo C, Scotti G, Smeraldi E, Soares JC, Brambilla P (2011) Disruption of white matter integrity in bipolar depression as a possible structural marker of illness. Biol Psychiatry 69:309–317CrossRefPubMedGoogle Scholar
  16. 16.
    Birch PJ, Grossman CJ, Hayes AG (1988) Kynurenate and FG9041 have both competitive and non-competitive antagonist actions at excitatory amino acid receptors. Eur J Pharmacol 151:313–315CrossRefPubMedGoogle Scholar
  17. 17.
    Boretius S, Escher A, Dallenga T, Wrzos C, Tammer R, Bruck W, Nessler S, Frahm J, Stadelmann C (2012) Assessment of lesion pathology in a new animal model of MS by multiparametric MRI and DTI. Neuroimage 59:2678–2688CrossRefPubMedGoogle Scholar
  18. 18.
    Bullmore ET, Suckling J, Overmeyer S, Rabe-Hesketh S, Taylor E, Brammer MJ (1999) Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain. IEEE Trans Med Imaging 18:32–42CrossRefPubMedGoogle Scholar
  19. 19.
    Carpenedo R, Pittaluga A, Cozzi A, Attucci S, Galli A, Raiteri M, Moroni F (2001) Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur J Neurosci 13:2141–2147CrossRefPubMedGoogle Scholar
  20. 20.
    Chaddock CA, Barker GJ, Marshall N, Schulze K, Hall MH, Fern A, Walshe M, Bramon E, Chitnis XA, Murray R, McDonald C (2009) White matter microstructural impairments and genetic liability to familial bipolar I disorder. Br J Psychiatry 194:527–534CrossRefPubMedGoogle Scholar
  21. 21.
    Chiappelli J, Postolache TT, Kochunov P, Rowland LM, Wijtenburg SA, Shukla DK, Tagamets M, Du X, Savransky A, Lowry CA, Can A, Fuchs D, Hong LE (2016) Tryptophan metabolism and white matter integrity in schizophrenia. Neuropsychopharmacology 41(10):2587–2595CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chuang DM (2005) The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci 1053:195–204CrossRefPubMedGoogle Scholar
  23. 23.
    Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, Dunner DL, Renshaw PF (2004) Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 61:450–458CrossRefPubMedGoogle Scholar
  24. 24.
    Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K (2002) Depression: perspectives from affective neuroscience. Annu Rev Psychol 53:545–574CrossRefPubMedGoogle Scholar
  25. 25.
    Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 47:411–418CrossRefPubMedGoogle Scholar
  26. 26.
    Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB (2004) The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology 174:525–529CrossRefPubMedGoogle Scholar
  27. 27.
    Emsell L, Leemans A, Langan C, Van Hecke W, Barker GJ, McCarthy P, Jeurissen B, Sijbers J, Sunaert S, Cannon DM, McDonald C (2013) Limbic and callosal white matter changes in euthymic bipolar I disorder: an advanced diffusion magnetic resonance imaging tractography study. Biol Psychiatry 73:194–201CrossRefPubMedGoogle Scholar
  28. 28.
    Fan LW, Bhatt A, Tien LT, Zheng B, Simpson KL, Lin RC, Cai Z, Kumar P, Pang Y (2014) Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro. J Neurochem 133(4):532–543CrossRefGoogle Scholar
  29. 29.
    Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN (2012) Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. Bipolar Disord 14:478–487CrossRefPubMedGoogle Scholar
  30. 30.
    Guillemin GJ, Kerr SJ, Pemberton LA, Smith DG, Smythe GA, Armati PJ, Brew BJ (2001) IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment. J Interferon Cytokine Res 21:1097–1101CrossRefPubMedGoogle Scholar
  31. 31.
    Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 62:1310–1316CrossRefPubMedGoogle Scholar
  32. 32.
    Herting MM, Maxwell EC, Irvine C, Nagel BJ (2011) The Impact of sex, puberty, and hormones on white matter microstructure in adolescents. Cereb Cortex 22(9):1979–1992CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Heyes MP, Saito K, Major EO, Milstien S, Markey SP, Vickers JH (1993) A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from l-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate. Brain 116(Pt 6):1425–1450CrossRefPubMedGoogle Scholar
  34. 34.
    Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21:7463–7473PubMedGoogle Scholar
  35. 35.
    Hoekstra R, Fekkes D, Loonen AJ, Pepplinkhuizen L, Tuinier S, Verhoeven WM (2006) Bipolar mania and plasma amino acids: increased levels of glycine. Eur Neuropsychopharmacol 16:71–77CrossRefPubMedGoogle Scholar
  36. 36.
    Jenkinson M, Smith S (2001) A global optimisation method for robust affine registration of brain images. Med Image Anal 5:143–156CrossRefPubMedGoogle Scholar
  37. 37.
    Jokinen J, Nordstrom AL, Nordstrom P (2009) CSF 5-HIAA and DST non-suppression–orthogonal biologic risk factors for suicide in male mood disorder inpatients. Psychiatry Res 165:96–102CrossRefPubMedGoogle Scholar
  38. 38.
    Kochunov P, Thompson PM, Lancaster JL, Bartzokis G, Smith S, Coyle T, Royall DR, Laird A, Fox PT (2007) Relationship between white matter fractional anisotropy and other indices of cerebral health in normal aging: tract-based spatial statistics study of aging. Neuroimage 35:478–487CrossRefPubMedGoogle Scholar
  39. 39.
    Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Le Bihan D (2003) Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 4:469–480CrossRefPubMedGoogle Scholar
  41. 41.
    Leklem JE (1971) Quantitative aspects of tryptophan metabolism in humans and other species: a review. Am J Clin Nutr 24:659–672CrossRefPubMedGoogle Scholar
  42. 42.
    Lemonde S, Du L, Bakish D, Hrdina P, Albert PR (2004) Association of the C(1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Psychopharmacology 24:24Google Scholar
  43. 43.
    Lu LH, Zhou XJ, Keedy SK, Reilly JL, Sweeney JA (2011) White matter microstructure in untreated first episode bipolar disorder with psychosis: comparison with schizophrenia. Bipolar Disord 13:604–613CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Mann JJ, Brent DA, Arango V (2001) The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. Neuropsychopharmacology 24:467–477CrossRefPubMedGoogle Scholar
  45. 45.
    Marchi M, Risso F, Viola C, Cavazzani P, Raiteri M (2002) Direct evidence that release-stimulating alpha7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J Neurochem 80:1071–1078CrossRefPubMedGoogle Scholar
  46. 46.
    Matsuo K, Nielsen N, Nicoletti MA, Hatch JP, Monkul ES, Watanabe Y, Zunta-Soares GB, Nery FG, Soares JC (2010) Anterior genu corpus callosum and impulsivity in suicidal patients with bipolar disorder. Neurosci Lett 469:75–80CrossRefPubMedGoogle Scholar
  47. 47.
    McIntosh AM, Munoz Maniega S, Lymer GK, McKirdy J, Hall J, Sussmann JE, Bastin ME, Clayden JD, Johnstone EC, Lawrie SM (2008) White matter tractography in bipolar disorder and schizophrenia. Biol Psychiatry 64:1088–1092CrossRefPubMedGoogle Scholar
  48. 48.
    Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130:1007S–1015SCrossRefPubMedGoogle Scholar
  49. 49.
    Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:469–473CrossRefPubMedGoogle Scholar
  50. 50.
    Michael N, Erfurth A, Ohrmann P, Gossling M, Arolt V, Heindel W, Pfleiderer B (2003) Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex. Psychopharmacology 168:344–346CrossRefPubMedGoogle Scholar
  51. 51.
    Miranda AF, Boegman RJ, Beninger RJ, Jhamandas K (1997) Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid. Neuroscience 78:967–975CrossRefPubMedGoogle Scholar
  52. 52.
    Miranda AF, Sutton MA, Beninger RJ, Jhamandas K, Boegman RJ (1999) Quinolinic acid lesion of the nigrostriatal pathway: effect on turning behaviour and protection by elevation of endogenous kynurenic acid in Rattus norvegicus. Neurosci Lett 262:81–84CrossRefPubMedGoogle Scholar
  53. 53.
    Moffett JR, Blinder KL, Venkateshan CN, Namboodiri MA (1998) Differential effects of kynurenine and tryptophan treatment on quinolinate immunoreactivity in rat lymphoid and non-lymphoid organs. Cell Tissue Res 293:525–534CrossRefPubMedGoogle Scholar
  54. 54.
    Muller N, Schwarz MJ (2007) The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 12:988–1000CrossRefPubMedGoogle Scholar
  55. 55.
    Myint AM, Bondy B, Baghai TC, Eser D, Nothdurfter C, Schule C, Zill P, Muller N, Rupprecht R, Schwarz MJ (2013) Tryptophan metabolism and immunogenetics in major depression: a role for interferon-gamma gene. Brain Behav Immun 31:128–133CrossRefPubMedGoogle Scholar
  56. 56.
    Myint AM, Kim YK (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61:519–525CrossRefPubMedGoogle Scholar
  57. 57.
    Myint AM, Kim YK (2013) Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 48:304–313CrossRefPubMedGoogle Scholar
  58. 58.
    Myint AM, Kim YK, Verkerk R, Park SH, Scharpe S, Steinbusch HW, Leonard BE (2007) Tryptophan breakdown pathway in bipolar mania. J Affect Disord 102:65–72CrossRefPubMedGoogle Scholar
  59. 59.
    Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98:143–151CrossRefPubMedGoogle Scholar
  60. 60.
    Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15:1–25CrossRefPubMedGoogle Scholar
  61. 61.
    Nordstrom P, Samuelsson M, Asberg M, Traskman-Bendz L, Aberg-Wistedt A, Nordin C, Bertilsson L (1994) CSF 5-HIAA predicts suicide risk after attempted suicide. Suicide Life Threat Behav 24:1–9PubMedGoogle Scholar
  62. 62.
    Oertel-Knochel V, Reinke B, Alves G, Jurcoane A, Wenzler S, Prvulovic D, Linden D, Knochel C (2014) Frontal white matter alterations are associated with executive cognitive function in euthymic bipolar patients. J Affect Disord 155:223–233CrossRefPubMedGoogle Scholar
  63. 63.
    Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113CrossRefPubMedGoogle Scholar
  64. 64.
    Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247:184–187CrossRefPubMedGoogle Scholar
  65. 65.
    Peters A (2009) The effects of normal aging on myelinated nerve fibers in monkey central nervous system. Front Neuroanat 3:11CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Poletti S, Bollettini I, Mazza E, Locatelli C, Radaelli D, Vai B, Smeraldi E, Colombo C, Benedetti F (2015) Cognitive performances associate with measures of white matter integrity in bipolar disorder. J Affect Disord 174:342–352CrossRefPubMedGoogle Scholar
  67. 67.
    Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirshner MA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ (2000) Allelic Variation in the Serotonin Transporter Promoter Affects Onset of Paroxetine Treatment Response in Late-Life Depression. Neuropsychopharmacology 23:587–590CrossRefPubMedGoogle Scholar
  68. 68.
    Rausch JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM, Ganapathy V, Leibach FH (2002) Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 51:723–732CrossRefPubMedGoogle Scholar
  69. 69.
    Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO, Hawkes DJ (1999) Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 18:712–721CrossRefPubMedGoogle Scholar
  70. 70.
    Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C (1986) The Inventory for Depressive Symptomatology (IDS): preliminary findings. Psychiatry Res 18:65–87CrossRefPubMedGoogle Scholar
  71. 71.
    Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH (1996) The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 26:477–486CrossRefPubMedGoogle Scholar
  72. 72.
    Sakash JB, Byrne GI, Lichtman A, Libby P (2002) Cytokines induce indoleamine 2,3-dioxygenase expression in human atheroma-associated cells: implications for persistent Chlamydophila pneumoniae infection. Infect Immun 70:3959–3961CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Savitz J, Dantzer R, Wurfel BE, Victor TA, Ford BN, Bodurka J, Bellgowan PS, Teague TK, Drevets WC (2014) Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder. Psychoneuroendocrinology 52:200–211CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Saxena K, Tamm L, Walley A, Simmons A, Rollins N, Chia J, Soares JC, Emslie GJ, Fan X, Huang H (2012) A preliminary investigation of corpus callosum and anterior commissure aberrations in aggressive youth with bipolar disorders. J. Child Adolesc Psychopharmacol 22:112–119CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Schmahmann JD, Pandya DN, Wang R, Dai G, D’Arceuil HE, de Crespigny AJ, Wedeen VJ (2007) Association fibre pathways of the brain: parallel observations from diffusion spectrum imaging and autoradiography. Brain 130:630–653CrossRefPubMedGoogle Scholar
  76. 76.
    Schwarcz R, Whetsell WO Jr, Mangano RM (1983) Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219:316–318CrossRefPubMedGoogle Scholar
  77. 77.
    Sher L, Carballo JJ, Grunebaum MF, Burke AK, Zalsman G, Huang YY, Mann JJ, Oquendo MA (2006) A prospective study of the association of cerebrospinal fluid monoamine metabolite levels with lethality of suicide attempts in patients with bipolar disorder. Bipolar Disord 8:543–550CrossRefPubMedGoogle Scholar
  78. 78.
    Smeraldi E, Benedetti F, Zanardi R (2002) Serotonin transporter promoter genotype and illness recurrence in mood disorders. Eur Neuropsychopharmacol 12:73–75CrossRefPubMedGoogle Scholar
  79. 79.
    Smeraldi E, Zanardi R, Benedetti F, Dibella D, Perez J, Catalano M (1998) Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 3:508–511CrossRefPubMedGoogle Scholar
  80. 80.
    Smith SM (2002) Fast robust automated brain extraction. Hum Brain Mapp 17:143–155CrossRefPubMedGoogle Scholar
  81. 81.
    Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487–1505CrossRefPubMedGoogle Scholar
  82. 82.
    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23(Suppl 1):S208–S219CrossRefPubMedGoogle Scholar
  83. 83.
    Smith SM, Johansen-Berg H, Jenkinson M, Rueckert D, Nichols TE, Miller KL, Robson MD, Jones DK, Klein JC, Bartsch AJ, Behrens TE (2007) Acquisition and voxelwise analysis of multi-subject diffusion data with tract-based spatial statistics. Nat Protoc 2:499–503CrossRefPubMedGoogle Scholar
  84. 84.
    Smith SM, Nichols TE (2009) Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage 44:83–98CrossRefPubMedGoogle Scholar
  85. 85.
    Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH (2002) Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17:1429–1436CrossRefPubMedGoogle Scholar
  86. 86.
    Sprooten E, Sussmann JE, Clugston A, Peel A, McKirdy J, Moorhead TW, Anderson S, Shand AJ, Giles S, Bastin ME, Hall J, Johnstone EC, Lawrie SM, McIntosh AM (2011) White matter integrity in individuals at high genetic risk of bipolar disorder. Biol Psychiatry 70:350–356CrossRefPubMedGoogle Scholar
  87. 87.
    Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C, Brisch R, Bielau H, Meyer zu Schwabedissen L, Bogerts B, Myint AM (2011) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation 8:94CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Sun Y (1989) Indoleamine 2,3-dioxygenase–a new antioxidant enzyme. Mater Med Pol 21:244–250PubMedGoogle Scholar
  89. 89.
    Sussmann JE, Lymer GK, McKirdy J, Moorhead TW, Munoz Maniega S, Job D, Hall J, Bastin ME, Johnstone EC, Lawrie SM, McIntosh AM (2009) White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging. Bipolar Disord 11:11–18CrossRefPubMedGoogle Scholar
  90. 90.
    Szalardy L, Zadori D, Toldi J, Fulop F, Klivenyi P, Vecsei L (2012) Manipulating kynurenic acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction. Curr Top Med Chem 12:1797–1806CrossRefPubMedGoogle Scholar
  91. 91.
    Taylor WD, Hsu E, Krishnan KR, MacFall JR (2004) Diffusion tensor imaging: background, potential, and utility in psychiatric research. Biol Psychiatry 55:201–207CrossRefPubMedGoogle Scholar
  92. 92.
    Torgerson CM, Irimia A, Leow AD, Bartzokis G, Moody TD, Jennings RG, Alger JR, Van Horn JD, Altshuler LL (2012) DTI tractography and white matter fiber tract characteristics in euthymic bipolar I patients and healthy control subjects. Brain Imaging BehavGoogle Scholar
  93. 93.
    Varentsova A, Zhang S, Arfanakis K (2014) Development of a high angular resolution diffusion imaging human brain template. Neuroimage 91:177–186CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Versace A, Almeida JR, Quevedo K, Thompson WK, Terwilliger RA, Hassel S, Kupfer DJ, Phillips ML (2010) Right orbitofrontal corticolimbic and left corticocortical white matter connectivity differentiate bipolar and unipolar depression. Biol Psychiatry 68:560–567CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Wheeler-Kingshott CA, Cercignani M (2009) About “axial” and “radial” diffusivities. Magn Reson Med 61:1255–1260CrossRefPubMedGoogle Scholar
  96. 96.
    Woolrich MW, Jbabdi S, Patenaude B, Chappell M, Makni S, Behrens T, Beckmann C, Jenkinson M, Smith SM (2009) Bayesian analysis of neuroimaging data in FSL. Neuroimage 45:S173–S186CrossRefPubMedGoogle Scholar
  97. 97.
    Xie M, Tobin JE, Budde MD, Chen CI, Trinkaus K, Cross AH, McDaniel DP, Song SK, Armstrong RC (2010) Rostrocaudal analysis of corpus callosum demyelination and axon damage across disease stages refines diffusion tensor imaging correlations with pathological features. J Neuropathol Exp Neurol 69:704–716CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Yuksel C, Ongur D (2010) Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 68:785–794CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Zanardi R, Benedetti F, DiBella D, Catalano M, Smeraldi E (2000) Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of serotonin transporter gene. J Clin Psychopharmacol 20:105–107CrossRefPubMedGoogle Scholar
  100. 100.
    Zanetti MV, Jackowski MP, Versace A, Almeida JR, Hassel S, Duran FL, Busatto GF, Kupfer DJ, Phillips ML (2009) State-dependent microstructural white matter changes in bipolar I depression. Eur Arch Psychiatry Clin Neurosci 259:316–328CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Sara Poletti
    • 1
  • Aye Mu Myint
    • 2
  • Gregor Schüetze
    • 3
  • Irene Bollettini
    • 1
  • Elena Mazza
    • 1
  • Doris Grillitsch
    • 4
  • Clara Locatelli
    • 1
  • Markus Schwarz
    • 3
  • Cristina Colombo
    • 1
  • Francesco Benedetti
    • 1
  1. 1.Department of Clinical Neurosciences, San Raffaele Turro, Istituto Scientifico Ospedale San RaffaeleUniversity Vita-Salute San RaffaeleMilanItaly
  2. 2.Psychiatry DepartmentLudwig-Maximilian UniversityMunichGermany
  3. 3.Institute for Laboratory Medicine of Munich UniversityLudwig-Maximilian UniversityMunichGermany
  4. 4.Clinical ChemistryLudwig-Maximilian UniversityMunichGermany

Personalised recommendations