Glia and immune cell signaling in bipolar disorder: Insights from neuropharmacology and molecular imaging to clinical application

Translational Psychiatry

Volumn 4, Issue , 2014, Pages

  Watkins, C C ^a   Sawa, A ^a   Pomper, M G ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Bipolar disorder; GSK 3 ; Inflammation; Microglia; TSPO; Wnt

Indexed keywords

4 AMINOBUTYRIC ACID; ANTIDEPRESSANT AGENT; C REACTIVE PROTEIN; GAMMA INTERFERON; INTERLEUKIN 2; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; KYNURENINE; LITHIUM ION; MOOD STABILIZER; NEUROTRANSMITTER; REACTIVE NITROGEN SPECIES; SEROTONIN; VALPROIC ACID; WNT PROTEIN; SEROTONIN TRANSPORTER;

BIPOLAR DISORDER; CYTOKINE PRODUCTION; DNA POLYMORPHISM; FUNCTIONAL MAGNETIC RESONANCE IMAGING; FUNCTIONAL NEUROIMAGING; GENETIC DIFFERENCE; GLIA CELL; HERITABILITY; HUMAN; IMMUNOCOMPETENT CELL; INTRACELLULAR SIGNALING; MACROPHAGE; MICROGLIA; MOLECULAR IMAGING; MONOAMINERGIC SYSTEM; NERVE CELL PLASTICITY; NEUROPHARMACOLOGY; NONHUMAN; NORADRENERGIC SYSTEM; PATHOPHYSIOLOGY; POSITRON EMISSION TOMOGRAPHY; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; T LYMPHOCYTE ACTIVATION; TRYPTOPHAN METABOLISM; WNT SIGNALING PATHWAY; BIPOLAR DEPRESSION; CELL ACTIVATION; IN VIVO STUDY; INFLAMMATION; PROTEIN PROTEIN INTERACTION; SIGNAL TRANSDUCTION; TARGET CELL; DRUG EFFECTS; IMMUNOLOGY; METABOLISM; PHYSIOLOGY;

BIPOLAR DISORDER; HUMANS; INFLAMMATION; MICROGLIA; MOLECULAR IMAGING; NEUROPHARMACOLOGY; SIGNAL TRANSDUCTION;

EID: 84892978352     PISSN: None     EISSN: 21583188     Source Type: Journal    
DOI: 10.1038/tp.2013.119     Document Type: Review

References (149)

1. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatr 2005; 62: 617-627. (Pubitemid 40973437)
2. Bartels SJ, Forester B, Miles KM, Joyce T Mental health service use by elderly patients with bipolar disorder and unipolar major depression. Am J Geriatr Psychiatry 2000; 8 : 160-166. (Pubitemid 30226966)
3. Stensland MD, Schultz JF, Frytak JR Depression diagnoses following the identification of bipolar disorder: costly incongruent diagnoses. BMC Psychiatry 2010; 10: 39.
4. Begley CE, Annegers JF, Swann AC, Lewis C, Coan S, Schnapp WB et al. The lifetime cost of bipolar disorder in the US: an estimate for new cases in 1998. PharmacoEconomics 2001; 19(Pt 1): 483-495. (Pubitemid 32488750)
5. Association AP. Clinical Practice Guidelines 2005, http://www.psychiatry. org/ practice/clinical-practice-guidelines. Accessed August 2013.
6. Goodwin FK, Jamison KR Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd edn. Oxford Univeristy Press: Oxford, UK, 2007.
7. Schloesser RJ, Huang J, Klein PS, Manji HK Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 2008; 33: 110-133. (Pubitemid 350191320)
8. Manji HK, Lenox RH The nature of bipolar disorder. J Clin Psychiatry 2000; 61 (Supp 13): 42-57. (Pubitemid 32062305)
9. Ekdahl CT, Kokaia Z, Lindvall O Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 2009; 158: 1021-1029.
10. Kapczinski F, Frey BN, Kauer-Sant'Anna M, Grassi-Oliveira R Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. Exp Rev Neurother 2008; 8: 1101-1113. (Pubitemid 351962077)
11. Koo JW, Duman RS IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 2008; 105: 751-756. (Pubitemid 351171780)
12. Miller AH, Maletic V, Raison CL Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732-741.
13. Blank T, Prinz M Microglia as modulators of cognition and neuropsychiatric disorders. Glia 2013; 61: 62-70.
14. Beumer W, Drexhage RC, De Wit H, Versnel MA, Drexhage HA, Cohen D Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome. Psychoneuroendocrinology 2012; 37: 1901-1911.
15. Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leuk Biol 2012; 92: 959-975.
16. Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen Lvd, Beumer W, Versnel MA et al. The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Exp Rev Neurother 2010; 10: 59-76.
17. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 2004; 161: 217-222. (Pubitemid 38419270)
18. Schloesser RJ, Martinowich K, Manji HK Mood-stabilizing drugs: mechanisms of action. Trends Neurosci 2012; 35: 36-46.
19. Rapaport MH, Manji HK The effects of lithium on ex vivo cytokine production. Biol Psychiatry 2001; 50: 217-224. (Pubitemid 32763100)
20. Kilander MB, Halleskog C, Schulte G Recombinant Wnts differentially activate beta-catenin-dependent and -independent signalling in mouse microglialike cells. Acta Physiol 2011; 203: 363-372.
21. Halleskog C, Schulte G WNT-3A and WNT-5A counteract lipopolysaccharideinduced pro-inflammatory changes in mouse primary microglia. J Neurochem 2013; 125: 803-808.
22. Zarate CA Jr., Singh J, Manji HK Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006; 59: 1006-1020. (Pubitemid 43849653)
23. Wichers MC, Maes M The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci 2004; 29: 11-17. (Pubitemid 38570008)
24. Miller CL, Llenos IC, Cwik M, Walkup J, Weis S Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder. Neurochem Int 2008; 52: 1297-1303.
25. Myint AM, Kim YK, Verkerk R, Park SH, Scharpe S, Steinbusch HW et al. Tryptophan breakdown pathway in bipolar mania. J Affect Dis 2007; 102: 65-72. (Pubitemid 47042175)
26. Munkholm K, Vinberg M, Vedel Kessing L Cytokines in bipolar disorder: a systematic review and meta-analysis. J Affect Dis 2013; 144: 16-27.
27. Miller CL, Llenos IC, Dulay JR, Weis S Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res 2006; 1073-1074: 25-37.
28. Dean B The neurobiology of bipolar disorder: findings using human postmortem central nervous system tissue. Aust N Z J Psychiatry 2004; 38 : 135-140. (Pubitemid 38488923)
29. Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996; 1: 453-460. (Pubitemid 126439785)
30. Bull SJ, Huezo-Diaz P, Binder EB, Cubells JF, Ranjith G, Maddock C et al. Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry 2009; 14: 1095-1104.
31. Felger JC, Lotrich FE. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience 2013; 246: 199-229.
32. Cannon DM, Ichise M, Rollis D, Klaver JM, Gandhi SK, Charney DS et al. Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. Biol Psychiatry 2007; 62: 870-877. (Pubitemid 47488222)
33. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386-389. (Pubitemid 36877077)
34. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005; 62: 529-535. (Pubitemid 40628882)
35. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL et al. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994; 95: 157-162.
36. Collier DA, Arranz MJ, Sham P, Battersby S, Vallada H, Gill P et al. The serotonin transporter is a potential susceptibility factor for bipolar affective disorder. Neuroreport 1996; 7: 1675-1679. (Pubitemid 26332347)
37. Rees M, Norton N, Jones I, McCandless F, Scourfield J, Holmans P et al. Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). Mol Psychiatry 1997; 2: 398-402. (Pubitemid 127702160)
38. Heyes MP, Saito K, Crowley JS, Davis LE, Demitrack MA, Der M et al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and noninflammatory neurological disease. Brain 1992; 115(Pt 5): 1249-1273.
39. Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Dis 2007; 98: 143-151. (Pubitemid 46048912)
40. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC et al. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci USA 2008; 105: 1333-1338. (Pubitemid 351397053)
41. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflam 2011; 8: 94.
42. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004; 61 : 705-713. (Pubitemid 38890805)
43. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A et al. Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 2007; 61: 806-812. (Pubitemid 46330250)
44. Strakowski SM, Adler CM, Holland SK, Mills NP, DelBello MP, Eliassen JC. Abnormal FMRI brain activation in euthymic bipolar disorder patients during a counting Stroop interference task. Am J Psychiatry 2005; 162: 1697-1705. (Pubitemid 41318240)
45. Oquendo MA, Hastings RS, Huang YY, Simpson N, Ogden RT, Hu XZ et al. Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography. Arch Gen Psychiatry 2007; 64: 201-208. (Pubitemid 46220777)
46. Cerullo MA, Fleck DE, Eliassen JC, Smith MS, DelBello MP, Adler CM et al. A longitudinal functional connectivity analysis of the amygdala in bipolar I disorder across mood states. Bipolar Dis 2012; 14: 175-184.
47. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry 2009; 70: 1078-1090.
48. Craddock N, Sklar P. Genetics of bipolar disorder. Lancet 2013; 381: 1654-1662.
49. Ichiyama T, Okada K, Lipton JM, Matsubara T, Hayashi T, Furukawa S. Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. Brain Res 2000; 857: 246-251. (Pubitemid 30107811)
50. Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H et al. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 2007; 149 : 203-212. (Pubitemid 47488650)
51. Nahman S, Belmaker RH, Azab AN. Effects of lithium on lipopolysaccharide- induced inflammation in rat primary glia cells. Innate Immun 2012; 18: 447-458.
52. Knijff EM, Breunis MN, Kupka RW, de Wit HJ, Ruwhof C, Akkerhuis GW et al. An imbalance in the production of IL-1beta and IL-6 by monocytes of bipolar patients: restoration by lithium treatment. Bipolar Dis 2007; 9: 743-753. (Pubitemid 350042410)
53. Boufidou F, Nikolaou C, Alevizos B, Liappas IA, Christodoulou GN. Cytokine production in bipolar affective disorder patients under lithium treatment. J Affect Dis 2004; 82: 309-313. (Pubitemid 39370835)
54. O'Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S et al. Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004; 24 : 6791-6798. (Pubitemid 38993901)
55. Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 2006; 11: 1116-1125. (Pubitemid 44867481)
56. Barrientos RM, Sprunger DB, Campeau S, Higgins EA, Watkins LR, Rudy JW et al. Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist. Neuroscience 2003; 121: 847-853. (Pubitemid 37324583)
57. Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996; 93: 8455-8459. (Pubitemid 26269579)
58. Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ et al. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry 2008; 65: 395-407. (Pubitemid 351519889)
59. Peineau S, Bradley C, Taghibiglou C, Doherty A, Bortolotto ZA, Wang YT et al. The role of GSK-3 in synaptic plasticity. Br J Pharmacol 2008; 153(Suppl 1): S428-S437. (Pubitemid 351341021)
60. Zandi PP, Belmonte PL, Willour VL, Goes FS, Badner JA, Simpson SG et al. Association study of Wnt signaling pathway genes in bipolar disorder. Arch Gen Psychiatry 2008; 65: 785-793. (Pubitemid 351957704)
61. Gould TD, Manji HK. The Wnt signaling pathway in bipolar disorder. Neuroscientist 2002; 8: 497-511.
62. Beasley C, Cotter D, Everall I. An investigation of the Wnt-signalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder. Schizophr Res 2002; 58: 63-67. (Pubitemid 35287284)
63. Prickaerts J, Moechars D, Cryns K, Lenaerts I, van Craenendonck H, Goris I et al. Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania. J Neurosci 2006; 26: 9022-9029. (Pubitemid 44319393)
64. Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK et al. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 2009; 136: 1017-1031.
65. Godbout JP, Johnson RW Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol Allergy Clin North Am 2009; 29: 321-337.
66. Matigian N, Windus L, Smith H, Filippich C, Pantelis C, McGrath J et al. Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway. Mol Psychiatry 2007; 12: 815-825. (Pubitemid 47347793)
67. Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K et al. Wholegenome association study of bipolar disorder. Mol Psychiatry 2008; 13: 558-569. (Pubitemid 351704939)
68. Schulze TG, Buervenich S, Badner JA, Steele CJ, Detera-Wadleigh SD, Dick D et al. Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees. Biol Psychiatry 2004; 56: 18-23. (Pubitemid 38813401)
69. Raybould R, Green EK, MacGregor S, Gordon-Smith K, Heron J, Hyde S et al. Bipolar disorder and polymorphisms in the dysbindin gene (DTNBP1). Biol Psychiatry 2005; 57: 696-701. (Pubitemid 40487912)
70. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34-48. (Pubitemid 36793778)
71. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337-348. (Pubitemid 34800250)
72. Berger J, Moller DE. The mechanisms of action of PPARs. Ann Rev Med 2002; 53: 409-435. (Pubitemid 34177889)
73. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPARalpha, -beta, and -gamma in the adult rat. Endocrinology 1996; 137: 354-366. (Pubitemid 26005011)
74. Iwashita A, Muramatsu Y, Yamazaki T, Muramoto M, Kita Y, Yamazaki S et al. Neuroprotective efficacy of the peroxisome proliferator-activated receptor deltaselective agonists in vitro and in vivo. J Pharmacol Exp Ther 2007; 320: 1087-1096. (Pubitemid 46294065)
75. Goes FS, Sanders LL, Potash JB The genetics of psychotic bipolar disorder. Curr Psychiatry Rep 2008; 10 : 178-189.
76. Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 2007; 6: 219-233. (Pubitemid 46916253)
77. Watkins CC, Endres CJ, Rosenberg PB, Venkadatrii A, Coughlin J, Kassiou M et al. In Vivo PET Imaging of Glial Activation in Normal Aging Annual Meeting of the Society for Neuroscience. New Orleans, LA, 2012.
78. Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immunity 2012; 26: 469-479.
79. Hashioka S, Klegeris A, Monji A, Kato T, Sawada M, McGeer PL et al. Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol 2007; 206 : 33-42. (Pubitemid 46935120)
80. Couch Y, Anthony DC, Dolgov O, Revischin A, Festoff B, Santos AI et al. Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia. Brain Behav Immunity 2013; 29: 136-146.
81. Horikawa H, Kato TA, Mizoguchi Y, Monji A, Seki Y, Ohkuri T et al. Inhibitory effects of SSRIs on IFN-gamma induced microglial activation through the regulation of intracellular calcium. Prog Neuropsychopharmacology Biol Psychiatry 2010; 34: 1306-1316.
82. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Pychiatry 2000; 48: 766-777.
83. Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry 2001; 49: 741-752. (Pubitemid 32452295)
84. Cotter DR, Pariante CM, Everall IP. Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 2001; 55: 585-595. (Pubitemid 32888377)
85. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep 2007; 9: 512-520. (Pubitemid 350284943)
86. Sani G, Napoletano F, Forte AM, Kotzalidis GD, Panaccione I, Porfiri GM et al. The wnt pathway in mood disorders. Curr Neuropharmacol 2013; 10 : 239-253.
87. Halleskog C, Schulte G. Pertussis toxin-sensitive heterotrimeric G(alphai/o) proteins mediate WNT/beta-catenin and WNT/ERK1/2 signaling in mouse primary microglia stimulated with purified WNT-3A. Cell Signal 2013; 25: 822-828.
88. Gallinat J, Bauer M, Heinz A. Genes and neuroimaging: advances in psychiatric research. Neurodegener Dis 2008; 5 277-285. (Pubitemid 351787050)
89. Laruelle M, Slifstein M, Huang Y. Positron emission tomography: imaging and quantification of neurotransporter availability. Methods 2002; 27: 287-299.
90. DelBello MP, Zimmerman ME, Mills NP, Getz GE, Strakowski SM. Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. Bipolar Dis 2004; 6: 43-52. (Pubitemid 38256503)
91. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213: 93-118.
92. Ichimiya T, Suhara T, Sudo Y, Okubo Y, Nakayama K, Nankai M et al. Serotonin transporter binding in patients with mood disorders: a PET study with [11C](+) McN5652. Biol Psychiatry 2002; 51 : 715-722. (Pubitemid 34450807)
93. Savitz J, Drevets WC. Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci Biobehav Rev 2009; 33: 699-771.
94. Smith GS, Kahn A, Sacher J, Rusjan P, van Eimeren T, Flint A et al. Serotonin transporter occupancy and the functional neuroanatomic effects of citalopram in geriatric depression. Am J Geriatr Psychiatry 2011; 19: 1016-1025.
95. Frankle WG, Slifstein M, Gunn RN, Huang Y, Hwang DR, Darr EA et al. Estimation of serotonin transporter parameters with 11C-DASB in healthy humans: reproducibility and comparison of methods. J Nucl Med 2006; 47 : 815-826. (Pubitemid 46768446)
96. Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S. Positron emission tomography quantification of [(11)C]-DASB binding to the human serotonin transporter: modeling strategies. J Cereb Blood Flow Metab 2001; 21: 1342-1353. (Pubitemid 33130946)
97. Ichise M, Liow JS, Lu JQ, Takano A, Model K, Toyama H et al. Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 2003; 23: 1096-1112. (Pubitemid 37082435)
98. Brown AK, George DT, Fujita M, Liow JS, Ichise M, Hibbeln J et al. PET [11C]DASB imaging of serotonin transporters in patients with alcoholism. Alcohol Clin Exp Res 2007; 31: 28-32. (Pubitemid 46025362)
99. Praschak-Rieder N, Wilson AA, Hussey D, Carella A, Wei C, Ginovart N et al. Effects of tryptophan depletion on the serotonin transporter in healthy humans. Biol Psychiatry 2005; 58: 825-830. (Pubitemid 41677421)
100. Hammoud DA, Endres CJ, Hammond E, Uzuner O, Brown A, Nath A et al. Imaging serotonergic transmission with [11C]DASB-PET in depressed and non-depressed patients infected with HIV. NeuroImage 2010; 49: 2588-2595.
101. Parsey RV, Kent JM, Oquendo MA, Richards MC, Pratap M, Cooper TB et al. Acute occupancy of brain serotonin transporter by sertraline as measured by [11C] DASB and positron emission tomography. Biol Psychiatry 2006; 59: 821-828.
102. Reimold M, Batra A, Knobel A, Smolka MN, Zimmer A, Mann K et al. Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study. Mol Psychiatry 2008; 13: 606-613, 557. (Pubitemid 351704938)
103. Meyer JH. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 2007; 32: 86-102. (Pubitemid 46597955)
104. Meyer JH, Houle S, Sagrati S, Carella A, Hussey DF, Ginovart N et al. Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 2004; 61: 1271-1279. (Pubitemid 39602843)
105. Cannon TD, Keller MC. Endophenotypes in the genetic analyses of mental disorders. Ann Rev Clin Psychol 2006; 2: 267-290. (Pubitemid 43799806)
106. Wilson AA, Ginovart N, Hussey D, Meyer J, Houle S. In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography. Nucl Med Biol 2002; 29: 509-515. (Pubitemid 34667112)
107. Bowley MP, Drevets WC, Ongur D, Price JL. Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 2002; 52: 404-412. (Pubitemid 35266731)
108. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 1998; 95: 13290-13295. (Pubitemid 28509564)
109. Drevets WC, Ongur D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry 1998; 3: 220-226, 190-1. (Pubitemid 28266331)
110. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 2006; 27: 402-409. (Pubitemid 44069585)
111. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533-1539. (Pubitemid 47301451)
112. Banati RB. Brain plasticity and microglia: is transsynaptic glial activation in the thalamus after limb denervation linked to cortical plasticity and central sensitisation? J Physiol 2002; 96: 289-299. (Pubitemid 36090367)
113. Banati RB, Myers R, Kreutzberg GW. PK ('peripheral benzodiazepine') - binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3 H]PK11195 binding to activated microglia. J Neurocytol 1997; 26: 77-82. (Pubitemid 27242473)
114. Myers R, Manjil LG, Cullen BM, Price GW, Frackowiak RS, Cremer JE. Macrophage and astrocyte populations in relation to [3 H]PK 11195 binding in rat cerebral cortex following a local ischaemic lesion. J Cereb Blood Flow Metab 1991; 11: 314-322.
115. Cagnin A, Kassiou M, Meikle SR, Banati RB. Positron emission tomography imaging of neuroinflammation. Neurotherapeutics 2007; 4: 443-452. (Pubitemid 46962405)
116. Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A et al. Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med 2007; 48: 158-167. (Pubitemid 47555390)
117. Venneti S, Lopresti BJ, Wiley CA. Molecular imaging of microglia/macrophages in the brain. Glia 2013; 61: 10-23.
118. Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC et al. Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J Neurovirol 2005; 11: 346-355. (Pubitemid 41614514)
119. Boutin H, Chauveau F, Thominiaux C, Gregoire MC, James ML, Trebossen R et al. 11C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J Nucl Med 2007; 48: 573-581. (Pubitemid 47571413)
120. Endres CJ, Pomper MG, James M, Uzuner O, Hammoud DA, Watkins CC et al. Initial Evaluation of 11C-DPA-713, a Novel TSPO PET Ligand, in Humans. J Nucl Med 2009; 50: 1276-1282.
121. Endres CJ, Coughlin JM, Gage KL, Watkins CC, Kassiou M, Pomper MG. Radiation dosimetry and biodistribution of the TSPO ligand 11C-DPA-713 in humans. J Nucl Med 2012; 53: 330-335.
122. Kreisl WC, Fujita M, Fujimura Y, Kimura N, Jenko KJ, Kannan P et al. Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18kDa) in human and monkey: Implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage 2010; 49: 2924-2932.
123. Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC et al. Mixedaffinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 2011; 52: 24-32.
124. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 2012; 32: 1-5.
125. Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL et al. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab 2013; 33: 53-58.
126. Gulyas B, Toth M, Vas A, Shchukin E, Kostulas K, Hillert J et al. Visualising neuroinflammation in post-stroke patients: a comparative PET study with the TSPO molecular imaging biomarkers [11C]PK11195 and [11C]vinpocetine. Curr Radiopharm 2011; 5: 19-28.
127. Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y et al. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [(1)(1)C]DAA1106. Psychiatry Res 2012; 203: 67-74.
128. Fujimura Y, Zoghbi SS, Simeon FG, Taku A, Pike VW, Innis RB et al. Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, (18)F-PBR06. Journal of nuclear medicine: official publication. Soc Nucl Med 2009; 50: 1047-1053.
129. Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease. Brain 2013; 136(Pt 7): 2228-2238.
130. McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003; 60: 497-502. (Pubitemid 36539059)
131. Serretti A, Mandelli L. The genetics of bipolar disorder: genome 'hot regions,' genes, new potential candidates and future directions. Mol Psychiatry 2008; 13 : 742-771. (Pubitemid 352032111)
132. Wong ML, Dong C, Maestre-Mesa J, Licinio J. Polymorphisms in inflammationrelated genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 2008; 13: 800-812.
133. Savitz J, Frank MB, Victor T, Bebak M, Marino JH, Bellgowan PS et al. Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities. Brain Behav Immunity 2012; 31: 161-171.
134. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 2008; 63: 1022-1029.
135. Lotrich FE, Rabinovitz M, Gironda P, Pollock BG. Depression following pegylated interferon-alpha: characteristics and vulnerability. J Psychosom Res 2007; 63: 131-135. (Pubitemid 47088561)
136. Brietzke E, Kapczinski F. TNF-alpha as a molecular target in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1355-1361. (Pubitemid 352033661)
137. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56. (Pubitemid 350295688)
138. Tsai SY, Lee CH, Kuo CJ, Chen CC. A retrospective analysis of risk and protective factors for natural death in bipolar disorder. J Clin Psychiatry 2005; 66: 1586-1591.
139. Otte C, McCaffery J, Ali S, Whooley MA. Association of a serotonin transporter polymorphism (5-HTTLPR) with depression, perceived stress, and norepinephrine in patients with coronary disease: the Heart and Soul Study. Am J Psychiatry 2007; 164: 1379-1384. (Pubitemid 47461138)
140. McIntyre RS, Rasgon NL, Kemp DE, Nguyen HT, Law CW, Taylor VH et al. Metabolic syndrome and major depressive disorder: co-occurrence and pathophysiologic overlap. Curr Diabetes Rep 2009; 9: 51-59.
141. Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev 2007; 65(Pt 2): S253-S259.
142. Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 952-955. (Pubitemid 46660310)
143. Montgomery P, Richardson AJ. Omega-3 fatty acids for bipolar disorder. Cochrane Database Syst Rev 2008: CD005169.
144. Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin- 1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 2006; 31: 2121-2131. (Pubitemid 44413189)
145. Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002; 7 : 468-473. (Pubitemid 34712898)
146. Capuron L, Pagnoni G, Demetrashvili M, Woolwine BJ, Nemeroff CB, Berns GS et al. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 2005; 58: 190-196. (Pubitemid 41112266)
147. Carter CS, Braver TS, Barch DM, Botvinick MM, Noll D, Cohen JD. Anterior cingulate cortex, error detection, and the online monitoring of performance. Science 1998; 280: 747-749. (Pubitemid 28243351)
148. Slavich GM, Way BM, Eisenberger NI, Taylor SE. Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci USA 2010; 107: 14817-14822.
149. Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon- alpha. Biol Psychiatry 2004; 56: 819-824. (Pubitemid 39575454)