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Current Psychiatry Reports

, Volume 14, Issue 6, pp 667–675 | Cite as

Staging and Neuroprogression in Bipolar Disorder

  • Gabriel Rodrigo Fries
  • Bianca Pfaffenseller
  • Laura Stertz
  • André Vinicius Contri Paz
  • Aroldo Ayub Dargél
  • Maurício Kunz
  • Flávio Kapczinski
Bipolar Disorders (MA Frye, Section Editor)

Abstract

The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression.

Keywords

Bipolar disorder BD Staging Clinical staging model Neuroprogression Cellular resilience Neuroplasticity Biomarkers Allostatic load Treatment Remission Psychiatry 

Notes

Disclosure

G. R. Fries: none; B. Pfaffenseller: none; L. Stertz: none; A. V. C. Paz: none; A. Ayub Dargél: none; M. Kunz: travel/accommodations/meeting expenses reimbursed by Eli Lilly and Company; F. Kapczinski: grants from NARSAD, Stanley Medical Research Institute, CNPq (National Council for Scientific and Technological Development), and CAPES, and payment for lectures including service on speakers bureaus from Eli Lilly and Company, Lundbeck, AstraZeneca, Servier, and Janssen.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Post RM, Fleming J, Kapczinski F. Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res. 2012;46(5):561–73. This is a full review regarding progression of bipolar disorder, including data on clinical aspects, effects of medications and neurobiological findings.PubMedCrossRefGoogle Scholar
  2. 2.
    •• Berk M, Kapczinski F, Andreazza AC, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35(3):804–17. This review discuss the several biological mechanisms responsible for bipolar disorder progression, including oxidative stress, neurotrophic factors, among others.PubMedCrossRefGoogle Scholar
  3. 3.
    Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev. 2008;32(4):675–92.PubMedCrossRefGoogle Scholar
  4. 4.
    • Berk M, Brnabic A, Dodd S, et al. Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. Bipolar Disord. 2011;13(1):87–98. This study employs a staging model to classify the patients and shows that individuals at the earliest stages of illness have a more favourable response to treatment when compared to later stages.PubMedCrossRefGoogle Scholar
  5. 5.
    Kessing LV, Andersen PK, Mortensen PB. Predictors of recurrence in affective disorder. A case register study. J Affect Disord. 1998;49(2):101–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Roy-Byrne P, Post RM, Uhde TW, Porcu T, Davis D. The longitudinal course of recurrent affective illness: life chart data from research patients at the NIMH. Acta Psychiatr Scand Suppl. 1985;317:1–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Ketter TA, Houston JP, Adams DH, et al. Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes. J Clin Psychiatry. 2006;67(1):95–101.PubMedCrossRefGoogle Scholar
  8. 8.
    Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry. 1999;156(8):1264–6.PubMedGoogle Scholar
  9. 9.
    Scott J, Paykel E, Morriss R, et al. Cognitive-behavioural therapy for severe and recurrent bipolar disorders: randomised controlled trial. Br J Psychiatry. 2006;188:313–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Reinares M, Colom F, Rosa AR, et al. The impact of staging bipolar disorder on treatment outcome of family psychoeducation. J Affect Disord. 2010;123(1–3):81–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Matza LS, Rajagopalan KS, Thompson CL, de Lissovoy G. Misdiagnosed patients with bipolar disorder: comorbidities, treatment patterns, and direct treatment costs. J Clin Psychiatry. 2005;66(11):1432–40.PubMedCrossRefGoogle Scholar
  12. 12.
    Rosa AR, González-Ortega I, González-Pinto A, et al. One-year psychosocial functioning in patients in the early vs. late stage of bipolar disorder. Acta Psychiatr Scand. 2012;125(4):335–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Torres IJ, Boudreau VG, Yatham LN. Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr Scand Suppl. 2007;434:17–26.PubMedCrossRefGoogle Scholar
  14. 14.
    Kessing LV, Andersen PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry. 2004;75(12):1662–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Hawton K, Sutton L, Haw C, Sinclair J, Harriss L. Suicide and attempted suicide in bipolar disorder: a systematic review of risk factors. J Clin Psychiatry. 2005;66(6):693–704.PubMedCrossRefGoogle Scholar
  16. 16.
    Goldberg JF, Ernst CL. Features associated with the delayed initiation of mood stabilizers at illness onset in bipolar disorder. J Clin Psychiatry. 2002;63(11):985–91.PubMedCrossRefGoogle Scholar
  17. 17.
    Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry. 1992;149(8):999–1010.PubMedGoogle Scholar
  18. 18.
    Vieta E, Reinares M, Rosa AR. Staging bipolar disorder. Neurotox Res. 2011;19(2):279–85.PubMedCrossRefGoogle Scholar
  19. 19.
    Vieta E, Popovic D, Rosa AR, et al. The clinical implications of cognitive impairment and allostatic load in bipolar disorder. Eur Psychiatry 2012. doi: 10.1016/j.eurpsy.2011.11.007.
  20. 20.
    McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav. 2003;43(1):2–15.PubMedCrossRefGoogle Scholar
  21. 21.
    Strakowski SM, Delbello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry. 2005;10(1):105–16.PubMedCrossRefGoogle Scholar
  22. 22.
    Lyoo IK, Sung YH, Dager SR, et al. Regional cerebral cortical thinning in bipolar disorder. Bipolar Disord. 2006;8(1):65–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry. 2001;49(9):741–52.PubMedCrossRefGoogle Scholar
  24. 24.
    López-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM. Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry. 2002;52(2):93–100.PubMedCrossRefGoogle Scholar
  25. 25.
    Ongür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA. 1998;95(22):13290–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Sassi RB, Brambilla P, Hatch JP, et al. Reduced left anterior cingulate volumes in untreated bipolar patients. Biol Psychiatry. 2004;56(7):467–75.PubMedCrossRefGoogle Scholar
  27. 27.
    Doris A, Belton E, Ebmeier KP, Glabus MF, Marshall I. Reduction of cingulate gray matter density in poor outcome bipolar illness. Psychiatry Res. 2004;130(2):153–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Drevets WC, Price JL, Simpson JR, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386(6627):824–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Bora E, Fornito A, Yücel M, Pantelis C. Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biol Psychiatry. 2010;67(11):1097–105.PubMedCrossRefGoogle Scholar
  30. 30.
    Rosso IM, Killgore WD, Cintron CM, et al. Reduced amygdala volumes in first-episode bipolar disorder and correlation with cerebral white matter. Biol Psychiatry. 2007;61(6):743–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Javadapour A, Malhi GS, Ivanovski B, et al. Hippocampal volumes in adults with bipolar disorder. J Neuropsychiatry Clin Neurosci. 2010;22(1):55–62.PubMedCrossRefGoogle Scholar
  32. 32.
    Berk M, Hallam K, Malhi GS, et al. Evidence and implications for early intervention in bipolar disorder. J Ment Health. 2010;19(2):113–26.PubMedCrossRefGoogle Scholar
  33. 33.
    Mills NP, Delbello MP, Adler CM, Strakowski SM. MRI analysis of cerebellar vermal abnormalities in bipolar disorder. Am J Psychiatry. 2005;162(8):1530–2.PubMedCrossRefGoogle Scholar
  34. 34.
    Hwang J, Lyoo IK, Dager SR, et al. Basal ganglia shape alterations in bipolar disorder. Am J Psychiatry. 2006;163(2):276–85.PubMedCrossRefGoogle Scholar
  35. 35.
    Strakowski SM, DelBello MP, Sax KW, et al. Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry. 1999;56(3):254–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Atmaca M, Ozdemir H, Yildirim H. Corpus callosum areas in first-episode patients with bipolar disorder. Psychol Med. 2007;37(5):699–704.PubMedCrossRefGoogle Scholar
  37. 37.
    Barnea-Goraly N, Chang KD, Karchemskiy A, Howe ME, Reiss AL. Limbic and corpus callosum aberrations in adolescents with bipolar disorder: a tract-based spatial statistics analysis. Biol Psychiatry. 2009;66(3):238–44.PubMedCrossRefGoogle Scholar
  38. 38.
    Brambilla P, Nicoletti M, Sassi RB, et al. Corpus callosum signal intensity in patients with bipolar and unipolar disorder. J Neurol Neurosurg Psychiatry. 2004;75(2):221–5.PubMedGoogle Scholar
  39. 39.
    Moorhead TW, McKirdy J, Sussmann JE, et al. Progressive gray matter loss in patients with bipolar disorder. Biol Psychiatry. 2007;62(8):894–900.PubMedCrossRefGoogle Scholar
  40. 40.
    Frey BN, Zunta-Soares GB, Caetano SC, et al. Illness duration and total brain gray matter in bipolar disorder: evidence for neurodegeneration? Eur Neuropsychopharmacol. 2008;18(10):717–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Strakowski SM, DelBello MP, Zimmerman ME, et al. Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. Am J Psychiatry. 2002;159(11):1841–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Rajkowska G. Cell pathology in bipolar disorder. Bipolar Disord. 2002;4(2):105–16.PubMedCrossRefGoogle Scholar
  43. 43.
    Hunsberger JG, Austin DR, Chen G, Manji HK. Cellular mechanisms underlying affective resiliency: the role of glucocorticoid receptor- and mitochondrially-mediated plasticity. Brain Res. 2009;1293:76–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Schloesser RJ, Huang J, Klein PS, Manji HK. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology. 2008;33(1):110–33.PubMedCrossRefGoogle Scholar
  45. 45.
    Kato T. Molecular neurobiology of bipolar disorder: a disease of 'mood-stabilizing neurons'? Trends Neurosci. 2008;31(10):495–503.PubMedCrossRefGoogle Scholar
  46. 46.
    Perova T, Wasserman MJ, Li PP, Warsh JJ. Hyperactive intracellular calcium dynamics in B lymphoblasts from patients with bipolar I disorder. Int J Neuropsychopharmacol. 2008;11(2):185–96.PubMedCrossRefGoogle Scholar
  47. 47.
    McCurdy RD, Féron F, Perry C, et al. Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophr Res. 2006;82(2–3):163–73.PubMedCrossRefGoogle Scholar
  48. 48.
    Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry. 2005;10(10):900–19.PubMedCrossRefGoogle Scholar
  49. 49.
    So J, Warsh JJ, Li PP. Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder. Biol Psychiatry. 2007;62(2):141–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Hayashi A, Kasahara T, Kametani M, et al. Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder. Int J Neuropsychopharmacol. 2009;12(1):33–43.PubMedCrossRefGoogle Scholar
  51. 51.
    •• Manji H, Kato T, Di Prospero NA, et al. Impaired mitochondrial function in psychiatric disorders. Nat Rev Neurosci. 2012;13(5):293–307. This study reviews data on mitochondrial function in psychiatric disorders, including clinical and preclinical data.PubMedGoogle Scholar
  52. 52.
    • Du J, Wang Y, Hunter R, et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc Natl Acad Sci USA. 2009;106(9):3543–8. This study shows that glucocorticoids have a biphasic effect on mitochondrial functions, relating chronic stress to reduced mitochondrial membrane potential, calcium holding capacity and oxygen consumption.PubMedCrossRefGoogle Scholar
  53. 53.
    Gong Y, Chai Y, Ding JH, Sun XL, Hu G. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci Lett. 2011;488(1):76–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Daban C, Vieta E, Mackin P, Young AH. Hypothalamic-pituitary-adrenal axis and bipolar disorder. Psychiatr Clin North Am. 2005;28(2):469–80.PubMedCrossRefGoogle Scholar
  55. 55.
    Benes FM, Matzilevich D, Burke RE, Walsh J. The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Mol Psychiatry. 2006;11(3):241–51.PubMedCrossRefGoogle Scholar
  56. 56.
    Eastwood SL, Harrison PJ. Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Res Bull. 2001;55(5):569–78.PubMedCrossRefGoogle Scholar
  57. 57.
    Pfaffenseller B. Disfunção na Resposta ao Estresse do Retículo Endoplasmático em linfócitos de pacientes com Transtorno de Humor Bipolar. Dissertation. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2012.Google Scholar
  58. 58.
    Bachmann RF, Schloesser RJ, Gould TD, Manji HK. Mood stabilizers target cellular plasticity and resilience cascades: implications for the development of novel therapeutics. Mol Neurobiol. 2005;32(2):173–202.PubMedCrossRefGoogle Scholar
  59. 59.
    Kim HW, Rapoport SI, Rao JS. Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Neurobiol Dis. 2010;37(3):596–603.PubMedCrossRefGoogle Scholar
  60. 60.
    Fernandes BS, Gama CS, Ceresér KM, et al. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res. 2011;45(8):995–1004.PubMedCrossRefGoogle Scholar
  61. 61.
    Walz JC, Andreazza AC, Frey BN, et al. Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder. Neurosci Lett. 2007;415(1):87–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Walz JC, Magalhães PV, Giglio LM, et al. Increased serum neurotrophin-4/5 levels in bipolar disorder. J Psychiatr Res. 2009;43(7):721–3.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosa AR, Frey BN, Andreazza AC, et al. Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder. Neurosci Lett. 2006;407(2):146–50.PubMedCrossRefGoogle Scholar
  64. 64.
    Kapczinski F, Dal-Pizzol F, Teixeira AL, et al. Peripheral biomarkers and illness activity in bipolar disorder. J Psychiatr Res. 2011;45(2):156–61.PubMedCrossRefGoogle Scholar
  65. 65.
    Andreazza AC, Kapczinski F, Kauer-Sant'Anna M, et al. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci. 2009;34(4):263–71.PubMedGoogle Scholar
  66. 66.
    Kauer-Sant'Anna M, Kapczinski F, Andreazza AC, et al. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol. 2009;12(4):447–58.PubMedCrossRefGoogle Scholar
  67. 67.
    Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57(10):925–35.PubMedCrossRefGoogle Scholar
  68. 68.
    Grande I, Fries GR, Kunz M, Kapczinski F. The role of BDNF as a mediator of neuroplasticity in bipolar disorder. Psychiatry Investig. 2010;7(4):243–50.PubMedCrossRefGoogle Scholar
  69. 69.
    Young LT. Neuroprotective effects of antidepressant and mood stabilizing drugs. J Psychiatry Neurosci. 2002;27(1):8–9.PubMedGoogle Scholar
  70. 70.
    Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5(11):845–56.PubMedCrossRefGoogle Scholar
  71. 71.
    Barbosa IG, Huguet RB, Mendonça VA, et al. Increased plasma levels of brain-derived neurotrophic factor in patients with long-term bipolar disorder. Neurosci Lett. 2010;475(2):95–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Barbosa IG, Rocha NP, Huguet RB, et al. Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers. J Affect Disord. 2012;137(1–3):151–5.PubMedCrossRefGoogle Scholar
  73. 73.
    Lin PY. State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study. Neurosci Lett. 2009;466(3):139–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Magalhães PV, Jansen K, Pinheiro RT, et al. A nested population-based case-control study on peripheral inflammation markers and brainderived neurotrophic factor in early-stage mood disorders. Istambul: Presented at the 5th Biennial Conference of the International Society for Bipolar Disorders; 2012.Google Scholar
  75. 75.
    Hope S, Dieset I, Agartz I, et al. Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia. J Psychiatr Res. 2011;45(12):1608–16.PubMedCrossRefGoogle Scholar
  76. 76.
    Tsai SY, Chung KH, Wu JY, et al. Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord. 2012;136(1–2):110–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Barbosa IG, Huguet RB, Mendonça VA, et al. Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2011;261(2):139–43.PubMedCrossRefGoogle Scholar
  78. 78.
    Kunz M, Ceresér KM, Goi PD, et al. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr. 2011;33(3):268–74.PubMedCrossRefGoogle Scholar
  79. 79.
    Söderlund J, Olsson SK, Samuelsson M, et al. Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder. J Psychiatry Neurosci. 2011;36(2):114–8.PubMedGoogle Scholar
  80. 80.
    Barbosa IG, Rocha NP, Bauer ME, et al. Chemokines in bipolar disorder: Trait or state? Eur Arch Psychiatry Clin Neurosci. 2012. doi: 10.1007/s00406-012-0327-6.
  81. 81.
    Herberth M, Koethe D, Levin Y, et al. Peripheral profiling analysis for bipolar disorder reveals markers associated with reduced cell survival. Proteomics. 2011;11(1):94–105.PubMedCrossRefGoogle Scholar
  82. 82.
    Kato T. Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications. CNS Drugs. 2007;21(1):1–11.PubMedCrossRefGoogle Scholar
  83. 83.
    Regenold WT, Phatak P, Marano CM, et al. Elevated cerebrospinal fluid lactate concentrations in patients with bipolar disorder and schizophrenia: implications for the mitochondrial dysfunction hypothesis. Biol Psychiatry. 2009;65(6):489–94.PubMedCrossRefGoogle Scholar
  84. 84.
    Halliwell B. Free radicals and antioxidants: updating a personal view. Nutr Rev. 2012;70(5):257–65.PubMedCrossRefGoogle Scholar
  85. 85.
    Magalhães PV, Jansen K, Pinheiro RT, et al. Peripheral oxidative damage in early-stage mood disorders: a nested population-based case-control study. Int J Neuropsychopharmacol. 2011;19:1–8.Google Scholar
  86. 86.
    Andreazza AC, Kauer-Sant'anna M, Frey BN, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 2008;111(2–3):135–44.PubMedCrossRefGoogle Scholar
  87. 87.
    Kunz M, Gama CS, Andreazza AC, et al. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(7):1677–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Yumru M, Savas HA, Kalenderoglu A, et al. Oxidative imbalance in bipolar disorder subtypes: a comparative study. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(6):1070–4.PubMedCrossRefGoogle Scholar
  89. 89.
    Simon NM, Smoller JW, McNamara KL, et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry. 2006;60(5):432–5.PubMedCrossRefGoogle Scholar
  90. 90.
    Elvsåshagen T, Vera E, Bøen E, et al. The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder. J Affect Disord. 2011;135(1–3):43–50.PubMedCrossRefGoogle Scholar
  91. 91.
    Berk M, Hallam KT, McGorry PD. The potential utility of a staging model as a course specifier: a bipolar disorder perspective. J Affect Disord. 2007;100(1–3):279–81.PubMedCrossRefGoogle Scholar
  92. 92.
    Kapczinski F, Dias VV, Kauer-Sant'Anna M, et al. Clinical implications of a staging model for bipolar disorders. Expert Rev Neurother. 2009;9(7):957–66.PubMedCrossRefGoogle Scholar
  93. 93.
    McGorry PD, Purcell R, Hickie IB, et al. Clinical staging: a heuristic model for psychiatry and youth mental health. Med J Aust. 2007;187(7 Suppl):S40–2.PubMedGoogle Scholar
  94. 94.
    Magalhães PV, Dodd S, Nierenberg AA, Berk M. Cumulative morbidity and prognostic staging of illness in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Australian & New Zealand Journal of Psychiatry. Aust N Z J Psychiatry. 2012. doi: 10.1177/0004867412460593.
  95. 95.
    Magalhães PV, Kapczinski F, Nierenberg AA, Deckersbach T, Weisinger D, Dodd S, Berk M. Illness burden and medical comorbidity in the Systematic Treatment Enhancement Program for Bipolar Disorder. Acta Psychiatr Scand. 2012;125(4):303–308.PubMedCrossRefGoogle Scholar
  96. 96.
    Reinares M, Papachristou E, Harvey P, Mar Bonnín C, Sánchez-Moreno J, Torrent C, Ayuso-Mateos JL, Ploubidis GB, Vieta E, Frangou S. Towards a clinical staging for bipolar disorder: Defining patient subtypes based on functional outcome. J Affect Disord. doi: 10.1016/j.jad.2012.06.005.
  97. 97.
    McGorry PD. Staging in neuropsychiatry: a heuristic model for understanding, prevention and treatment. Neurotox Res. 2010;18(3–4):244–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Gabriel Rodrigo Fries
    • 1
    • 2
  • Bianca Pfaffenseller
    • 1
    • 2
  • Laura Stertz
    • 1
    • 2
  • André Vinicius Contri Paz
    • 1
  • Aroldo Ayub Dargél
    • 1
    • 3
  • Maurício Kunz
    • 1
    • 3
  • Flávio Kapczinski
    • 1
    • 2
    • 3
  1. 1.Laboratory of Molecular Psychiatry, Centro de Pesquisas ExperimentaisHospital de Clínicas de Porto Alegre, and INCT for Translational MedicinePorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em Ciências Biológicas: BioquímicaUniversidade Federal do Rio Grande do Sul, UFRGSPorto AlegreBrazil
  3. 3.Programa de Pós-Graduação em Medicina: PsiquiatriaUniversidade Federal do Rio Grande do Sul, UFRGSPorto AlegreBrazil

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