{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T20:29:42Z","timestamp":1768681782530,"version":"3.49.0"},"reference-count":101,"publisher":"FapUNIFESP (SciELO)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Trends Psychiatry Psychother."],"abstract":"<jats:p>INTRODUCTION: A growing body of evidence suggests that bipolar disorder (BD) is a progressive disease according to clinical, biochemical and neuroimaging findings. This study reviewed the literature on the relationship between specific biomarkers and BD stages.METHODS: A comprehensive literature search of MEDLINE and PubMed was conducted to identify studies in English and Portuguese using the keywords biomarker, neurotrophic factors, inflammation, oxidative stress, neuroprogression and staging models cross-referenced with bipolar disorder.RESULTS: Morphometric studies of patients with BD found neuroanatomic abnormalities, such as ventricular enlargement, grey matter loss in the hippocampus and cerebellum, volume decreases in the prefrontal cortex and variations in the size of the amygdala. Other studies demonstrated that serum concentrations of neurotrophic factors, inflammatory mediators and oxidative stress may be used as BD biomarkers.CONCLUSIONS: The analysis of neurobiological changes associated with BD progression and activity may confirm the existence of BD biomarkers, which may be then included in staging models that will lead to improvements in treatment algorithms and more effective, individually tailored treatment regimens. Biomarkers may also be used to define early interventions to control disease progression.<\/jats:p>","DOI":"10.1590\/2237-6089-2014-0002","type":"journal-article","created":{"date-parts":[[2015,1,10]],"date-time":"2015-01-10T19:38:51Z","timestamp":1420918731000},"page":"03-11","source":"Crossref","is-referenced-by-count":38,"title":["Biomarkers and staging of bipolar disorder: a systematic review"],"prefix":"10.1590","volume":"37","author":[{"given":"\u00c2ngela","family":"Roda","sequence":"first","affiliation":[{"name":"Faculdade de Medicina de Lisboa, Portugal"}]},{"given":"In\u00eas","family":"Chendo","sequence":"additional","affiliation":[{"name":"University Clinic, Portugal"}]},{"given":"Mauricio","family":"Kunz","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio Grande do Sul, Brazil"}]}],"member":"530","published-online":{"date-parts":[[2014,12,9]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1001\/archgenpsychiatry.2011.12","article-title":"Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative","volume":"68","author":"Merikangas KR","year":"2011","journal-title":"Arch Gen Psychiatry"},{"key":"ref2","series-title":"The global burden of disease: 2004 update","year":"2008"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0165-0327(01)00377-9","article-title":"Mortality of patients with mood disorders: follow-up over 34-38 years","volume":"68","author":"Angst F","year":"2002","journal-title":"J Affect Disord"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1001\/jama.293.20.2528","article-title":"The increasing medical burden in bipolar disorder","volume":"293","author":"Kupfer DJ","year":"2005","journal-title":"JAMA"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jad.2011.12.049","article-title":"Can bipolar disorder be viewed as a multi-system inflammatory disease?","volume":"141","author":"Leboyer M","year":"2012","journal-title":"J Affect Disord"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s11920-012-0319-2","article-title":"Staging and neuroprogression in bipolar disorder","volume":"14","author":"Fries GR","year":"2012","journal-title":"Curr Psychiatry Rep"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.jpsychires.2012.02.004","article-title":"Neurobiological correlates of illness progression in the recurrent affective disorders","volume":"46","author":"Post RM","year":"2012","journal-title":"J Psychiatr Res"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.neubiorev.2010.10.001","article-title":"Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors","volume":"35","author":"Berk M","year":"2011","journal-title":"Neurosci Biobehav Rev"},{"key":"ref9","series-title":"Manic-depressive insanity and paranoia","author":"Kraepelin E","year":"1899"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1007\/s12640-010-9182-2","article-title":"Mechanisms of illness progression in the recurrent affective disorders","volume":"18","author":"Post RM","year":"2010","journal-title":"Neurotox Res"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.4088\/JCP.v67n0113","article-title":"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","volume":"67","author":"Ketter TA","year":"2006","journal-title":"J Clin Psychiatry"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1176\/ajp.156.8.1264","article-title":"Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania","volume":"156","author":"Swann AC","year":"1999","journal-title":"Am J Psychiatry"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1192\/bjp.188.4.313","article-title":"Cognitive-behavioural therapy for severe and recurrent bipolar disorders: randomised controlled trial","volume":"188","author":"Scott J1","year":"2006","journal-title":"Br J Psychiatry"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1111\/j.1399-5618.2004.00111.x","article-title":"Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome","volume":"6","author":"Mart\u00ednez-Ar\u00e1n A","year":"2004","journal-title":"Bipolar Disord"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1399-5618.2007.00327.x","article-title":"Functional outcome in bipolar disorder: the role of clinical and cognitive factors","volume":"9","author":"Martinez-Aran A","year":"2007","journal-title":"Bipolar Disord"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1017\/S1461145708009310","article-title":"Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder","volume":"12","author":"Kauer-Sant'Anna M","year":"2009","journal-title":"Int J Neuropsychopharmacol"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s12640-010-9197-8","article-title":"Staging bipolar disorder","volume":"19","author":"Vieta E","year":"2011","journal-title":"Neurotox Res"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1067\/mcp.2001.113989","article-title":"Biomarkers and surrogate endpoints: preferred definitions and conceptual framework","volume":"69","year":"2001","journal-title":"Clin Pharmacol Ther"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1517\/17530059.2013.734807","article-title":"Novel biomarkers for bipolar disorder","volume":"7","author":"Teixeira AL","year":"2012","journal-title":"Expert Opin Med Diagn"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1136\/pgmj.2008.073759","article-title":"How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease","volume":"85","author":"Puntmann VO","year":"2009","journal-title":"Postgrad Med J"},{"issue":"Suppl 1","key":"ref21","doi-asserted-by":"crossref","first-page":"S133","DOI":"10.1038\/sj.bjp.0707658","article-title":"The utility of biomarker discovery approaches for the detection of disease mechanisms in psychiatric disorders","volume":"153","author":"Schwarz E","year":"2008","journal-title":"Br J Pharmacol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1177\/0004867413478217","article-title":"Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force","volume":"47","author":"Frey BN","year":"2013","journal-title":"Aust N Z J Psychiatry"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/00001756-200504250-00004","article-title":"Structural brain changes in bipolar disorder using deformation field morphometry","volume":"16","author":"Soares JC","year":"2005","journal-title":"Neuroreport"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1176\/appi.ajp.159.11.1841","article-title":"Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder","volume":"159","author":"Strakowski SM","year":"2002","journal-title":"Am J Psychiatry"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.biopsych.2007.03.005","article-title":"Progressive gray matter loss in patients with bipolar disorder","volume":"62","author":"Moorhead TW","year":"2007","journal-title":"Biol Psychiatry"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0022-3956(01)00036-X","article-title":"MRI study of posterior fossa structures and brain ventricles in bipolar patients","volume":"35","author":"Brambilla P","year":"2001","journal-title":"J Psychiatr Res"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.biopsych.2005.08.031","article-title":"Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study","volume":"59","author":"Blumberg HP","year":"2006","journal-title":"Biol Psychiatry"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0006-3223(02)01350-1","article-title":"Regional prefrontal gray and white matter abnormalities in bipolar disorder","volume":"52","author":"L\u00f3pez-Larson MP","year":"2002","journal-title":"Biol Psychiatry"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1034\/j.1399-5618.2002.01157.x","article-title":"Volumetric brain imaging findings in mood disorders","volume":"4","author":"Beyer JL","year":"2002","journal-title":"Bipolar Disord"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1097\/01.chi.0000159948.75136.0d","article-title":"Reduced amygdalar gray matter volume in familial pediatric bipolar disorder","volume":"44","author":"Chang K","year":"2005","journal-title":"J Am Acad Child Adolesc Psychiatry"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1046\/j.1399-5618.2003.00087.x","article-title":"Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder","volume":"6","author":"DelBello MP","year":"2004","journal-title":"Bipolar Disord"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.biopsych.2010.08.029","article-title":"Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data","volume":"69","author":"Hallahan B","year":"2011","journal-title":"Biol Psychiatry"},{"key":"ref33","first-page":"663","article-title":"Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity","volume":"55","author":"Altshuler LL","year":"1998","journal-title":"Arch Gen Psychiatry"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0006-3223(00)00836-2","article-title":"An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia","volume":"48","author":"Altshuler LL","year":"2000","journal-title":"Biol Psychiatry"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0022-3956(03)00024-4","article-title":"MRI investigation of temporal lobe structures in bipolar patients","volume":"37","author":"Brambilla P","year":"2003","journal-title":"J Psychiatr Res"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1001\/archpsyc.56.3.254","article-title":"Brain magnetic resonance imaging of structural abnormalities in bipolar disorder","volume":"56","author":"Strakowski SM","year":"1999","journal-title":"Arch Gen Psychiatry"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/WNR.0b013e3282f48108","article-title":"Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium","volume":"19","author":"Foland LC","year":"2008","journal-title":"Neuroreport"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1001\/archpsyc.65.9.1017","article-title":"Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder","volume":"65","author":"Kempton MJ","year":"2008","journal-title":"Arch Gen Psychiatry"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.arcmed.2005.04.009","article-title":"T2 hyperintensities in bipolar patients and their healthy siblings","volume":"37","author":"Gulseren S","year":"2006","journal-title":"Arch Med Res"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nrn1726","article-title":"The yin and yang of neurotrophin action","volume":"6","author":"Lu B","year":"2005","journal-title":"Nat Rev Neurosci"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.jpsychires.2006.09.009","article-title":"Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications","volume":"41","author":"Post RM","year":"2007","journal-title":"J Psychiatr Res"},{"key":"ref42","first-page":"60","article-title":"[Peripheral markers and the pathophysiology of bipolar disorder]","volume":"39","author":"Magalh\u00e3es PV","year":"2012","journal-title":"Rev Psiquiatr Clin"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1586\/14737175.2013.811981","article-title":"Neurotrophins, inflammation and oxidative stress as illness activity biomarkers in bipolar disorder","volume":"13","author":"Pfaffenseller B1","year":"2013","journal-title":"Expert Rev Neurother"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"871","DOI":"10.2217\/bmm.10.111","article-title":"Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function","volume":"4","author":"Teixeira AL","year":"2010","journal-title":"Biomark Med"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.jpsychires.2011.03.002","article-title":"Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis","volume":"45","author":"Fernandes BS","year":"2011","journal-title":"J Psychiatr Res"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.neulet.2009.09.044","article-title":"State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study","volume":"466","author":"Lin PY","year":"2009","journal-title":"Neurosci Lett"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1016\/j.jpsychires.2009.04.010","article-title":"Serum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis","volume":"43","author":"Fernandes BS","year":"2009","journal-title":"J Psychiatr Res"},{"key":"ref48","series-title":"Diagnostic and Statistical Manual of Mental Disorders","year":"2013","edition":"5th"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.neulet.2005.12.085","article-title":"Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes","volume":"398","author":"Cunha AB","year":"2006","journal-title":"Neurosci Lett"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"243","DOI":"10.4306\/pi.2010.7.4.243","article-title":"The role of BDNF as a mediator of neuroplasticity in bipolar disorder","volume":"7","author":"Grande I","year":"2010","journal-title":"Psychiatry Investig"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/j.1601-5215.2009.00410.x","article-title":"The concept of staging in bipolar disorder: the role of BDNF and TNF-alpha as biomarkers","volume":"21","author":"Kapczinski F","year":"2009","journal-title":"Acta Neuropsychiatr"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.neulet.2009.01.028","article-title":"Brain-derived neurotrophic factor serum levels before and after treatment for acute mania","volume":"452","author":"Tramontina JF","year":"2009","journal-title":"Neurosci Lett"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jpsychires.2010.05.015","article-title":"Peripheral biomarkers and illness activity in bipolar disorder","volume":"45","author":"Kapczinski F","year":"2011","journal-title":"J Psychiatr Res"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1017\/S1461145710000404","article-title":"Excellent lithium responders have normal cognitive functions and plasma BDNF levels","volume":"13","author":"Rybakowski JK1","year":"2010","journal-title":"Int J Neuropsychopharmacol"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/sj.mp.4001058","article-title":"Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor","volume":"7","author":"Sklar P","year":"2002","journal-title":"Mol Psychiatry"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1086\/342288","article-title":"The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study","volume":"71","author":"Neves-Pereira M","year":"2002","journal-title":"Am J Hum Genet"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1176\/appi.ajp.161.9.1698","article-title":"Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype","volume":"161","author":"Geller B","year":"2004","journal-title":"Am J Psychiatry"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1080\/15622970410029936","article-title":"Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder","volume":"5","author":"Skibinska M","year":"2004","journal-title":"World J Biol Psychiatry"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/ajmg.b.30215","article-title":"Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder","volume":"139B","author":"Lohoff FW","year":"2005","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1192\/bjp.bp.105.009969","article-title":"Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case-control study of over 3000 individuals from the UK","volume":"188","author":"Green EK","year":"2006","journal-title":"Br J Psychiatry"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/ajmg.b.30041","article-title":"Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder","volume":"131B","author":"Strauss J","year":"2004","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0304-3940(02)01292-2","article-title":"Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder","volume":"337","author":"Nakata K","year":"2003","journal-title":"Neurosci Lett"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000074636","article-title":"Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior","volume":"48","author":"Hong CJ","year":"2003","journal-title":"Neuropsychobiology"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.biopsych.2004.06.017","article-title":"No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study","volume":"56","author":"Kunugi H","year":"2004","journal-title":"Biol Psychiatry"},{"key":"ref65","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/sj.mp.4001575","article-title":"BDNF gene is a risk factor for schizophrenia in a Scottish population","volume":"10","author":"Neves-Pereira M","year":"2005","journal-title":"Mol Psychiatry"},{"key":"ref66","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.neulet.2007.01.002","article-title":"Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder","volume":"415","author":"Walz JC","year":"2007","journal-title":"Neurosci Lett"},{"key":"ref67","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.jpsychires.2009.11.020","article-title":"Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes","volume":"44","author":"Fernandes BS","year":"2010","journal-title":"J Psychiatr Res"},{"key":"ref68","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.jpsychires.2008.10.005","article-title":"Increased serum neurotrophin-4\/5 levels in bipolar disorder","volume":"43","author":"Walz JC","year":"2009","journal-title":"J Psychiatr Res"},{"key":"ref69","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/j.pnpbp.2008.01.006","article-title":"TNF-alpha as a molecular target in bipolar disorder","volume":"32","author":"Brietzke E","year":"2008","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"ref70","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jad.2007.02.018","article-title":"Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder","volume":"104","author":"Kim YK","year":"2007","journal-title":"J Affect Disord"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.jad.2008.12.001","article-title":"Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder","volume":"116","author":"Brietzke E","year":"2009","journal-title":"J Affect Disord"},{"key":"ref72","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s11920-013-0387-y","article-title":"Immunity, inflammation, and bipolar disorder: diagnostic and therapeutic implications","volume":"15","author":"Hamdani N","year":"2013","journal-title":"Curr Psychiatry Rep"},{"key":"ref73","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/j.pnpbp.2009.07.027","article-title":"The potential use of biomarkers as an adjunctive tool for staging bipolar disorder","volume":"33","author":"Kapczinski F1","year":"2009","journal-title":"Prog Neuropsychopharmacol Biol Psychiatr"},{"key":"ref74","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.pnpbp.2007.02.018","article-title":"Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder","volume":"31","author":"Dickerson F","year":"2007","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"ref75","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.bbi.2011.02.008","article-title":"Brain inflammation is induced by co-morbidities and risk factors for stroke","volume":"25","author":"Drake C","year":"2011","journal-title":"Brain Behav Immun"},{"key":"ref76","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.4088\/JCP.08m04871","article-title":"Medical comorbidity among youth diagnosed with bipolar disorder in the United States","volume":"70","author":"Evans-Lacko SE","year":"2009","journal-title":"J Clin Psychiatry"},{"key":"ref77","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.4088\/JCP.08r04505","article-title":"Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature","volume":"70","author":"Goldstein BI","year":"2009","journal-title":"J Clin Psychiatry"},{"key":"ref78","series-title":"Free Radicals in Biology and Medicine","author":"Halliwell B","year":"2007","edition":"4th"},{"key":"ref79","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.neuint.2011.11.009","article-title":"Reactive oxygen species and ischemic cerebrovascular disease","volume":"60","author":"Olmez I","year":"2012","journal-title":"Neurochem Int"},{"key":"ref80","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jad.2008.04.013","article-title":"Oxidative stress markers in bipolar disorder: a meta-analysis","volume":"111","author":"Andreazza AC","year":"2008","journal-title":"J Affect Disord"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.pnpbp.2006.06.011","article-title":"Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report","volume":"31","author":"Frey BN","year":"2007","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"ref82","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.jpsychires.2006.07.013","article-title":"Serum S100B and antioxidant enzymes in bipolar patients","volume":"41","author":"Andreazza AC","year":"2007","journal-title":"J Psychiatr Res"},{"key":"ref83","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1080\/15622970510029993","article-title":"Elevated serum nitric oxide and superoxide dismutase in euthymic bipolar patients: impact of past episodes","volume":"7","author":"Savas HA","year":"2006","journal-title":"World J Biol Psychiatry"},{"key":"ref84","first-page":"263","article-title":"3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder","volume":"34","author":"Andreazza AC","year":"2009","journal-title":"J Psychiatry Neurosci"},{"key":"ref85","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/j.pnpbp.2008.07.001","article-title":"Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia","volume":"32","author":"Kunz M","year":"2008","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"ref86","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neulet.2007.05.016","article-title":"Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects","volume":"421","author":"Machado-Vieira R","year":"2007","journal-title":"Neurosci Lett"},{"key":"ref87","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.pnpbp.2012.07.013","article-title":"Reduced antioxidant defense systems in schizophrenia and bipolar I disorder","volume":"39","author":"Raffa M","year":"2012","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"ref88","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.psychres.2006.03.025","article-title":"DNA damage in bipolar disorder","volume":"153","author":"Andreazza AC","year":"2007","journal-title":"Psychiatry Res"},{"key":"ref89","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jad.2011.08.006","article-title":"The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder","volume":"135","author":"Elvs\u00e5shagen T","year":"2011","journal-title":"J Affect Disord"},{"key":"ref90","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1749-6632.2002.tb02079.x","article-title":"Replicative aging, telomeres, and oxidative stress","volume":"959","author":"Saretzki G","year":"2002","journal-title":"Ann N Y Acad Sci"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.biopsych.2006.02.004","article-title":"Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging","volume":"60","author":"Simon NM1","year":"2006","journal-title":"Biol Psychiatry"},{"key":"ref92","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.biopsych.2008.04.022","article-title":"N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial","volume":"64","author":"Berk M","year":"2008","journal-title":"Biol Psychiatry"},{"key":"ref93","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1590\/S1516-44462011000400011","article-title":"N-acetylcysteine for major depressive episodes in bipolar disorder","volume":"33","author":"Magalh\u00e3es PV","year":"2011","journal-title":"Rev Bras Psiquiatr"},{"key":"ref94","first-page":"680","article-title":"Effects of lithium on oxidative stress parameters in healthy subjects","volume":"5","author":"Khairova R","year":"2012","journal-title":"Mol Med Report"},{"key":"ref95","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1038\/mp.2009.112","article-title":"A systemic toxicity index developed to assess peripheral changes in mood episodes","volume":"15","author":"Kapczinski F","year":"2010","journal-title":"Mol Psychiatry"},{"key":"ref96","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/bdi.12099","article-title":"Stage managing bipolar disorder","volume":"16","author":"Berk M","year":"2014","journal-title":"Bipolar Disord"},{"issue":"7 Suppl","key":"ref97","first-page":"S40","article-title":"Clinical staging: a heuristic model for psychiatry and youth mental health","volume":"187","author":"McGorry PD","year":"2007","journal-title":"Med J Aust"},{"key":"ref98","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.jad.2007.03.007","article-title":"The potential utility of a staging model as a course specifier: a bipolar disorder perspective","volume":"100","author":"Berk M","year":"2007","journal-title":"J Affect Disord"},{"key":"ref99","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1111\/j.1399-5618.2007.00484.x","article-title":"Setting the stage: from prodrome to treatment resistance in bipolar disorder","volume":"9","author":"Berk M","year":"2007","journal-title":"Bipolar Disord"},{"key":"ref100","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1586\/ern.09.31","article-title":"Clinical implications of staging bipolar disorders","volume":"9","author":"Kapczinski F1","year":"2009","journal-title":"Expert Rev Neurother"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jad.2008.08.011","article-title":"Early intervention in bipolar disorders: clinical, biochemical and neuroimaging imperatives","volume":"114","author":"Berk M","year":"2009","journal-title":"J Affect Disord"}],"container-title":["Trends in Psychiatry and Psychotherapy"],"original-title":[],"link":[{"URL":"http:\/\/www.scielo.br\/pdf\/trends\/v37n1\/2237-6089-trends-2237-6089-2014-0002.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T19:42:44Z","timestamp":1690832564000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.scielo.br\/scielo.php?script=sci_arttext&pid=S2237-60892015000100003&lng=en&tlng=en"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,9]]},"references-count":101,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,3]]}},"alternative-id":["S2237-60892015000100003"],"URL":"https:\/\/doi.org\/10.1590\/2237-6089-2014-0002","relation":{},"ISSN":["2238-0019","2237-6089"],"issn-type":[{"value":"2238-0019","type":"electronic"},{"value":"2237-6089","type":"print"}],"subject":[],"published":{"date-parts":[[2014,12,9]]}}}