Trends in Psychiatry and Psychotherapy
https://trends.org.br/article/doi/10.1590/2237-6089-2014-0002
Trends in Psychiatry and Psychotherapy
Review Article

Biomarkers and staging of bipolar disorder: a systematic review

Dos biomarcadores ao estadiamento do transtorno bipolar: uma revisão sistemática

Ângela Roda; Inês Chendo; Mauricio Kunz

http://dx.doi.org/10.1590/2237-6089-2014-0002 Trends Psychiatry Psychother, vol.37, n1, p.3-11, 2015
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Abstract

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.

Keywords

Bipolar disorder, neuroimaging changes, neurotrophic factors, inflammation, oxidative stress, staging

Resumo

INTRODUÇÃO:Níveis crescentes de evidência sugerem que o transtorno bipolar (TB) exibe um caráter progressivo, em nível tanto clínico, quanto bioquímico e neuroimagiológico. Este estudo revisa a literatura existente sobre a relação entre biomarcadores específicos e estágios do TB.MÉTODOS:Uma busca extensa da literatura nas bases de dados MEDLINE e PubMed foi conduzida para identificar estudos publicados em inglês e em português utilizando as palavras-chave biomarker (biomarcador), neurotrophic factors (fatores neurotróficos), inflammation (inflamação), oxidative stress (estresse oxidativo), neuroprogression (neuroprogressão) e staging models (modelos de estadiamento), em referência cruzada com o termo bipolar disorder (transtorno bipolar).RESULTADOS:Estudos morfométricos em doentes bipolares mostraram a existência de alterações neuroanatômicas, tais como o alargamento dos ventrículos, a perda de substância cinzenta no hipocampo e no cerebelo, a diminuição do volume de determinadas áreas do córtex pré-frontal e variações no tamanho da amígdala. Além disso, outros estudos apontam para a potencialidade do uso dos valores séricos dos fatores neurotróficos, de mediadores inflamatórios e de estresse oxidativo como biomarcadores do TB.CONCLUSÕES: O conhecimento das alterações neurobiológicas, associadas à progressão e atividade do TB, é fundamental para a identificação de biomarcadores. A incorporação de biomarcadores nos modelos de estadiamento do TB poderá permitir um aperfeiçoamento dos algoritmos terapêuticos, possibilitando a elaboração de esquemas de tratamento mais personalizados e eficazes, com destaque para a importância da intervenção precoce na atenuação da progressão da doença.

Palavras-chave

Transtorno bipolar, alterações neuroimagiológicas, fatores neurotróficos, inflamação, estresse oxidativo, estadiamento

References

Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241-51.

The global burden of disease: 2004 update. 2008.

Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord. 2002;68:167-81.

Kupfer DJ. The increasing medical burden in bipolar disorder. JAMA. 2005;293:2528-30.

Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R. Can bipolar disorder be viewed as a multi-system inflammatory disease?. J Affect Disord. 2012;141:1-10.

Fries GR, Pfaffenseller B, Stertz L, Paz AV, Dargél AA, Kunz M. Staging and neuroprogression in bipolar disorder. Curr Psychiatry Rep. 2012;14:667-75.

Post RM, Fleming J, Kapczinski F. Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res. 2012;46:561-73.

Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35:804-17.

Kraepelin E. Manic-depressive insanity and paranoia. 1899.

Post RM. Mechanisms of illness progression in the recurrent affective disorders. Neurotox Res. 2010;18:256-71.

Ketter TA, Houston JP, Adams DH, Risser RC, Meyers AL, Williamson DJ. 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;67:95-101.

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;156:1264-6.

Scott J1, Paykel E, Morriss R, Bentall R, Kinderman P, Johnson T. Cognitive-behavioural therapy for severe and recurrent bipolar disorders: randomised controlled trial. Br J Psychiatry. 2006;188:313-20.

Martínez-Arán A, Vieta E, Colom F, Torrent C, Sánchez-Moreno J, Reinares M. Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord. 2004;6:224-32.

Martinez-Aran A, Vieta E, Torrent C, Sanchez-Moreno J, Goikolea JM, Salamero M. Functional outcome in bipolar disorder: the role of clinical and cognitive factors. Bipolar Disord. 2007;9:103-13.

Kauer-Sant'Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol. 2009;12:447-58.

Vieta E, Reinares M, Rosa AR. Staging bipolar disorder. Neurotox Res. 2011;19:279-85.

Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89-95.

Teixeira AL, Barbosa IG, Machado-Vieira R, Rizzo LB, Wieck A, Bauer ME. Novel biomarkers for bipolar disorder. Expert Opin Med Diagn. 2012;7:147-59.

Puntmann VO. How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease. Postgrad Med J. 2009;85:538-45.

Schwarz E, Bahn S. The utility of biomarker discovery approaches for the detection of disease mechanisms in psychiatric disorders. Br J Pharmacol. 2008;153(Suppl 1):S133-6.

Frey BN, Andreazza AC, Houenou J, Jamain S, Goldstein BI, Frye MA. Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Aust N Z J Psychiatry. 2013;47:321-32.

Soares JC, Kochunov P, Monkul ES, Nicoletti MA, Brambilla P, Sassi RB. Structural brain changes in bipolar disorder using deformation field morphometry. Neuroreport. 2005;16:541-4.

Strakowski SM, DelBello MP, Zimmerman ME, Getz GE, Mills NP, Ret J. Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. Am J Psychiatry. 2002;159:1841-7.

Moorhead TW, McKirdy J, Sussmann JE, Hall J, Lawrie SM, Johnstone EC. Progressive gray matter loss in patients with bipolar disorder. Biol Psychiatry. 2007;62:894-900.

Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ. MRI study of posterior fossa structures and brain ventricles in bipolar patients. J Psychiatr Res. 2001;35:313-22.

Blumberg HP, Krystal JH, Bansal R, Martin A, Dziura J, Durkin K. Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study. Biol Psychiatry. 2006;59:611-8.

López-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM. Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry. 2002;52:93-100.

Beyer JL, Krishnam KR. Volumetric brain imaging findings in mood disorders. Bipolar Disord. 2002;4:89-104.

Chang K, Karchemskiy A, Barnea-Goraly N, Garrett A, Simeonova DI, Reiss A. Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44:565-73.

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 Disord. 2004;6:43-52.

Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE. Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry. 2011;69:326-35.

Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J. Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry. 1998;55:663-4.

Altshuler LL, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K. An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry. 2000;48:147-62.

Brambilla P, Harenski K, Nicoletti M, Sassi RB, Mallinger AG, Frank E. MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res. 2003;37:287-95.

Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM. Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry. 1999;56:254-60.

Foland LC, Altshuler LL, Sugar CA, Lee AD, Leow AD, Townsend J. Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport. 2008;19:221-4.

Kempton MJ, Geddes JR, Ettinger U, Williams SC, Grasby PM. Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry. 2008;65:1017-32.

Gulseren S, Gurcan M, Gulseren L, Gelal F, Erol A. T2 hyperintensities in bipolar patients and their healthy siblings. Arch Med Res. 2006;37:79-85.

Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci. 2005;6:603-14.

Post RM. Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J Psychiatr Res. 2007;41:979-90.

Magalhães PV, Fries GR, Kapczinski F. [Peripheral markers and the pathophysiology of bipolar disorder]. Rev Psiquiatr Clin. 2012;39:60-7.

Pfaffenseller B1, Fries GR, Wollenhaupt-Aguiar B, Colpo GD, Stertz L, Panizzutti B. Neurotrophins, inflammation and oxidative stress as illness activity biomarkers in bipolar disorder. Expert Rev Neurother. 2013;13:827-42.

Teixeira AL, Barbosa IG, Diniz BS, Kummer A. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med. 2010;4:871-87.

Fernandes BS, Gama CS, Ceresér KM, Yatham LN, Fries GR, Colpo G. 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;45:995-1004.

Lin PY. State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study. Neurosci Lett. 2009;466:139-43.

Fernandes BS, Gama CS, Kauer-Sant'Anna M, Lobato MI, Belmonte-de-Abreu P, Kapczinski F. Serum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis. J Psychiatr Res. 2009;43:1200-4.

Diagnostic and Statistical Manual of Mental Disorders. 2013.

Cunha AB, Frey BN, Andreazza AC, Goi JD, Rosa AR, Gonçalves CA. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett. 2006;398:215-9.

Grande I, Fries GR, Kunz M, Kapczinski F. The role of BDNF as a mediator of neuroplasticity in bipolar disorder. Psychiatry Investig. 2010;7:243-50.

Kapczinski F, Fernandes BS, Kauer-Sant'Anna M, Gama CS, Yatham LN, Berk M. The concept of staging in bipolar disorder: the role of BDNF and TNF-alpha as biomarkers. Acta Neuropsychiatr. 2009;21:272-4.

Tramontina JF, Andreazza AC, Kauer-Sant'anna M, Stertz L, Goi J, Chiarani F. Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neurosci Lett. 2009;452:111-3.

Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, Kauer-Sant'Anna M, Klamt F. Peripheral biomarkers and illness activity in bipolar disorder. J Psychiatr Res. 2011;45:156-61.

Rybakowski JK1, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol. 2010;13:617-22.

Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim Y-, Tsan G. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry. 2002;7:579-93.

Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet. 2002;71:651-5.

Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook EH Jr. Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry. 2004;161:1698-700.

Skibinska M, Hauser J, Czerski PM, Leszczynska-Rodziewicz A, Kosmowska M, Kapelski P. Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. World J Biol Psychiatry. 2004;5:215-20.

Lohoff FW, Sander T, Ferraro TN, Dahl JP, Gallinat J, Berrettini WH. Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2005;139B:51-3.

Green EK, Raybould R, Macgregor S, Hyde S, Young AH, O'Donovan MC. Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case-control study of over 3000 individuals from the UK. Br J Psychiatry. 2006;188:21-5.

Strauss J, Barr CL, George CJ, King N, Shaikh S, Devlin B. Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. Am J Med Genet B Neuropsychiatr Genet. 2004;131B:16-9.

Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T. Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Lett. 2003;337:17-20.

Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology. 2003;48:186-9.

Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study. Biol Psychiatry. 2004;56:376-8.

Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry. 2005;10:208-12.

Walz JC, Andreazza AC, Frey BN, Cacilhas AA, Ceresér KM, Cunha AB. Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder. Neurosci Lett. 2007;415:87-9.

Fernandes BS, Gama CS, Walz JC, Ceresér KM, Fries GR, Colpo G. Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes. J Psychiatr Res. 2010;44:561-5.

Walz JC, Magalhães PV, Giglio LM, Cunha AB, Stertz L, Fries GR. Increased serum neurotrophin-4/5 levels in bipolar disorder. J Psychiatr Res. 2009;43:721-3.

Brietzke E, Kapczinski F. TNF-alpha as a molecular target in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1355-61.

Kim YK, Jung HG, Myint AM, Kim H, Park SH. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord. 2007;104:91-5.

Brietzke E, Stertz L, Fernandes BS, Kauer-Sant'anna M, Mascarenhas M, Escosteguy Vargas A. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord. 2009;116:214-7.

Hamdani N, Doukhan R, Kurtlucan O, Tamouza R, Leboyer M. Immunity, inflammation, and bipolar disorder: diagnostic and therapeutic implications. Curr Psychiatry Rep. 2013;15:387.

Kapczinski F1, Dias VV, Kauer-Sant'Anna M, Brietzke E, Vázquez GH, Vieta E. The potential use of biomarkers as an adjunctive tool for staging bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatr. 2009;33:1366-71.

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;31:952-5.

Drake C, Boutin H, Jones MS, Denes A, McColl BW, Selvarajah JR. Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immun. 2011;25:1113-22.

Evans-Lacko SE, Zeber JE, Gonzalez JM, Olvera RL. Medical comorbidity among youth diagnosed with bipolar disorder in the United States. J Clin Psychiatry. 2009;70:1461-6.

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;70:1078-90.

Halliwell B, Gutteridge JM. Free Radicals in Biology and Medicine. 2007.

Olmez I, Ozyurt H. Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int. 2012;60:208-12.

Andreazza AC, Kauer-Sant'anna M, Frey BN, Bond DJ, Kapczinski F, Young LT. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 2008;111:135-44.

Frey BN, Andreazza AC, Kunz M, Gomes FA, Quevedo J, Salvador M. Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:283-5.

Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res. 2007;41:523-9.

Savas HA, Gergerlioglu HS, Armutcu F, Herken H, Yilmaz HR, Kocoglu E. Elevated serum nitric oxide and superoxide dismutase in euthymic bipolar patients: impact of past episodes. World J Biol Psychiatry. 2006;7:51-5.

Andreazza AC, Kapczinski F, Kauer-Sant'Anna M, Walz JC, Bond DJ, Gonçalves CA. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci. 2009;34:263-71.

Kunz M, Gama CS, Andreazza AC, Salvador M, Ceresér KM, Gomes FA. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1677-81.

Machado-Vieira R, Andreazza AC, Viale CI, Zanatto V, Cereser V Jr, da Silva Vargas R. Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett. 2007;421:33-6.

Raffa M, Barhoumi S, Atig F, Fendri C, Kerkeni A, Mechri A. Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:371-5.

Andreazza AC, Frey BN, Erdtmann B, Salvador M, Rombaldi F, Santin A. DNA damage in bipolar disorder. Psychiatry Res. 2007;153:27-32.

Elvsåshagen T, Vera E, Bøen E, Bratlie J, Andreassen OA, Josefsen D. The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder. J Affect Disord. 2011;135:43-50.

Saretzki G, Von-Zglinicki T. Replicative aging, telomeres, and oxidative stress. Ann N Y Acad Sci. 2002;959:24-9.

Simon NM1, Smoller JW, McNamara KL, Maser RS, Zalta AK, Pollack MH. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry. 2006;60:432-5.

Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I. N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-75.

Magalhães PV, Dean OM, Bush AI, Copolov DL, Malhi GS, Kohlmann K. N-acetylcysteine for major depressive episodes in bipolar disorder. Rev Bras Psiquiatr. 2011;33:374-8.

Khairova R, Pawar R, Salvadore G, Juruena MF, de Sousa RT, Soeiro-de-Souza MG. Effects of lithium on oxidative stress parameters in healthy subjects. Mol Med Report. 2012;5:680-2.

Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, Kauer-Sant'Anna M, Klamt F. A systemic toxicity index developed to assess peripheral changes in mood episodes. Mol Psychiatry. 2010;15:784-6.

Berk M, Berk L, Dodd S, Cotton S, Macneil C, Daglas R. Stage managing bipolar disorder. Bipolar Disord. 2014;16:471-7.

McGorry PD, Purcell R, Hickie IB, Yung AR, Pantelis C, Jackson HJ. Clinical staging: a heuristic model for psychiatry and youth mental health. Med J Aust. 2007;187(7 Suppl):S40-2.

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;100:279-81.

Berk M, Conus P, Lucas N, Hallam K, Malhi GS, Dodd S. Setting the stage: from prodrome to treatment resistance in bipolar disorder. Bipolar Disord. 2007;9:671-8.

Kapczinski F1, Dias VV, Kauer-Sant'Anna M, Frey BN, Grassi-Oliveira R, Colom F. Clinical implications of staging bipolar disorders. Expert Rev Neurother. 2009;9:957-66.

Berk M, Malhi GS, Hallam K, Gama CS, Dodd S, Andreazza AC. Early intervention in bipolar disorders: clinical, biochemical and neuroimaging imperatives. J Affect Disord. 2009;114:1-13.

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