Areas of controversy in neuroprogression in bipolar disorder.
We aimed to review clinical features and biological underpinnings related to neuroprogression in bipolar disorder (BD). Also, we discussed areas of controversy and future research in the field.



We systematically reviewed the extant literature pertaining to neuroprogression and BD by searching PubMed and EMBASE for articles published up to March 2016.



A total of 114 studies were included. Neuroimaging and clinical evidence from cross-sectional and longitudinal studies show that a subset of patients with BD presents a neuroprogressive course with brain changes and unfavorable outcomes. Risk factors associated with these unfavorable outcomes are number of mood episodes, early trauma, and psychiatric and clinical comorbidity.



Illness trajectories are largely variable, and illness progression is not a general rule in BD. The number of manic episodes seems to be the clinical marker more robustly associated with neuroprogression in BD. However, the majority of the evidence came from cross-sectional studies that are prone to bias. Longitudinal studies may help to identify signatures of neuroprogression and integrate findings from the field of neuroimaging, neurocognition, and biomarkers.
Bipolar Disorder Program, Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.|Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
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Passos
Center of Excellence on Mood Disorder, Department of Psychiatry and Behavioral Sciences, The University of Texas Science Center at Houston, Houston, TX, USA.
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Mwangi
Bipolar Disorders Program, Institut d'Investigacions Biomédiques Agustí Pi Sunyer, CIBERSAM, University of Barcelona Hospital Clinic, Barcelona, Catalonia, Spain.
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Vieta
IMPACT Strategic Research Centre, School of Medicine, Faculty of Health, Deakin University, Geelong, VIC, Australia.|Orygen, The National Centre of Excellence in Youth Mental Health and the Centre for Youth Mental Health, the Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, the University of Melbourne, Parkville, VIC, Australia.
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Berk
Bipolar Disorder Program, Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.|Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
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Kapczinski
D001714:Bipolar Disorder / Q000000981:diagnostic imaging / Q000473:pathology / Q000523:psychology*; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D003430:Cross-Sectional Studies; D018450:Disease Progression; D006801:Humans; D008137:Longitudinal Studies; D059906:Neuroimaging / Q000379:methods*; D012307:Risk Factors
bipolar disorder; functional impairment; inflammation; machine learning; neuroprogression; treatment refractoriness