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The Bipolar Illness Onset study: research protocol for the BIO cohort study
  1. Lars Vedel Kessing1,2,
  2. Klaus Munkholm1,
  3. Maria Faurholt-Jepsen1,
  4. Kamilla Woznica Miskowiak1,2,
  5. Lars Bo Nielsen2,3,
  6. Ruth Frikke-Schmidt2,3,
  7. Claus Ekstrøm4,
  8. Ole Winther5,6,
  9. Bente Klarlund Pedersen7,
  10. Henrik Enghusen Poulsen8,
  11. Roger S McIntyre9,
  12. Flavio Kapczinski10,
  13. Wagner F Gattaz11,
  14. Jakob Bardram5,
  15. Mads Frost12,
  16. Oscar Mayora13,
  17. Gitte Moos Knudsen14,
  18. Mary Phillips15,
  19. Maj Vinberg1,3
  1. 1 Department of Psychiatry, Psychiatric Center Copenhagen, Copenhagen, Denmark
  2. 2 Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  3. 3 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
  4. 4 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
  5. 5 Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kongens Lyngby, Denmark
  6. 6 Gene Regulation Bioinformatics at the Bioinformatics Centre, Department of Biology/BRIC, University of Copenhagen, Copenhagen, Denmark
  7. 7 The Centre of Inflammation and Metabolism at Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
  8. 8 Laboratory of Clinical Pharmacology, Rigshospitalet, Copenhagen, Denmark
  9. 9 Department of Psychiatry and Pharmacology, University of Toronto, Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
  10. 10 McMaster University, Hamilton, Ontario, Canada
  11. 11 Department and Institute of Psychiatry, and Laboratory of Neuroscience (LIM27), University of São Paulo Medical School, São Paulo, Brazil
  12. 12 IT University Copenhagen, Copenhagen, Denmark
  13. 13 Create-Net: Center for Research and Telecommunications Experimentation for Networked Communities, Trento, Italy
  14. 14 Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark
  15. 15 Department of Psychiatry, University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Proffesor Lars Vedel Kessing; lars.vedel.kessing{at}


Introduction Bipolar disorder is an often disabling mental illness with a lifetime prevalence of 1%–2%, a high risk of recurrence of manic and depressive episodes, a lifelong elevated risk of suicide and a substantial heritability. The course of illness is frequently characterised by progressive shortening of interepisode intervals with each recurrence and increasing cognitive dysfunction in a subset of individuals with this condition. Clinically, diagnostic boundaries between bipolar disorder and other psychiatric disorders such as unipolar depression are unclear although pharmacological and psychological treatment strategies differ substantially. Patients with bipolar disorder are often misdiagnosed and the mean delay between onset and diagnosis is 5–10 years. Although the risk of relapse of depression and mania is high it is for most patients impossible to predict and consequently prevent upcoming episodes in an individual tailored way. The identification of objective biomarkers can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Accurate diagnosis of bipolar disorder in its early stages could help prevent the long-term detrimental effects of the illness.

The present Bipolar Illness Onset study aims to identify (1) a composite blood-based biomarker, (2) a composite electronic smartphone-based biomarker and (3) a neurocognitive and neuroimaging-based signature for bipolar disorder.

Methods and analysis The study will include 300 patients with newly diagnosed/first-episode bipolar disorder, 200 of their healthy siblings or offspring and 100 healthy individuals without a family history of affective disorder. All participants will be followed longitudinally with repeated blood samples and other biological tissues, self-monitored and automatically generated smartphone data, neuropsychological tests and a subset of the cohort with neuroimaging during a 5 to 10-year study period.

Ethics and dissemination The study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023), and the findings will be widely disseminated at international conferences and meetings including conferences for the International Society for Bipolar Disorders and the World Federation of Societies for Biological Psychiatry and in scientific peer-reviewed papers.

Trial registration number NCT02888262.

  • Depression and mood disorders
  • bipolar disorder
  • smartphone
  • biomarker
  • MRI scanning
  • cognition

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  • Contributors LVK designed the study together with MV, KM, KWM and MFJ. LVK drafted the study protocol and the manuscript. All authors contributed to development of the study protocol and to editing the manuscript and read and approved the final version. KM, LBN, RFS, CE, BKP, HEP, RSM, FK, WFG and MV contributed specifically to BIO-1 on peripheral blood-based biomarkers. MFJ, OW, JB, MF and OM contributed specifically to BIO-2 on smartphone-based electronic biomarkers. KWM, GMK and MP contributed specifically to BIO-3 on neurocognitive and brain imaging signatures. MV contributed specifically to BIO-4 on at risk or prodromal phase of bipolar disorder (in addition to BIO).

  • Funding The study is funded by grants from the Mental Health Services, Capital Region of Denmark, TheDanish Council for Independent Research, Medical Sciences (DFF-4183-00570), Weimans Fund, Markedsmodningsfonden (the Market Development Fund 2015-310), Gangstedfonden (A29594), Helsefonden (16-B-0063), Innovation Fund Denmark (the Innovation Fund, Denmark, 5164-00001B), Copenhagen Center for Health Technology (CACHET), EU H2020 ITN (EU project 722561), Augustinusfonden (16-0083), Lundbeck Foundation (R215-2015-4121).

  • Competing interests LVK has within the preceding three years been a consultant for Lundbeck, AstraZeneca and Sunovion. KWM has received consultancy fees in the past three years from Lundbeck and Allergan. MFJ has been a consultant for Eli-Lilly and Lundbeck. MV has within the preceding three years been a consultant for AstraZeneca and Servier. FK has been a speaker for Ache, Daiichi Sankyoand Janssen. MP is a consultant for Roche Pharmaceuticals. RSM: Advisory boards: Lundbeck, Pfizer, AstraZeneca, Eli-Lilly, Janssen, Ortho Purdue, Johnson & Johnson, Moksha8, Sunovion, Mitsubishi, Takeda, Forest, Otsuka, Bristol-Myers Squibb, Shire. Speaker fees: Lundbeck, Pfizer, AstraZeneca, Eli-Lilly, Janssen Ortho, Purdue, Johnson & Johnson, Moksha8, Sunovion, Mitsubishi, Takeda, Forest, Otsuka, Bristol-Myers Squibb, Shire. Research grants: Lundbeck, Janssen Ortho, Shire, Purdue, AstraZeneca, Pfizer, Otsuka, Allergan. HEP has received a research grant from Boehringer Ingelheim. GMK has received honoraria as Field Editor of the International Journal of Neuropsychopharmacology and as scientific advisor for H Lundbeck A/S. JB and MF are co-founders and shareholders in Monsenso. LBN, RFS and WFG declare no competing interests. The validity of the research cannot be influenced by any of these potential secondary interests (such as financial gain or personal relationship).

  • Patient consent The informed consent form from the Local Ethical Committee in Copenhagen is signed by the participants and the researcher.

  • Ethics approval The study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This paper has been amended since it was published Online First. Owing to a scripting error, some of the publisher names in the references were replaced with 'BMJ Publishing Group'. This only affected the full text version, not the PDF. We have since corrected these errors and the correct publishers have been inserted into the references.