ABSTRACT
Bipolar disorder (BD) is a devastating and poorly understood illness. Its burden exceeds $202 billion a year in
direct treatment, societal and family costs. With no known cure and limited therapeutic options, 50% of patients
attempt suicide at least once; up to 30% of patients do not respond to first-line treatment - even with the latest
medications and psychosocial therapy - yet bipolar disorder has only received a small fraction of the amount of
research attention that goes into serious non-psychiatric illness. Differentiating BD from major depression is
crucial for understanding BD pathophysiology. Advances in imaging are beginning to offer the first detailed,
reproducible, and reliable data on brain changes in BD and how they progress, but the lack of global initiatives
in bipolar disorder has stalled research. The high cost of data collection - few studies scan more than a hundred
patients - has led to underpowered studies whose findings often fail to replicate, cannot adequately model
confounds, and often lack power to identify factors that modulate disease progression or recovery. Our ENIGMA
Bipolar Initiative offers a new, cost-effective, innovative global approach - a new source of power to unblock this
logjam by merging resources, capital infrastructure and talents of leading BD centers including data from
48 cohorts across the world. ENIGMA’s Global Alliance for Worldwide Imaging Genomics in Bipolar
Disorder - builds on our thriving ENIGMA Consortium. ENIGMA’s approach merges data from tens of thousands
of individuals and “gives us a power we have not had”, and is “breaking the logjam in neuroscience” (New York
Times). The Lancet hailed ENIGMA as “Crowdsourcing meets Neuroscience”. In designing the ENIGMA-Bipolar
initiative, we identified the most productive activities in the ENIGMA Bipolar working group, and organized them
into 3 themes - imaging, genomics, and cross-disorder comparisons. This global initiative tackles key
questions in BD: how does the illness affect the brain? What imaging and genomic biomarkers assist diagnosis,
monitor treatment, and predict outcomes? How do BD genetic susceptibility loci affect the brain? With global
data and expert teams from 15 countries (see Support Letters), we tackle imaging, genomic, and predictive
questions about BD with unprecedented power. Across Brazil, Japan, the US, Canada, Norway, The
Netherlands, Germany, France, Australia, and South Africa - what brain differences do we reproducibly
detect in BD (with structural/diffusion MRI, connectomics and resting state fMRI)? How do they vary across life,
with illness duration, by demographics, in women versus men, by age of onset, subtype and treatment? Using
ENIGMA’s harmonized protocols, we will analyze the largest collection of multisite neuroimaging data in BD -
diverse in age, ethnicity, treatment response - to track disease worldwide. In a new Cross-Disorder partnership
of ENIGMA-BD and MDD, we use ENIGMA’s data-driven models to detect imaging and genomic biomarkers to
distinguish the 2 disorders and identify subtypes. After harmonizing data elements across disorders, we will
create a ranked list of actionable factors that affect prognosis in BD.