This study addresses the need for mechanism-based understanding and diagnosis of bipolar depression. Using dynamic contrast-enhanced MRI we identified extensive blood-brain barrier (BBB) leakage in 28% of bipolar patients (and zero controls). All bipolar patients with extensive BBB leakage also had insulin resistance and worse metabolic, psychiatric and cognitive symptoms. We found depression to be associated with region-specific BBB leakage, with the nucleus accumbens best predicting depression severity. Our findings highlight BBB damage as a mechanism contributing to the dysfunction of depression-associated brain regions, and suggest that insulin resistance increases the risk of extensive BBB leakage.