Background-To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD.

Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

Type 2 diabetes mellitus (T2DM) damages the brain, especially the hippocampus, and frequently co-occurs with bipolar disorders (BD). Reduced hippocampal volumes are found only in some studies of BD subjects and may thus be secondary to the presence of certain clinical variables. Studying BD patients with abnormal glucose metabolism could help identify preventable risk factors for hippocampal atrophy in BD. We compared brain structure using optimized voxel-based morphometry of 1.5T MRI scans in 33 BD subjects with impaired glucose metabolism (19 with insulin resistance/glucose intolerance (IR/GI), 14 with T2DM), 15 euglycemic BD participants and 11 euglycemic, nonpsychiatric controls. The group of BD patients with IR, GI or T2DM had significantly smaller hippocampal volumes than the euglycemic BD participants (corrected p ¼ 0.02) or euglycemic, nonpsychiatric controls (corrected p ¼ 0.004). Already the BD subjects with IR/GI had smaller hippocampal volumes than euglycemic BD participants (t(32) ¼ À 3.15, p ¼ 0.004). Age was significantly more negatively associated with hippocampal volumes in BD subjects with IR/GI/T2DM than in the euglycemic BD participants (F(2, 44) ¼ 9.96, p ¼ 0.0003). The gray matter reductions in dysglycemic subjects extended to the cerebral cortex, including the insula. In conclusion, this is the first study demonstrating that T2DM or even prediabetes may be risk factors for smaller hippocampal and cortical volumes in BD. Abnormal glucose metabolism may accelerate the age-related decline in hippocampal volumes in BD. These findings raise the possibility that improving diabetes care among BD subjects and intervening already at the level of prediabetes could slow brain aging in BD.

Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.

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