Insulin Resistance and Treatment Nonresponse in Bipolar Depression

Insulin resistance is common in bipolar disorders and may be a driver of both chronic depressive symptoms and treatment nonresponse. Research suggests that insulin resistance is associated with certain structural brain changes, including blood brain barrier leakage, and may lead to neuroprogression of the illness. Importantly, insulin resistance may not be detected through use of conventional laboratory tests, i.e., fasting glucose and glycosylated hemoglobin, but by measuring fasting insulin and glucose in the same blood draw. Reversal of insulin resistance by insulin sensitizers may provide a path out of treatment resistant bipolar depression (TRBD). In a proof-of-concept, pilot, randomized placebo-controlled trial with adjunctive metformin, significant improvements in depression, anxiety, and general functioning were evident. Early data suggest that reversal of insulin resistance in TRBD may also be associated with blood brain barrier repair. Use of metformin earlier, i.e., lower body mass index and lower insulin resistance levels appears to improve chances of conversion to insulin sensitivity. Further study is needed to determine if reversal of insulin resistance with other medications, dietary interventions, and/or lifestyle changes would also lead to improvements in bipolar depression and related symptoms.