Links Between Mixed Depression, Insulin Resistance, Inflammation, and Cognitive Deficits
At the 2019 meeting of the International Society for Bipolar Disorders, researcher Roger McIntyre discussed links between obesity, diabetes, and cardiovascular problems; increased inflammation; and decreased functioning of the neural networks involved in cognition.
He and his colleagues analyzed 121 studies that included empirical research and meta-analyses. McIntyre and colleagues found that patients with higher levels of inflammatory markers have more insulin resistance and cognitive dysfunction. A meta-analysis revealed that the inflammatory markers IL-6, TNF alpha, and CRP were significantly elevated in people with bipolar disorder compared to normal controls, while IL-1B was not.
People with depression who had a few manic traits (mixed depression) were particularly likely to have insulin resistance and elevated levels of pro-inflammatory markers.
People with mixed depression have increases in inflammation and increased incidence of cardiovascular disorder. People experiencing a first episode of mixed depression who are overweight show increased signs of brain aging.
In studies McIntyre and colleagues analyzed, diabetes or pre-diabetes occurred in 50% of depressed patients, and these patients had the greatest amount of cognitive dysfunction.
Treatment
McIntyre noted that taking the antipsychotic drug lurasidone for bipolar depression worked best in both adults and children who had elevated levels of CRP at baseline. The fast-acting antidepressant ketamine also works well in those who show baseline inflammation .
The anti-diabetes drug liraglutide (Victoza, Saxenda) improves mixed depression symptoms and cognition in obesity, diabetes, and mixed depression. Liraglutide belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists or incretin mimetics. They work by increasing insulin release from the pancreas and decreasing excessive glucagon release.
McIntyre now routinely uses liraglutide for cognitive deficits in patients with obesity or diabetes, including patients with mixed depression. It is injected under the skin at 0.6 mg daily, then the dosage is increased to 1.2 mg and then 1.8 mg. Victoza reduces major cardiovascular events in those with type 2 diabetes. The higher-dose Saxenda (3mg) can be used for weight control.
Another anti-diabetes drug, pioglitazine, has also been reported to be helpful in bipolar depression.
McIntyre found that the antibody infliximab, which can be used as an intravenous treatment for chronic inflammation and works by blocking the effects of TNF-alpha, did not improve depression, but did improve cognition.
McIntyre also supports the use of acetyl-L-carnitine, a potential adjunctive treatment that can reverse the insulin resistance that often occurs with obesity and thus could theoretically improve cognition.
McIntyre described preliminary literature suggesting the effectiveness of drugs such as statins, calcium channel blockers, and biguanides such as the diabetes treatment metformin in reducing inflammation.
Bariatric surgery to reduce the size of the stomach was another option discussed by McIntyre. He said the intervention is safe for patients with bipolar disorder and can help them recover cognitive function.
McIntyre noted that offspring of a mother with obesity have decreased response to sensory cues, reward preference, cognitive control, and motor control. Obesity and the inflammation that goes along with it apparently affect offspring via epigenetic mechanisms, meaning obesity may change the structure of inherited DNA (without changing its sequence).
