Exercise and Ketamine for Treatment-Resistant Depression

Exercise and depression

Studies have proposed a possible dose-response relationship between exercise and depression. Essentially, active individuals are generally less likely to develop depression. More recent studies have found an interesting qualification that might help to explain how exercise affects mood: The effects of exercise show an exponential decay. Meaning there is decreasing benefit as the total time spent exercising increases. The conclusion drawn from this finding is that mental health benefits are gained only from relatively moderate levels of exercise.

More detailed studies reported that the protective effects of exercise develop only within the first hour of exercise performed each week. These findings contrast with the ability of physical activity to prevent cardiovascular disease; beneficial cardiovascular effects continue to increase up to about 2–3 hours of exercise per week.

In contrast to the protective effects against cardiovascular disease, vigorous-intensity exercise had no additional protective effects against future diagnoses of depression. Thus, the upper limit to the mood benefit of exercise is achieved quickly. The authors of one study concluded that about 12 percent of new cases of depression might be prevented by one hour of exercise each week.

How does modest exercise reduce the likelihood of developing depression?

Exercise may contribute to better mood health in multiple ways, including the perceived social benefits of exercise, changes in self-esteem, increased serotonin release, increased neurogenesis, increased activity in the hypothalamic-pituitary axis, and increased expression of the protein brain-derived neurotrophic factor (BDNF). Exercising is associated with high levels of BDNF in the blood and muscles. Although muscles produce BDNF, they do not release it into the blood. The BDNF in the blood comes entirely from platelets. Science is still without a viable mechanism to explain why blood platelets release so much BDNF following exercise.

BDNF was once thought to enter the brain and reduce the symptoms of depression. However, recent studies have failed to find a relationship between increased blood levels of BDNF and depression, probably because BDNF is not capable of passing through the blood-brain barrier. These findings have led scientists to consider other chemical messengers between muscles and the brain. We now know that the brain is informed about the activity of muscles by a diverse group of hormones, including beta-hydroxybutyrate, lactate, Cathepsin B, Lipocalin-2, VEGF, PGC-1alpha, and irisin. [For more information on the role of these potential factors, see “Your Brain on Exercise.”]

The link between irisin, ketamine and exercise

The hormone irisin is secreted into blood from skeletal muscles during exercise; it enters the brain and concentrates in two brain regions that are critical for controlling mood and cognitive function, the hippocampus and cortex. Consistent with this role are findings showing that depressed humans have reduced levels of irisin in their brain.

Scientists have speculated that increasing the level of irisin in these brain regions may reduce depressive symptoms by promoting the expression of BDNF. A recent study confirmed that esketamine treatment can enhance levels of irisin. Esketamine is a modified version of ketamine that has a rapid, antidepressant effect, particularly for treatment-resistant depression.

Conclusion

Taken together, these findings outline a mechanistic sequence that connects moderate levels of weekly exercising with protection from depression. Exercising muscles release irisin, which enters the brain and stimulates the production of BDNF in critical brain regions. Elevations in hippocampal BDNF levels is correlated with reduced symptoms of depression. These data further suggest that a combination of the ketamine derivative esketamine with regular moderate exercise might significantly reduce the number of depressive symptoms in treatment-resistant patients.