(Xie et al., 2020 | Journal of Affective Disorders) The image illustrates a scheme by which NMN supplementation decreases depressive behavior in mice. NMN boosts NAD+ levels which stimulate SIRT3 activation. SIRT3 activation, in turn, enhances mitochondrial energy metabolism.

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About 16.2 million US adults, 6.7% of the population, had at least one major depressive episode in the year 2016, according to the National Institute of Mental Health (NIMH). Symptoms of depression include an inability to feel pleasure, reduced energy, and cognitive deficits. Although doctors can prescribe antidepressant medications to treat depression, about two-thirds of people with depression don’t respond to initial treatments. About 15%-40% do not respond after multiple treatments, either.

In February, a team of scientists published a study in the Journal of Affective Disorders where they described beneficial effects of nicotinamide mononucleotide (NMN) injections on alleviating symptoms of depression in mice. They found NMN supplementation increased levels of a molecule important for energy production in the body, nicotinamide adenine dinucleotide (NAD+). Increasing NAD+ levels with NMN also improved energy metabolism in the cell’s powerhouse, the mitochondria, in the brain and liver.

Experimentation showed that induced depression decreases body weight in mice but NMN injections reversed it. The researchers induced depression by injecting mice with a stress hormone, corticosterone. Following four weeks of stress hormone injections, the researchers added NMN to the injections for two weeks and found  the animals’ body weight measurements returned to near normal.

(Xie et al., 2020 | Journal of Affective Disorders) NMN supplementation improves body weight to normal in mice with stress hormone-induced depressive symptoms. After four weeks of stress hormone injections, NMN was added to the injections. Following two weeks of NMN injections, body weight levels returned to near normal.

Behavioral evaluations of the mice also showed that after NMN treatment, the mice with corticosterone injections exhibited less depressive-like behavior. Scientists measure depressive-like behaviour through a “forced swim test,” in which healthy mice will struggle to stay afloat in a swimming tank, while “depressed” mice give up swimming sooner. After treating the depression-induced-mice with NMN, the animals started to swim longer in order to survive in the tank, reversing the depressive-like behavior.

(Xie et al., 2020 | Journal of Affective Disorders) Stress hormone-induced depressive-like behavior includes reduced mobility on the “forced swim test.” NMN reversed this depressive-like behavior, improving mobility in this test.

Past studies have found decreased production of the body’s energy molecule, adenosine triphosphate (ATP), in patients with major depressive disorder. This reduced ATP generation could stem from dysfunction of the cell’s powerhouse, the mitochondria, leading to correlations with depression. Promoting mitochondrial function may be an intervention for improving depression-like behaviors. As a crucial molecule to keep the energy manufacturing line running, boosting NAD+ with NMN or NR can promote mitochondrial function.

NMN injections enhanced mitochondrial energy production in the brain, which is associated with NMN’s reversal of depressive-like behaviors, according to the current study. Stress hormone-induced depression also reduced NAD+ levels in the brains of mice but NMN administration restored NAD+ levels. 

The team of scientists also looked at the activity of proteins which regulate cellular energy production and depend on healthy levels of NAD+ for their function. They examined a protein called SIRT3 that plays an important role in regulating mitochondrial health. Recent studies have also associated the protein’s role in depression. Although levels of SIRT3 dissipated with induced depression in mice, NMN rescued SIRT3 activity toward normal levels. The improved SIRT3 activity with NMN treatment correlates with reduced depressive behavioral symptoms such as better performance in the “forced swim test.”

“Our findings indicate that NMN supplementation can effectively enhance SIRT3 activity to improve mitochondrial energy metabolism in the hippocampus and liver, thereby mitigating [corticosterone]-induced depression-like behavior in mice,” stated the researchers in their study.

The scientists noted that the small sample size may be a limitation of the study and call for future studies with larger sample size and long-term studies to further investigate the mechanism of NMN on depression-like behaviors.