Most research on the pathology of depression has focused on the role of neurotransmitters such as serotonin and their receptors in the brain. But a recent study points to another mechanism linked to depression: irregularities in the immune system.

 

A research team lead by 2009 NARSAD Young Investigator grant recipient Jonathan Savitz, Ph.D., of the Laureate Institute for Brain Research in Tulsa, has discovered a relationship between chemicals released in the brain in response to inflammation and features of the brain unique to people with depression. The team also included Wayne C. Drevets, M.D., a Scientific Council member, 1996 and 1999 Young Investigator grantee, and 2014 Colvin Prize winner. The research is published this month in Neuropsychopharmacology and previously appeared online.

Some chemicals released in the brain in response to inflammation in the body can help protect neurons by promoting the health of these cells. Such chemicals are considered to be “neuroprotective.” However, other chemicals produced by inflammation can have harmful effects, earning the label “neurotoxic.” The two different sets of chemicals are known to have different effects at important cellular docking ports in the brain called NMDA receptors. Previous research has implicated the receptors in depression.

To better understand the relationship between the body’s immune system response and depression, Dr. Savitz and his colleagues focused on the ratio between some of the neuroprotective versus neurotoxic chemicals in depressed patients. Specifically, the team looked at a set of chemicals known as kynurenine metabolites. (Metabolites are the products of important chemical processes in the body.) The researchers were especially interested in the ratio between metabolites thought to be neuroprotective and neurotoxic in the “kynurenine pathway.”

Among patients with depression, the team found fewer neuroprotective kynurenine metabolites relative to neurotoxic metabolites. That lower proportion of neuroprotective metabolites correlated with smaller sizes of two brain regions that help regulate mood: the amygdala, key for emotional processing, and the hippocampus, important for consolidating memories. This is consistent with previous research showing both structures to be significantly smaller in clinically depressed patients, compared to people without depression.

Indeed, the team found more direct evidence that the chemicals under study can affect mood. The higher the proportion of neuroprotective metabolites found in patients’ brains, the less likely those patients were to demonstrate anhedonia, or loss of pleasure, a common symptom of depression.

In this study, then, the neuroprotective metabolites truly appeared to play a protective role against symptoms of depression that were associated with bodily inflammation. The researchers note that these neuroprotective and neurotoxic chemicals don’t always have strictly positive or negative effects for mood. Still, they suggest that increasing levels of the neuroprotective metabolites they studied may be a worthwhile objective for antidepressant drug development.

 

Read the paper.