Inflammation Dampens Reward Circuits in Depression

The immune system helps to protect the body from injury and infection through a process called inflammation. This protective immune response involves the release of specialized cells like leukocytes (white blood cells) as well as other protective molecules to fight off invaders, remove damaged cells, and help facilitate tissue repair. But sometimes, this natural and adaptive immune process can become pathological in its own right, leading to auto-immune diseases like rheumatoid arthritis and inflammatory bowel disease. Researchers are now learning that inflammation is also linked to psychiatric conditions such as depression; this link may offer us new targets for treatment.

An observed link

Doctors have long observed a link between inflammation and a depressed state, says Joao De Quevado, director of the translational psychiatry program at the University of Texas Graduate School of Biomedical Sciences at Houston.

“When humans have an infection, they present with a behavioral state that resembles depression,” he says. “You see flat affect, sadness, the kind of behavior that looks very similar to what you see in depressed patients. And that raised the idea that perhaps there was a correlation between the two.”

Over the past few decades, many studies have substantiated that correlation. In fact, studies have demonstrated that approximately one-third of people diagnosed with depression also have high levels of inflammation markers, like C-reactive protein (CRP), a liver protein that is released as part of the inflammatory process. More and more, it looks like inflammation may drive some of depression’s hallmark symptoms, including anhedonia, loss of appetite, and sleep problems.

A chicken and egg problem

People with depression often have a host of other medical problems, including cardiovascular disease, obesity, and other issues that are also linked to inflammation, so it wasn’t clear whether the inflammation observed in depression was a consequence of the depression or just merely contributing to the immune state. To tease out the answer, William Copeland, a clinical psychologist and epidemiologist at Duke University Medical Center, conducted a longitudinal analysis, following individuals as they transitioned from childhood to adulthood, looking for bi-directional links between elevated CRP levels and depression. The researchers found that CRP levels were not associated with depression later in life, suggesting that depression contributes to the inflammation seen in the body as opposed to depression being the result of inflammation. The results were published in Biological Psychiatry in 2012.

“Inflammation, and particularly CRP, is a wonderful non-specific indicator of something being wrong. But there are a whole host of other factors, like if you’re not exercising, if you’re not eating right, if you’re not sleeping, or if you have a lot of stress in your life, that may contribute to inflammation and can also contribute to depression,” he says. “But what we see, when we tightly control for those outside factors, is that it’s not inflammation causing the depression. So while inflammation is a much broader problem that may apply to a lot of people who have depression, we think it’s important to treat people with depression early in life, to help reduce the risk of having higher inflammation, and a whole host of other problems, down the road.”

In fact, some work suggests that childhood stress may tweak the brain’s natural stress systems in such a way they produce inflammatory molecules even when no external stressors exist, creating a brain that is more susceptible to depression.  That kind of related inflammation that might affect the rest of the body, resulting in a host of medical issues across the lifespan.

Cutting off communication

The link between early stress in life and depression—as well as increased inflammation—is clear.  It is possible that depression with high inflammation may be a specific subset of what is a very heterogeneous psychiatric disorder. If that is the case, and we could better understand how inflammation is resulting in specific depressive symptoms, it might offer new targets for intervention, says Jennifer Felger, director of the behavioral immunology program at Emory University and Dana grantee.

One such symptom is anhedonia, or the inability to feel pleasure or joy. Felger wondered if high inflammation might be somehow influencing the normal function of the brain’s reward pathways.

“There may be neural pathways and neurotransmitters that are more affected by inflammation in the brain—and they may not be targeted by standard antidepressant therapies,” she says. “We know that the basal ganglia, part of the brain’s reward circuitry, communicate with so many other different regions of the brain. One of those is the ventromedial prefrontal cortical region, which has been implicated in depression in the past, so we thought might see something there.”

To test the idea, she and her colleagues scanned the brains of 48 people diagnosed with depression. The team found that those with elevated CRP not only showed greater anhedonia but a “failure to communicate” between the striatum, part of the basal ganglia, and the ventromedial prefrontal cortex. That is, there was lessened connectivity between these two key brain regions.

“This was a really robust and specific difference. There was low connectivity between the striatum and ventromedial prefrontal cortex—we didn’t see any other global change in communication with any other major brain region,” she says. “It really was just this reward pathway that was being affected in those with high inflammation.” This work was published in Molecular Psychiatry in November 2015.

This, she says, offers a new target for treatment for patients with anhedonia. She plans to use L-DOPA, a dopamine precursor drug, to see whether it might improve communication in this reward pathway in depressed patients. This work was published in Molecular Psychiatry in November 2015.

Moving forward

De Quevado says, taken together, there are now many studies now linking depression and inflammation.  And this link offers has the potential to offer scientists and clinicians new insights into the etiology and symptomology of this debilitating psychiatric disorder.  But many questions remain.  Felger says researchers still have significant work to do to understand the relationship between depression and inflammation—both at the whole-brain and the molecular level—and how that relationship may affect diagnosis and treatment in the future.

“We’re still at the early stages of saying that blocking inflammation may have the potential to reduce the behavioral symptoms of depression,” she says. “But we’re hoping to find new ways to treat patients faster and more effectively. And this inflammation link is providing us with some really promising targets.”