Conference Coverage

Are new medications on horizon for patients with depression, inflammation?



– Inflammation is inextricably linked to depression in a subset of patients who differ from other depressed patients in their responses to certain interventions, according to Charles L. Raison, MD.

“The brains of people who are depressed and who have inflammation look very different from those of people who are depressed without inflammation,” Dr. Raison said in an interview at the annual meeting of the American College of Psychiatrists. “They have different connectivity patterns, different glutaminergic patterns, different signaling. It seems that inflammatory processes change the way different parts of the brain talk to each other and seem to do so in consistent ways.”

Dr. Raison, the Mary Sue and Mike Shannon Chair for Healthy Minds, Children & Families at the University of Wisconsin–Madison, told a plenary audience at the meeting: “We [psychiatrists] are so brain centric, it’s easy to forget how much the immune system drives us. It’s either like a second brain, or it is at least part of the brain.”

Dr. Charles Raison, psychiatrist, University of Wisconsin, Madison

Dr. Charles Raison

Over the years, Dr. Raison and his colleagues have observed how inflammation can interfere with mood, leading to depression in people who previously did not report or describe depressive symptoms.

In the early 2000s, Dr. Raison and others such as Andrew H. Miller, MD, a psychiatric oncologist, investigated the inflammatory response and levels of depression in people treated with interferon-alpha for hepatitis C infection (J Clin Psychiatry. 2005 Jan;66[1]:41-8). They found that more than half of people who had not reported or described depressive symptoms at baseline subsequently reported depressive symptoms. “In a nutshell, we found that interferon-alpha induces every single brain-body function associated with regular old major depression,” said Dr. Raison, also a professor of psychiatry at the university.

In another study, this one led by neuropsychosomatic specialist Dominique L. Musselman, MD, a similar cohort of hepatitis C patients assessed for baseline depression was randomly assigned to either placebo or paroxetine during the course of interferon-alpha treatment. Patients treated with placebo had a 0.24 relative risk (95% confidence interval, 0.08-0.93) of developing depression, compared with the paroxetine group (N Eng J Med. 2001;344:961-6).

The real “breakthrough” in understanding the role of inflammation in depression, Dr. Raison said, came from studies that made the association between early-life adversity, depression, and inflammation. In one particular study, Dr. Raison and colleagues found that stress-induced spikes in interleukin-6 and NF-kappaB DNA-binding were greater in patients with higher baseline levels of depression and higher levels of early life stress (Am J Psychiatry. 2006 Sep;163[9]:1630-3).

Spikes in the inflammatory response independently correlated with depression severity but not with early life stress, which Dr. Raison said suggests that adversity likely can cause inflammation – and thus predisposes people to depression, and not necessarily vice versa.

“Something about early adversity in life programs the brain-body complex to run inflammatory systems hot, probably because it’s an effective way to be ready for [a stream of] unpredictable miseries,” Dr. Raison said during the session. “Chronic, elevated inflammation [early on] seems to predict increased depression later.”

Now that the link has been established between some depression and inflammation, the next step for science is to tease out who is most likely to respond to anti-inflammatory interventions for depression, Dr. Raison said.

“Something that is just starting to emerge is that maybe the relationship between inflammation and depression is not a straight line but a U-shaped curve, such that if you have too much inflammation, you’re in trouble, and if you have too little, you’re also in trouble,” he said in the interview, citing a study he and others conducted into blocking the inflammatory response. In that study, people with major depression who were otherwise medically healthy received either three infusions of the anti-inflammatory tumor necrosis factor–alpha antagonist infliximab (5 mg/kg), or of salt water. The investigators found that placebo worked just as well as infliximab. But patients with lower levels of inflammation at baseline had the greatest improvements in their Hamilton Rating Scale for Depression scores with placebo when compared with treatment (JAMA Psychiatry. 2013 Jan;70[1]:31-41).

Data are not yet conclusive, but Dr. Raison said the field soon could use biomarkers such as levels of C-reactive protein to determine whether patients will respond to anti-inflammatories such as omega-3 essential fatty acids. “Everyone in psychiatry is desperate to find clear, unambiguous answers. We’re right on the edge, but we’re not there yet.”

Until then, Dr. Raison cautioned against the “indiscriminate” use of anti-inflammatories, lest they exacerbate patients’ depressive symptoms. “For instance, omega-3 fatty acids might actually be counterproductive in a lot of depressed people,” he said. Still, he believes that “developing and studying anti-inflammatory strategies is probably going to lead to a novel way of treating depression in some people. What is beautiful is that if these studies continue, we might actually be able – for the first time – to target a subgroup of patients for a specific treatment.”

Dr. Raison is on the scientific advisory board of the Usona Institute, a nonprofit medical research firm.

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