Cytokine Antagonists May Help Some Depression Patients
Studying the relationship of inflammatory cytokines to depression may open doors to the origins of the disorder and possible treatments.
A few years ago, some researchers were hypothesizing that inflammatory cytokines were a cause of depression.
The evidence seemed initially persuasive, said Andrew Miller, M.D., at APA’s 2014 annual meeting in New York in May.
Inflammatory cytokines may play a role in depression, but not the only role, says psychiatric oncologist Andrew Miller, M.D.
David Hathcox
Levels of IL-6, tumor necrosis factor-α (TNF-α), and c-reactive protein (CRP) are indeed often elevated in patients with depression and are associated with treatment resistance, said Miller, a professor of psychiatry and behavioral sciences and director of psychiatric oncology at the Winship Cancer Institute at Emory University School of Medicine.
Experimentally, inflammatory cytokines induce depressive symptoms in healthy volunteers, as does therapeutic use of interferon in hepatitis-C patients, he said. Furthermore, inhibition of inflammatory cytokines reduces depressive symptoms in patients with cancer, depression, or psoriasis, among other illnesses.
“It all adds up to a good case, but one size does not fit all,” cautioned Miller. Only subgroups of depressed patients have elevated levels of cytokines, and cytokines are also higher in patients with other psychiatric disorders (such as bipolar disorder, schizophrenia, and anxiety) and in general medical conditions (such as cancer or heart disease).
“Cytokines are not about disorders but about the symptoms and the circuits that are related to those symptoms within those disorders,” he said.
Studies in humans and in nonhuman primates suggest that interferon-α (an antiviral/antiproliferative cytokine used to treat viral infections or cancers) taps into pathways known to be involved in depression, said Miller.
“Interferon-α alters glucose metabolism in the basal ganglia and leads to reduced prefrontal cortical metabolic activity,” he said. At the same time, there is increased activity in the globus pallidus and putamen, mimicking a pattern seen in Parkinson’s disease. “Neurons fire at a high rate because they are not being inhibited by dopamine.”
fMRI studies of patients taking interferon-α for hepatitis-C showed that in the ventral striatum, being on the drug correlated highly with reduced motivation and anhedonia. Other studies showed similar effects with a variety of inflammatory stimuli.
Miller then tested the effects of a TNF-α antagonist (infliximab) in patients with treatment-resistant depression. This was not a clinical trial, he emphasized, but a way to better understand the cytokine hypothesis of depression.
Even getting to that point wasn’t simple, he said. “It took us a tremendously long time to convince the drug companies to even test the drugs in a depressed population, because the FDA automatically issues a black-box warning that treatment with a potential new drug could precipitate suicide.”
Ultimately, they found that use of the drug reduced HAM-D scores overall equal to those found with placebo. However, the subset of patients with higher baseline CRP (>5 mg/L) levels demonstrated a greater treatment response, 62 percent among treated patients compared with 33 percent of those on placebo.
This information might ultimately guide diagnosis or measurement of treatment effects. Plasma CRP has a readily available test and correlates well with CRP in cerebrospinal fluid, he said.
“There are cells in the brain producing CRP, so we’re getting a sense of what’s going on in the brain in terms of neuroinflammation.”
Within six hours of an infliximab infusion, gene expression arrays reflected down-regulation of the TNF-α and NF-κB pathways and predicted who would respond and who would not, he said. “Also, symptoms like motivation, psychomotor retardation, suicidality, and anxiety all got better,” as did the brain regions he anticipated would get better after blocking cytokines.
Miller again cautioned that cytokine antagonists are not a panacea for depression and about the need to stratify patients: “Using cytokine antagonists in patients who have low inflammation actually causes them to do worse.” ■
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Published online: 16 June 2014
Published in print: June 7, 2014 – June 20, 2014
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