Could a drug that tamps down inflammation lift the fog of depression?
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One of the world’s largest drug makers is testing a radical new approach to treating depression — by dialing down inflammation in the body, rather than tinkering with chemicals in the brain.

If it works, it’s likely to be expensive, have serious side effects, and help only a subset of patients. But it could also open the door to a whole new field of drug development for other psychiatric conditions, including bipolar disorder, anxiety disorders, and schizophrenia, all of which might be propelled, at least in part, by excess immune activity in the brain.

“The notion that you can block inflammation and relieve some of the symptoms of depression is really just the tip of the iceberg,” said Dr. Andrew Miller, a psychiatrist at Emory University.

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The global trial is run by Johnson & Johnson. It’s a first industry-led clinical trial of its kind — and according to Dr. Ranga Krishnan, a psychiatrist and dean of Rush Medical College, “it’s about time.”

“Everybody knows there is enough evidence to say that this approach will probably work,” said Krishnan, who is not involved in the study but has been an unpaid consultant for Johnson & Johnson.

“But until now, no one pulled the trigger.”

Depression was long thought of as a simple imbalance of brain chemicals, and nearly all antidepressants used today work by tweaking levels of these neurotransmitters. Each year, more than 35 million Americans turn to those drugs. But 1 in 3 finds no relief.

Given that low response rate, especially in people with mild and moderate forms of depression, many psychiatrists have begun to reconsider the underlying drivers of the disease.

One possible culprit: inflammation, a process that occurs when the immune system shifts into high gear. Inflammation normally helps keep bacteria and viruses at bay. In the absence of an infection, however, it can also cause tissue damage, hay fever, autoimmune disease — and mental illness.

A long list of studies now support the idea of depression as an inflammatory disorder. Depressed patients often have high levels of inflammatory markers in their blood, for example. And a pro-inflammatory drug that was formerly used to treat hepatitis C caused depression in up to 40 percent of people who took it.

“As recently as 2000, this was considered a fringe area of science, viewed with considerable skepticism,” said Dr. Wayne Drevets, a psychiatrist who leads mood disease research at J&J. “It is now mainstream thinking in biological psychiatry.”

J&J started enrolling patients with major depressive disorder last summer at sites in Russia, Poland, Canada, and the United States. The company is testing an experimental drug called sirukumab, which blocks a key inflammatory protein called interleukin 6.

The company didn’t initially set out to create the drug for people with depression. Doctors were running a trial of sirukumab in patients with rheumatoid arthritis, a chronic inflammatory disorder of the joints, when they came across an encouraging finding. After sifting through the data, they noticed that many patients’ moods improved even when their disease symptoms stayed the same.

This intrigued the higher-ups at J&J, and the company decided to put its drug to a proper antidepressant test, launching a 142-person, Phase 2 trial that should wrap up by the end of this year. (At the same time, sirukumab remains in development for rheumatoid arthritis and an inflammatory disease of the arteries.)

Even with best-case results, however, anti-inflammatories are not set to be a cure-all for depression. “This treatment will end up being reserved for patients who aren’t getting better with other things,” Drevets said.

In part this is because the drug puts the brakes on the immune response, and so could increase the risk of infections, a side effect that might make it a tough sell for some patients. Sirukumab is also an antibody drug — a type of “biologic” therapy that typically commands a high price tag — and doctors may be loath to prescribe a costly new antidepressant over cheap, generic alternatives.

What’s more, anti-inflammatories are only likely to act as mood modulators in patients with higher than usual levels of inflammation.

J&J is using a biomarker called C-reactive protein to identify these patients. About half of all people with depression who do not respond to conventional therapies have high levels of this protein, according to Miller, the Emory psychiatrist, who is not involved in the sirukumab trial but has collaborated with J&J in the past.

There’s more at stake with the sirukumab study than just one drug, though. The pharmaceutical industry has been plagued by repeated failures to move beyond conventional antidepressants, and rival drug companies interested in psychiatric disease will be watching the sirukumab trial closely.

Positive results for J&J, said Miller, “could see [other] companies try to get back in on the act.”

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