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Psychiatry Newsletter - Reading the Book of Stress

Hopkins BrainWise - Fall 2012

Reading the Book of Stress

Date: November 1, 2012

Dr. Richard Lee
Richard Lee has a blood test that shows stress’s mark on mouse genes. Now he’s after the equivalent in humans.

For some patients with psychiatric disease, cortisol, the steroid hormone, is like nothing so much as Superman’s kryptonite.

Frequent release of the steroid, part of the body’s response to continued perceived stress, isn’t good for anyone, studies show. It raises the likelihood of diabetes, hypertension and coronary artery disease. It accelerates aging. Mental effects are equally dark: Elevated cortisol disturbs cognition and mood. It shrinks the hippocampus, jeopardizing short-term memory.

But for people vulnerable to stress-sensitive psychiatric diseases like anxiety disorders or major depression, their burden becomes heavier, says neuroscientist Richard S. Lee. “It’s just what they don’t need.” 

“Living a stressful life, with its subsequent wash of cortisol, can make people more prone to depression,” Lee says. Many patients with major depressive or bipolar illness test high for cortisol. Yet what hasn’t been clearly mapped, he says, is how the stress-triggered hormone promotes psychiatric disorders. “Also, no one fully understands the biology of stress in the context of an existing psychiatric illness.” That’s what Lee, Kellie Tamashiro, Gary Wand and Hopkins colleagues hope to reveal.

Rewards from such work aren’t hard to imagine: Safely lowering cortisol or finding where best to damp its action might, say, whittle depression enough for patients to need less medication. Tailored psychotherapy might suffice.

“Just being able to tell accurately how much stress people have been exposed to,” Lee says, “could let us predict how they’d respond to drugs.”

For now, the group is focused on the body’s prime stress-response system, the HPA axis connecting the hypothalamus, pituitary and adrenal glands. In particular, Lee is probing Fkbp5, an HPA axis-active gene.

Something of a celebrity in psychobiology circles, Fkbp5 helps regulate cortisol levels in the brain and body. Versions of the gene are tied to major depression, suicide and PTSD—yet intriguingly, only in patients who’ve suffered early life trauma such as injury or child abuse.

“That raises a flag,” says Lee.  When he read of Fkpb5’s likely sensitivity to mishaps in the environment, he explains, “my first thought was epigenetics.” Like a governor on a car engine, the small molecular add-ons called epigenetic marks—or their removal—can alter gene expression.

So does stress change Fkpb5? To see, Lee’s team added the mouse equivalent of cortisol for a few weeks to test lab animals’ drinking water. The mice exhibited mild anxiety. But more telling was that their Fkpb5 lost epigenetic marks: the more cortisol added, the greater the loss. The changes persisted for weeks.

The sense of this, the researchers say, is that we’re already wired for fight or flight, but epigenetic changes might let us fight harder or flee faster at the next sign of danger. This ultra-readiness, however, holds no benefit—far from it—for modern folk whose stressors are, say, tight work deadlines they can’t fight or run from.

So far, Lee has revealed epigenetic changes in test-mouse pituitary HPA axis cells and outside the HPA axis in an area that depression targets. A happy find is that Fkpb5 in the animals’ white blood cells also reads like the Book of Stress. That such an easily reached sample could parallel brain changes is a key find. Lee’s now working to see if a drop of human blood could also tell all.

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