MIND AND MATTER: ROBERT M. SAPOLSKY

Stress Starts Up The Machinery of Major Depression

New revelations about the nuts and bolts of major depression focus on the role of stress

Updated April 24, 2014 4:00 p.m. ET

It's hard not to be pulled by the sheer terror of some exotic diseases. Headlines are commanded by the tragedies of the likes of Ebola virus, mad-cow disease or progeria. But when it comes to everyday medical misery, nothing quite beats major depression. It sucks the very air out of life, cripples millions of people (about 15% of us) and, within a decade, is likely to be the second leading cause of global medical disability.

New research reveals some of the nuts-and-bolts biology of how depression works. Getty Images

Many factors increase the risk of major depression, including variants of a number of genes, childhood trauma and endocrine and immunological abnormalities. A frequent trigger is stress. Recent research shows how this might occur.

The stress angle concerns "anhedonia," psychiatric jargon for "the inability to feel pleasure." Anhedonia is at the core of the classic definition of major depression as "malignant sadness."

The abilities to anticipate, pursue and feel pleasure revolve around a neurotransmitter called dopamine in a brain region called the nucleus accumbens. Publishing in the journals Nature and Nature Neuroscience, Matthew Wanat and Paul Phillips of the University of Washington and colleagues explored the effects of stress on dopamine in mice. Rather than taking the easy path of studying the rewarding properties of a slam-dunk like sex or yummy food, the authors looked at a subtler pleasure.

Put a novel object—say, a ball—in a mouse's cage. When the mouse encounters the ball and explores it, the arousing mystery, puzzle and challenge cause the release of a molecule in the nucleus accumbens called CRF, which boosts dopamine release. If the unexpected novel object was a cat, that mouse's brain would work very differently. But getting the optimal amount of challenge, what we'd call "stimulation," feels good.

CRF mediates this reaction: Block the molecule's actions with a drug and there is no longer the dopamine surge or the exploration. Or, in another experimental approach, if you spritz CRF into the nucleus accumbens whenever a mouse wanders into one corner of the cage, the mouse returns to that spot repeatedly; in other words, CRF has "reinforcing properties."

But exposing a mouse to major, sustained stress for a few days changes everything. CRF no longer enhances dopamine release, and the mouse avoids the novel object. Moreover, the CRF is now aversive: Spritz CRF into the nucleus accumbens and the mouse now avoids the place in the cage where that happened. The authors showed that this is due to the effects of stress hormones called glucocorticoids. A switch has been flipped; stimuli that would normally evoke motivated exploration and a sense of reward now evoke the opposite. Remarkably, those few days of stress caused that anhedonic state to last in those mice for at least three months.

Like all good research, more questions are raised: How do glucocorticoids cause these changes? Do mice ever recover? Are some individuals resistant to these effects? And does it work this way in humans?

But meanwhile, these findings have an important implication. Life throws lousy things at us; at times, we all get depressed, with a small letter "d." And most people—as the clichés say—get back in the saddle, prove that when the going gets tough, the tough get going. What then to make of people who are incapacitated by major depression in the clinical sense? Unfortunately, for many, an easy explanation is that the illness is a problem of insufficient gumption: "Come on, pull yourself together." There is a vague moral taint.

Thus, it isn't just a medical but also a social good when scientists reveal more of the nuts-and-bolts biology of how depression works, because the studies underline in the process that the illness a real biological disorder. It is as real as diabetes, and we don't sit down a diabetic and say, "Come on, stop indulging yourself, you've got to overcome this fixation of yours about insulin."