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Psychiatry Newsletter - When Depression Is Elevating

Hopkins BrainWise Fall 2009

When Depression Is Elevating

By: Marjorie Centofanti
Date: November 2, 2009

Could late life depression set the stage for Alzheimer's?


Gwenn Smith
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Gwenn Smith explores the intersection of depression and Alzheimer’s disease. “It’s amazing,” she says, “how it seems to fit together.”

Research has laid to rest the myth that what looks like depression in older people is just a response to what life throws at them.

It’s the myth that stiff joints, fading hormones and a surfeit of funerals can get people down, but they don’t have an actual mood disorder.

The idea persists, however. And benign it’s not.

Trustworthy sources estimate that roughly a quarter of Americans age 65 or older experience either frank depression or the one-step-down of chronic dysthymia or the still milder “subsyndromal” mood disorder that skulks below clinicians’ radar screens.

With its higher rate of relapse and of suicide, late-life depression is a major public health problem.

For all that, the pathology of “melancholia” is poorly understood in this particular age group. That’s in part because there’s a second myth to cross off: that biologically, depression is depression, no matter what the age.

But a growing body of work by neuropsychologist Gwenn Smith, with Hopkins colleagues and others, shows subtle but telling differences in what elders suffer. Their affected brain circuitry is different, for one thing, she says, as is its metabolism.

Smith’s studies not only suggest a way to tell, at that age, who won’t respond well to antidepressants, but they also hold a hope of understanding depression’s impact on the brain.

What drives Smith these days—the proverbial carrot—is a tie-in to Alzheimer’s disease (AD). There’s the teaser that the seeds of late-life dementia are planted in the very brain abnormalities she’s found in depression.

“I didn’t start as a mood disorders researcher,” Smith explains. “My interests were originally in AD and in aging.” As an undergrad, she had worked in the first lab to use radiolabeled glucose to map human brain metabolism. Then she grew skilled in those PET scanning methods and others as a postdoc, applying them to patients with dementia.

One reason that assaying metabolic changes throughout the brain is hugely useful is because it can spot areas of change in nerve function, often before pathology has settled in.

In Smith’s early AD work, for example, key association areas of the cortex stood out. And the lights were turned off, metabolically, in those tissues.

Her shift to study late-life depression came in part after epidemiological reports—a key one was from Hopkins—suggested that having it raises the risk of Alzheimer’s.

“Of course, our first question was how?”

So Smith recruited older, depressed people for study, “expecting full well that their metabolism would hit a middle ground between healthy seniors and AD patients.”

But Smith was surprised: Rather than being down a tad, brain metabolism is elevated in cortical areas in late-life depression.

Why that’s the case isn’t clear. The metabolic overdrive, she suggests, could mean the brain’s trying to compensate for the onset of pathology.

“We now believe that late-life behavioral symptoms like depression or unusual irritability may reflect something wrong in the brain.”

It gets more interesting. The “hyper” areas, which include parts of the superior and middle frontal cortex, some temporal and parietal regions, lie in a “default network” —tissue that normally maintains a hum even when the brain is at rest.

There’s more: After hearing Smith lecture, a friend pointed out that the overactive areas overlap Alzheimer’s metabolic dead zones. “Could it be,” Smith asks, “that these areas just burn out?”

Also intriguing is that in several PET studies, Smith has shown that, with antidepressants, metabolism returns to normal in many older patients. And significantly, how much it drops after one dose predicts if depression will lift with longer treatment.

Now she’s entering a key phase of her work: finding what underlies the metabolic shift and what that says, if anything, about dementia.

The dots are there; Smith just has to connect them.  

For information: 410-550-0062

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