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Shrinkage, Not the Shrinks

 News from the Johns Hopkins Department of Psychiatry and Behavioral Sciences

“Intriguing” is how Potash describes work that adds to depression’s hottest hypothesis.

Dr. James Potash

Dr. James Potash

“Those who call psychiatrists head shrinkers have it wrong,” says psychiatric geneticist James Potash, M.D. In a recent departmental Grand Rounds, Potash described new evidence for an idea he finds intriguing: that chronic depression—and not clinicians—whittles the volume of specific brain areas, notably the hippocampus. It’s certainly plausible, he says, given known ties between depression, stress and the ample science that shows stress hormones can shrink that brain site.

The idea of basing therapy on reversing the shrinkage of an area devoted to memory and emotion, he adds, is equally intriguing.

While Potash is by no means the first to relate depression, stress and hippocampal change, his take on a possible mechanism is new. In his talk, he cited recent results from GenRED I, a large, nationwide genetics-of-depression study: A gene appeared whose workings may fit the hippocampal hypothesis like the proverbial glass slipper.

In past work, Potash has found probable psychosis genes, those common to psychosis in both bipolar disorder and schizophrenia. Currently, he’s one of a handful of psychiatrists nationwide studying epigenetic phenomena—unconventional ways of controlling conventional gene expression. Epigenetics may explain how environmental cues like day length, for example, might affect patients with mood disorders.

As director of research for Hopkins’ Mood Disorders Center, Potash has helped conduct large studies to link the risk of those illnesses with specific chromosomal areas. Now he hopes to identify culprit genes via gene chip assays of thousands of patients and their family members.

You’re focusing on the hippocampus in depression?

Yes. Imaging studies show that the frontal cortex—which we know behaves differently in depression—is connected with deeper limbic regions, especially the hippocampus.

Is there evidence it shrinks in depressed people?

More than 20 studies suggest the hippocampus is smaller in patients with major depression than in those without illness, about 10 percent, on average. Some work says it’s not just depression but how long depression’s untreated that correlates with brain loss.

How do you know that depressed people aren’t born with smaller hippocampi?

We don’t. And there’s some evidence that hippocampal volume can be inherited. One monkey study showed it’s 54 percent heritable. On the other hand, we know definitively that the hippocampus is a brain area that makes new neurons throughout life. And that ability can vary. It decreases with age, for example.

So you’re leaning toward shrinkage. What does it?

Stress. Stress sets off a cascade of steroid hormones that likely alters the hippocampus. The hormones also appear to retard its new growth.

So the hypothesis ...

... is that stress encourages depression. Brain and endocrine sites for our response to stress—circuitry called the HPA axis—become overactive in depression. And while the subsequent wash of steroid hormones doesn’t destroy hippocampal neurons, it likely prunes them back, changing their activity in brain circuits and perhaps producing symptoms of depression. Or maybe it’s the hormones’ slowing new growth that’s the cause. Perhaps it’s both!

Can depression therapy restore the hippocampus?

In animal models it can, both with antidepressants and with electroconvulsive therapy. The few studies in people suggest that too, though evidence is less clear. 


Nobody knows. Perhaps it’s by reducing stress. Or it could, we believe, affect the hippocampal neuron factory. Recently, from our genetic studies on families with major depressive disorder, we’ve marked a narrow area on chromosome 15 as having some tie to depression. Of nine genes in that vicinity that we analyzed, one, NTRK3, piqued our interest. It codes for receptors for a natural agent—a neurotrophin—that encourages nerve cell growth in the brain.

What’s next?

We’ve just launched a study about 2,000 times more powerful than the last to make the suspect genes far more obvious, one that should clarify what NTRK3 and others are doing. For the first time, we have the potential to understand the truth about what sets depression in motion. 

Winter 2008 IndexHopkins Newsletter Archive