It may also be that the action of antidepressant drugs on serotonin is less important than their action on glutamate. Researchers know that one effect of antidepressants is to reduce the sensitivity of receptors in the PFC for glutamate. "Suddenly," says Drevets, "that makes sense. Agents that desensitize the frontal cortex to glutamate may be compensating for the loss of glial cells."
Of course, that still leaves the possibility that a serotonin deficit in other parts of the brain could induce other depressive symptoms. But that's exactly the point; not only is serotonin not the whole story of depression, neurotransmitters may not even be the main story.
Changes in the structure of the brain—losses of cells—are relatively permanent types of alteration. So far, there's no evidence that such changes, once they occur (and it's not clear when in the lifetime course of depression they set in) are reversed with drug or other therapy. And that may account for the propensity of depression to recur. "What's less clear," Drevets says, "is why there are periods when the illness remits, then returns."
Nature, Nurture, Neuron
One of the most debilitating features of depression is the inability of the afflicted to see out of their rut, to imagine alternative ways of being and doing. "In depression," says Ronald Duman, associate professor of psychiatry and pharmacology at Yale, "there's a loss of appropriate adaptability."
Ordinarily, the neurons of the brain have an ability to change and adapt by sprouting new dendritic spines, tiny fibrous protrusions that are the primary receiving end of connections between nerve cells. By literally opening new neural pathways, this sprouting is what allows us to learn and remember, to change our behavior, to meet new challenges, to adapt to new circumstances. Scientists call this capacity neuronal plasticity.
Duman has tracked the inside operations of nerve cells and found evidence that the depressed have a deficit in specific nerve growth factors, the substances that make possible the sprouting of new nerve cell connections. One in particular is the brain-derived neurotrophic factor. BDNF strengthens synaptic connections in the hippocampus (a center of learning and memory) and enhances the growth of neurons that respond to serotonin.
Duman's studies also show, yet again, that how antidepressant agents are believed to work and what actually accounts for their effectiveness may be two different things. Long-term antidepressant treatments—including electroshock—do increase receptors for serotonin at the cell surface. But, Duman found, they also do something else inside the neuron that may be more important. They kick off a cascade of molecular steps that winds up amplifying a neuron's own production of BDNF—and the sprouting of new connections. Moreover, they do this in parts of the brain that have been linked to depression, such as the hippocampus. The real power of antidepressants, then, may be summed in two words: neuronal plasticity.
The molecular cascade Duman has exposed opens up a whole new realm of possibilities for improving treatment of depression. It may be possible to create therapies that more directly and more strongly augment BDNF output. At the same time, the molecular pathway of BDNF production suggests new target points for a more rapid-acting treatment.
Duman's evidence that neuronal plasticity is at stake in depression fits with imaging studies showing that structural changes are taking place in the brains of the depressed. The two strands of information suggest a way that depression might originate. In a word: stress.
New Stress on Stress
"There is elegant work showing that stress, whether environmental or social, actually changes the shape, size and number of neurons in the hippocampus," says Duman. "There are studies showing that stress decreases levels of BDNF." And right at its epicenter is Bruce McEwen, Ph.D., director of the neurobiology lab at New York's Rockefeller University and head of a MacArthur Foundation workgroup on socioeconomic status and health.
McEwen is studying what happens in the adult brain, specifically the hippocampus, of animals undergoing repeated stress. Imaging studies have found that this area, like the prefrontal cortex and the amygdala, shrinks in people with recurrent depression. Prolonged stress, research has shown, kills hippocampal cells, precipitating cognitive decline.
McEwen himself has documented that several kinds of stress—the psychosocial stress of being a subordinate among group-living animals, the stress of being physically restrained—can cause hippocampal cells to atrophy and retract their dendrites. Others have seen the same effects in animals subjected to the stresses of social isolation and, in infancy, to deprivation of maternal care. McEwen has also found that stress can suppress nerve cell growth in a part of the hippocampus recently shown capable of renewing nerve cells in adult life. He's trying to nail down what is cause and what is effect.
"So far," McEwen says, "all we know is that atrophy of these brain structures is seen in people who have a long history of recurrent depressive illness. It may be that those changes cannot be reversed."
But they may be preventable earlier in the course of depression, by use of an appropriate drug, before repeated bouts of depression kill off brain cells. "We've begun to look at this," reports Yale's Ronald Duman. "And we have found that antidepressant treatments are in fact able to induce the genesis of neurons."
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