Stress, not surprisingly, is bad news for the human brain. But the effects can be a lot more toxic, and a lot longer lasting, than medical researchers used to think. In short, as Dennis Charney, M.D., a professor of psychiatry at Yale University School of Medicine, puts it: "We have a greater respect now for the effects of stress on brain function than we used to."

At a recent conference on brain research and its applications to primary care and psychiatric medicine, Charney described some of the disturbing discoveries about stress and brain function that have been coming out of his lab and that of others. The conference was held in Washington, D.C., and was sponsored by APA, the Washington Psychiatric Society, and the Medical Society of the District of Columbia.

It’s not really unexpected that stress can lead to neurochemical changes in the brain, and that such changes in turn might help provoke mental distress. For instance, researchers now know that the stress hormone norepinephrine—the so-called "fright, flight, or fight" hormone made by the adrenal cortex—is released into the amygdala in victims of posttraumatic stress disorder. This norepinephrine spurt may in turn help trigger the excruciating memories associated with the disorder.

What is unexpected, however, and disturbing, is that stress can also lead to anatomical changes in the brain that, in turn, may also help set the stage for mental disarray. For example, PTSD victims have, in the hypothalamus, an abnormally large number of neurons that make corticotropin-releasing factor (CRF), the master hormone, so to speak, that reacts to stressful events and that then kicks into action adrenocorticotropic hormone (ACTH) and subsequently the adrenal gland stress hormones.

Thus, neurons that make CRF appear to be altered by stress: The stress seems to increase their number. Just the opposite seems to occur in the case of hippocampal neurons under the onslaught of stress. PTSD victims, as well as monkeys that have been traumatized, lose neurons in the hippocampus, that bastion of memory processing. In fact, the effects of stress on the hippocampus seem to be so daunting that the hippocampus actually shrinks in size: Persons with PTSD have a smaller hippocampus than normal. A smaller hippocampus also has been noted in depressed persons, which in turn may possibly be due to stress.

"So it looks as if severe stress can change brain anatomy," Charney said.

Moreover, the neurochemical and anatomical changes evoked by stress at one point in life may have repercussions many years later as far as mental health is concerned. For instance, rats that had been separated as pups from their mothers only three hours a day had abnormally high levels of CRF as adults, implying that CRF had been switched on at abnormally high levels during infancy and had stayed that way ever since. Similar results have been found in monkeys: Those stressed while young had abnormally high levels of CRF four years later. And similar findings have been obtained in humans: Military veterans who had suffered PTSD as a result of their war experiences had elevated CRF levels a quarter century later. And indeed, if you expose adults who had been abused as children to a psychosocial stress test, their ACTH overreacts, suggesting that their early-life traumas have put not just CRF but ACTH in permanent overdrive. Interestingly, elevated levels of both CRF and norepinephrine have been found in the spinal fluid of depressed patients, perhaps harking back to some early-life trauma, Charney pointed out.

Yet, can early-life distress produce long-standing changes in the brain that in turn lead to a permanent overreaction to stressful events later in life, and can this permanent overreaction later help create mental disorders? Although such links have not yet been proven, they are quite possible, Charney believes. For example, women who have been abused as children tend to suffer from a lot of mental health problems—substance abuse, depression, suicide—later in life.

However, such discoveries, while disquieting, are offering some new glimpses into how drugs for mental disorders work. For example, new neurons can grow in the adult hippocampus, both primate and human studies have shown. Whereas stress can decrease such growth, the neurotransmitter serotonin can increase it. Thus SSRI antidepressants may counter anxiety, depression, and PTSD not only by enhancing the activity of serotonin in the brain, but by serotonin in turn increasing neuronal growth in the hippocampus—or as Charney describes it, via a "remodeling of the central nervous system." In fact, such remodeling is more than speculation. Yale researchers are finding that the SSRIs can indeed increase neuron generation in the hippocampus.

On another positive note, such findings may lead to some new types of mental disorder therapies. In one experiment, healthy subjects were given a drug that countered norepinephrine in the amygdala, and as a result, their memories of emotional traumas were blunted. Suppose a victim of a traumatic event were given such a drug shortly after the event? Would it attenuate his or her memories of it? This possibility is currently under study. And since an excess CRF response to stress may be an important neurochemical-anatomical pathway to certain types of mental distress, might a drug that counters this response also counter the mental anguish? Some drug companies have developed CRF antagonists and are attempting to learn whether they have antianxiety, antidepressant, or antistress properties. Charney and his colleagues are also going to be doing research in this area.

"We hope a CRF antagonist will be effective for PTSD and certain types of depression," he said.