Stress, Depression and Brain Structure

Bruce S. McEwen, M.D.
Alfred E. Mirsky Professor, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University Member, DBSA Scientific Advisory Board (SAB)     

Depression often follows stressful experiences. The brain interprets events and decides if they are threatening, then controls the behavioral and physiological responses to those events. The brain’s reaction to stress is useful in that it supplies extra energy to help a person act on or flee from dangerous situations. Sometimes, however, brain chemical levels that increase during stressful situations stay at high levels and cause problems such as depression.

There is increasing evidence that stress and the resulting depression may involve structural changes in the brain. The good news is that these changes, known as remodeling, can be prevented and potentially reversed with the right treatment, such as antidepressant and mood-stabilizing medications. Brain imaging studies have shown that brain areas involved in mood, memory and decision making may change in size and function in response to depressive episodes. Studies on animal models have taught us that there may be physical changes in the brain when it is unable to effectively respond or adapt to stress.

Three brain structures – the hippocampus, amygdala and prefrontal cortex – help the brain determine what is stressful and how to respond. The hippocampus stores memories of events and responds to stress hormones in the blood. Many mental disorders, including depression, may cause it to shrink or weaken. In the dentate gyrus, part of the hippocampal formation, new neurons (brain cells) are produced throughout adult life. Repeated stress slows the production of new neurons in the dentate gyrus and may also cause neurons in the hippocampus to shrink.

The prefrontal cortex, a key structure in emotional regulation, decision-making and memory, may also shrink with depression. The amygdala, where emotional memories are stored, becomes more active in depressive illness and post-traumatic stress disorder. Repeated stress may enlarge the amygdala. A hyperactive amygdala, along with abnormal activity in other brain regions, leads to disrupted patterns of sleep and physical activity. It can also cause abnormal secretion of hormones and other chemicals that affect many systems of the body.

Animal studies have also shown that the stress hormone cortisol plays an important role in the remodeling of neurons in response to depression. A person’s normally low evening levels of cortisol are increased in depression. Elevated cortisol is also a symptom of Cushing’s Disease, a disorder of the endocrine system. Studies of this illness have taught us much of what we know about cortisol and depression, hippocampal shrinkage and memory impairment. The good news is that after correction of the excess cortisol with treatment, the hippocampal shrinkage and subsequent memory impairment are partially, or in some cases completely reversible, along with the depressive symptoms. This suggests that brain structural changes in major depression can be prevented or even reversed with the right treatments.

In general, antidepressants have indirect effects on the cortisol-producing system by altering the activity of neurotransmitters in the brain. Some antidepressants do reduce cortisol and help normalize the elevated evening cortisol that may be the worst part of depression. Experimentally, in human depression, there is some use of cortisol receptor blockers and they appear to reduce psychotic symptoms when they occur with depression. These medications may not be the best thing to treat depression over long periods because they would interfere with many good things that cortisol does, such as helping the immune system.

Work on a new generation of antidepressant treatments is in progress. The more we learn about stress, depression, brain changes and the connection between them; the better we are equipped to effectively relieve depressive symptoms.

Reference:
McEwen, B.S. Mood disorders and allostatic load. Biol. Psychiat. 54, 200–207 (2003).