For today’s “How Do You Move Beyond Blue?” post, I have published a comprehensive update of some fascinating studies that will lead to more effective treatments for depression and other mood disorders. This valuable summary by Karen Swartz was printed in the Fall 2007 Issue of The Johns Hopkins Depression and Anxiety Bulletin.
Dr. Swartz (above left) is one of the physicians at Johns Hopkins who evaluated me in March of 2006. She is Director of Clinical Programs at the Johns Hopkins Mood Disorders Center and Assistant Professor of Psychiatry at the Johns Hopkins University of Medicine. She is also Co-Director of the Women’s Mood Disorders Clinic (with Dr. Jennifer Payne, above right), founder of the Adolescent Depression Awareness Program, and an attending psychiatrist at Johns Hopkins with extensive clinical experience in mood disorders, anxiety disorders, and eating disorders. In other words, she knows her stuff, inside and out, and I am SO lucky to have found her and Dr. Smith.
I’ve made a few remarks in brackets (as always).

What happens within the brain when a person is depressed? Our concept of the anatomy and physiology of mood has rapidly shifted over the past decade, thanks to work in brain imaging and molecular medicine.
In the 1990s, several lines of research began turning our view of mood disorders upside down. Taken chronologically, the first step was research showing that neurogenesis—the birth of new brain cells—can continue throughout life. The second breakthrough was evidence that depression is associated with a loss of volume in parts of the brain.
Most of us remember being told at some point that we are born with all the brain cells we’ll ever have. But we now know that the process of neurogenesis is an ongoing one, with new brain cells being born even as old brain cells die off. Researchers have discovered, however, that depression appears to inhibit this birth of new brain cells.

And that may help explain the second line of research: why people who’ve had depression are likelier to have a smaller hippocampus—a part of the brain that plays a role in emotion and is associated with memory and learning. The more severe and long-lasting the depression, the greater the loss of brain volume. This process of brain atrophy also affects the brain’s frontal lobes (specifically, the prefrontal cortex), which are involved in regulating the emotional centers of the brain.
The good news is that most of the volume loss seems to be related to cell shrinkage rather than outright cell death, and thus can potentially be reversed. Genetic studies have also found that a subgroup of people are more susceptible to this process of brain atrophy.
Brain atrophy is only part of the depression story, however. In August, researchers at the University of Wisconsin-Madison reported the results of one of the first studies to use brain imaging to look at the brain circuits involved in emotional control in patients with depression. They found that the brains of people with clinical depression react very differently than those of healthy people when trying to cope with negative situations.
In the study, published in “The Journal of Neuroscience,” brain imaging revealed a breakdown in normal patterns of emotional processing that impairs the ability of depressed people to suppress negative emotional states. Efforts by depressed patients to suppress their feelings when viewing emotionally negative images increased activity in several brain areas, including the amygdala, known to play a role in generating emotion. [Reread that last sentence. Fascinating. And why “mind over mood” attempts can sometimes sabotage recovery.]
Mood disorders are believed to originate in the limbic system—the brain’s emotional center. This region includes all the structures mentioned so far—the hippocampus, prefrontal cortex, and amygdala—among others. Identifying the specific areas and circuits in the brain associated with mood disorders is one of the most pressing issues in psychiatric research today.
“It’s normal for people to have negative emotions in certain circumstances,” says lead study author Tom Johnstone, Ph.D., of the University of Wisconsin. “One of the features of major depression is not that people have negative reactions to negative situations; it’s that they can’t pull themselves out of those negative emotional moods. They seem to have a deficit in their ability to be able to regulate their emotions—to come back down to baseline after a negative experience.”
To evaluate this deficit, Dr. Johnstone and his colleagues monitored the brain activity of 21 adults diagnosed with major depressive disorder and 18 healthy subjects of comparable ages. Participants were asked to view a series of emotionally positive and negative images and then indicate their reaction to each one. Four seconds after the presentation of each picture, participants were asked either to increase their emotional response (for example, imagining a loved one experiencing what was depicted in the image), to decrease it (for instance, imagining the situation was acted out rather than real or envisioning a more positive outcome), or simply to continue watching the image.
During the test, a functional magnetic resonance imaging (fMRI) scanner detected changes in brain activity. Johnstone and his colleagues also recorded levels of emotional excitement by measuring pupil dilation.
In both healthy and depressed participants, efforts to reframe the content of what they were seeing increased brain regulatory activity in the prefrontal cortex. This was expected. The big difference was observed in the activity levels of the emotional response centers, including the amygdala.
In non-depressed participants, high levels of regulatory activity were associated with low levels of activity in the amygdala. In other words, the healthy subjects’ efforts to reduce their emotional responses were successful.
But in depressed participants, high levels of activity in the amygdala and other emotional response centers persisted despite intense activity in the regulatory regions. What’s more, the difference between healthy and depressed participants was even more pronounced the harder the participants tried. [Reread that sentence, too. Whenever you feel like you are failing at cognitive work, of thinking yourself to health, READ THAT SENTENCE.]
One possible explanation is that depressed people have a broken link between the brain regions, such that regulatory centers fail to send dampening signals to emotional centers.
Or perhaps depressed patients get stuck ruminating on negative thoughts. “When they try to engage in regulation of their negative responses, they just think more about the emotional content of the images. Instead of turning down their emotional responses, they turn them up.” [That paragraph is somewhat consoling to me, too, when I’m too hard on myself.]
Cognitive therapy, in which the patient and therapist focus on breaking negative thought patterns, uses mental strategies similar to those used in this study, suggesting that it might not be the best treatment for those patients whose mental efforts only increase their emotional responses. For these patients, other therapeutic approaches may be more beneficial. Perhaps, in the future, doctors will use measurements of activity in the amygdala to predict the effectiveness of treatments for depression such as cognitive therapy.
Of course emotional regulation underlies many psychiatric disorders, not just depression, and identifying and understanding the brain circuits involved will enable scientists to target these circuits with more refined treatments.