March 8, 2002

‘Malignant sadness’ linked to brain biology

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Dr. Huda Akil was the keynote speaker at this year’s Brain Awareness series sponsored by the Vanderbilt Brain Institute. (photo by Mary Donaldson)

‘Malignant sadness’ linked to brain biology

Speaking to a cross-section of scientists, doctors, researchers, students and interested community members, Dr. Huda Akil of the University of Michigan delivered the keynote address at this year’s Brain Awareness series sponsored by the Vanderbilt Brain Institute.

Akil’s address, “Brain Biology of Stress and Depression,” provided an overview of depression and outlined current research and new developments that could provide help to the millions who agonize through the “malignant sadness” of depression.

Millions of people wake up every morning to a sense of doom, of devastating even paralyzing melancholy. Normal stresses can seem overwhelming, concentrating becomes difficult, and sleeping and eating behaviors are disturbed. Self-critical and even self-loathing, the depressed person faces day after day of isolation and despair, looking down a dark tunnel that seems close and endless.

Despite notable advances, many people still do not understand depression. Those suffering with the debilitating disease are seen by some as weak, unable to cope with everyday problems or unwilling to simply change their attitude. These misconceptions lead many depressed individuals to live their entire lives trying to mask their illness to prevent being stereotyped.

Depression is an affective disorder that is extremely common worldwide. Akil estimates that 10 percent or more of the U.S. population suffers from it. Women are twice as likely as men are to develop the disease. The World Health Association has classified it as the most disabling diagnosis in the world in terms of loss of productivity and economic and personal loss for the patient and their family.

In addition to the emotional factors, other more outwardly visible elements are associated with depression. There are cognitive problems that impact how a depressed person thinks and processes information, as well as how they react to stress. The ability to concentrate also is affected, making it difficult to complete tasks. Physical symptoms may include problems sleeping, problems eating, and marked fatigue.

Sadly, according to Akil, depression is greatly underdiagnosed and undertreated, meaning those individuals afflicted by the disorder often suffer their entire lives without understanding the origins of the illness, much less that treatment is available. For many years, depression was treated primarily through verbal counseling, encouraging the patient to articulate their internal pain. Although this approach was successful for some, it still failed to truly address what scientists felt was a deeper disorder with a physiological, even genetic basis.

Approximately 14 years ago, scientists from fields such as neurobiology, psychiatry, and neuroscience began studying the biology of the brain and its impact on emotion with the hope of divining a physiological basis for depression. Research into this fascinating field continues. With a greater understanding of what happens in the brain to cause depression, scientists believe they can develop new treatments to combat this devastating illness.

Although there is much about the brain and specifically about emotion that remains a mystery, research has provided insight into the areas of the brain that control how we handle stress and emotion as well as genetic links.

Akil, and others in her field, have concluded that depression is a genetically based disorder. However, not everyone who carries genes for depression will develop it. Studies have shown a pair of identical twins who share the same genes may not both develop depression. Scientists have sought to understand how one of these twins may struggle with depression throughout their life while the other twin escapes it. Clearly, there are genes that may make a person vulnerable but the question remains: why are some people susceptible while others aren’t?

Although this may be a conundrum for scientists, Akil is encouraged.

“It tells you that genes are not destiny,” Akil said. “Such discoveries and studies offer hope that depression is not just a fate into which you’re born.”

Research has also shown that at least the first episode of depression is triggered by some type of “life event” such as the ending of a significant relationship, the loss of a job, or death of a close family member or friend. Once the first depressive episode has occurred, the person is predisposed to more episodes which may seem to almost take on a life of their own. Akil discussed research indicating these episodes could alter the biology of the brain further, a post-genetic kind of brain plasticity, which increase the likelihood of future depressive episodes.

There are some genes that may make a person vulnerable, developmental events and experiential triggers, combining to cause depression. Akil described this as a “complex genetic disorder,” a convergence of genetics, biology and environmental factors that can have a cataclysmic effect on a person’s ability to handle stress and relate to others.

Akil believes that it is important to understand the neural phenotype, meaning not just the behavior, not just the genes, but the brain as the intermediary where everything happens. Both experience and genes can alter the circuits of the brain and the expression of the genes. In the case of the identical twins, although they were born with the same genes, the variances in the way the genes are expressed as well as the different life experiences can trigger depression and cause physiological changes to the depressed twin’s brain with each depressive episode.

When research on the neurological causes of depression began, scientists were interested in endocrinology and the stress hormones in the body and how they affected emotional response. This research led to a greater understanding of the stress circuits and the brain, specifically the limbic system. Akil and her colleagues feel that the limbic system may be where depression starts, but also see it as providing clues to particular molecules that are active in the stress circuitry of the brain. Through imaging techniques such as MRIs, PET imaging, and neuroimaging, scientists are discovering more about the role of the limbic system and how drug treatment can target areas that are affected by the disease.

Microarray technology is one of the newer approaches to understanding the genetic basis for individual differences in emotional responsiveness. Microarray, or gene chip technology, allows scientists to study the complex genetic basis for emotional behavior. Researchers can simultaneously examine many thousands of genes to elucidate individual variations in emotional responses. These studies are promising, allowing scientists to discover which patterns of gene expression lead to particular neuronal phenotypes, resulting in particular behavioral profile such as high responsiveness to stress or the manifestation of severe depression.

The research of the last two decades has given the medical community a stronger understanding of depression and its causes. Akil and others have provided insight to the biological basis of emotional behavior through the study of the brain circuits that underlie stress. Such advances offer not only education to reduce the stigma of the disease, but also offer hope for effective drug treatments that will give the many sufferers of depression a light at the end of the tunnel.