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Butler Hospital

How nature and nurture may interact to cause severe psychiatric illness

Can one's genetic and biochemical makeup (nature), combined with unexpected personal experiences (nurture), lead to the development of serious psychiatric disorders?
A team at Butler Hospital is part of an international effort seeking answers to that and other complex questions about the origin of psychiatric disorders. Gaining understanding of the complex ways in which genetics can influence responses to life events necessitates multifaceted research on several fronts.

To this end, Audrey Tyrka, MD, PhD, associate chief of the Mood Disorders Research Program at Butler Hospital, is the principal investigator of several studies she is undertaking with her colleagues Linda Carpenter, MD, chief of the hospital's Mood Disorders Research Program, and Lawrence Price, MD, Butler's clinical director and director of research. The studies seek to understand how the interaction of complex genetic and other neurobiological mechanisms, combined with traumatic emotional events, may result in the development of major depression and anxiety disorders in adulthood.

Neurotoxic hormones and stress
The hypothalamic-pituitary-adrenal (HPA) axis is one of the primary interests of study for the Butler group. The HPA axis is a neuroendocrine system that coordinates the neural, hormonal, and behavioral responses to stressors. Findings of research at Butler and other facilities around the country indicate that a problem with HPA axis functioning plays an important role in major depression and anxiety disorders.
The receptor for a hormone acts like a receiver, or radar dish, for messages sent between cells. Two hormones of particular interest to Dr. Tyrka's research, cortisol and corticotropin-releasing hormone (CRH), are involved in the body's response to stress. CRH, which is produced by neuroendocrine cells, stimulates the pituitary gland to release another hormone, adrenocorticotropin, which in turn induces the release of cortisol from the adrenal cortex. In the context of everyday stress, cortisol release helps the body to respond adaptively by releasing energy from storage cells. But when this system is excessively activated by ongoing or severe stressors, it can have negative effects. "The hypothesis is that elevated levels of cortisol may be neurotoxic to the hippocampus and other regions of the brain," explains Dr. Tyrka.
People with major depression and other stress-related conditions frequently have increased cortisol concentrations and other abnormalities of the HPA stress axis, and brain imaging studies suggest that the hippocampus and other limbic areas of the brain may be involved.

Temperament and stress sensitivity
People who are extremely shy or inhibited and those with neuroticism (defined by a tendency to experience negative moods or affect) appear to be at increased risk for anxiety and depressive disorders. This may be partly due to an exaggerated psychological and hormonal response to stress. Studies show changes in HPA hormone responses in people with neuroticism. Dr. Tyrka and her colleagues recently found that people with inhibited personality styles have increased cortisol responses to a psychosocial stress test as well as a chemical stress test.

Early life stress and adult psychiatric disorders
Stress and trauma are strong risk factors for adult psychiatric disorders, and these adverse experiences can also alter cortisol levels and HPA axis function. Dr. Tyrka and her colleagues in the Mood Disorders Research Program are studying stress responses in individuals with different forms of early life stress, including childhood abuse and neglect, as well as childhood parental loss. "Studies of animals and humans have shown a correlation between stressful early life events and abnormal neuroendocrine responses," says Dr. Tyrka. "This may predispose people to developing depression or anxiety disorders later in life." Other studies in their laboratory are looking at the effects of a family history of depression and certain genes that may play a role in these disorders. This work explores the genetic underpinnings of the HPA axis and psychiatric disorders, and how the interactions of genes with environmental adversities may contribute to mental illnesses.

Risk genes and early life stress
As advances are made in the field of molecular genetics, genes known as risk genes are being identified and studied to see if they play a role in psychiatric disorders. The Mood Disorders Research Program is studying two of them that may cause problems with the HPA axis. One is the serotonin transporter gene known to scientists as 5-HTTLPR. Serotonin is a neurotransmitter that transmits information between neurons in the brain. This gene exists in two forms, a long version and a short version. The other gene is the CRHR1, which is a gene that codes for the receptor for CRH, an HPA axis hormone.
"We've known for a long time that stress doesn't affect everyone in the same way, and the difference is partly related to inherited vulnerabilities," explains Dr. Tyrka. Recent studies have shown that people with the short form of the 5-HTTLPR gene who are exposed to stress are more likely to develop depression. However, people who do not have this form of the gene may be protected against the effects of stress. "This is called a gene-environment interaction," says Dr. Tyrka. "A recent study found a similar effect with the CRHR1 gene."

Dr. Tyrka and her colleagues may have identified one cause for this type of gene-environment interaction. In a recent study, they found that people with the risk form of the CRHR1 gene who had been abused or neglected as children had excessive cortisol responses to a chemical stress test. People with the other form of the gene appeared to be protected against this effect of childhood maltreatment. "This suggests that such gene-environment effects may influence the developing stress hormone system, which may place people at risk for depression and other disorders," says Dr. Tyrka.

The mind/body connection
This research suggests that the hormonal stress response may be a key biological risk factor for certain psychiatric disorders. Dr. Tyrka's work, along with other studies being conducted at the hospital's Mood Disorders Research Program, indicates that genetic influences, as well as the experience of adversity, influence this stress response system and may put people at risk for depressive and anxiety disorders.

This research is providing new information about the underlying biological causes of depression and anxiety that could lead to the development of improved diagnostic and treatment procedures. While this research promises to expand our understanding of psychiatric illness, it also serves as a compelling reminder that there is an inseparable link between the mind and other organs in the body.

Ultimately, the goal of this work is to further the ability to prevent these illnesses from occurring and to develop improved treatment approaches. Better prevention strategies and treatments would substantially reduce the impact of these disorders on individuals, families, and society.
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