While the brain remains a largely unsolved mystery, University researchers are working to better understand what role it plays in mental illnesses.

Neuropsychiatric illnesses such as major depression, schizophrenia, bipolar disorder and anxiety are prevalent conditions in North America and Europe, yet scientists still don’t fully understand why they arise and how to treat them. But advances in neuroscience research are continuing to unfold in the areas of genetics, neural processes and sleep, which will allow for a better analysis and treatment of psychiatric conditions.

Huda Akil, co-director of the University’s Molecular & Behavioral Neuroscience Institute, co-authored “The Future of Psychiatric Research: Genomes and Neural Circuits.” The paper, which was published in March 2010 in Science magazine, outlines two types of research that are crucial to increasing scientific understanding of common neuropsychiatric conditions.

According to the paper, there have been no major breakthroughs in schizophrenia treatment in 50 years and no major breakthroughs in depression treatment in 20 years. Additionally, drugs developed in the last few decades to treat depression only work for a subset of the population.

Akil and her co-authors wrote that understanding these illnesses is a large endeavor due to the complexity of neural circuits and the thousands of genes involved in neural development. The root cause of mental illness also differs between among individuals.

Stanley Watson, the other co-director of the University’s MBNI, compared a mental illness to a fever, saying that it is necessary to find the specific underlying cause in order to treat the condition.

“There are over 200 ways you can get cough and fever in a human … so your treatment for an allergy is different than for a (bacterial) infection,” Watson said. “The real Holy Grail is precision about the illnesses … by knowing the pathways, then you’ve got a shot at beginning to deduce what to do.”

Watson said it is important to understand of the specific factors causing a person’s illness, so that doctors can determine the best treatment options.

Watson, who is Akil’s husband, also pointed to research in genomics — the study of genes and the mechanisms they control — and neural circuitry as the areas that will improve understanding of these illnesses.

Margit Burmeister, a research professor in the MBNI, said with recent progress being made in the fields of genetics, and genomics as well as in bioinformatics and statistics, it is now possible to do genetic testing on tens of thousands of people and on millions of gene variants to “tease out” genetic factors influencing mental illness.

The most well known genetic factor in the onset of mental illness is the serotonin transporter gene, Burmeister said. This gene is involved in recycling serotonin — a neurotransmitter that contributes to a person’s happiness — after it has been secreted into the synapse, or the space between neurons. Studies have shown that a certain variant of the serotonin transporter gene affects how people react to stress.

Srijan Sen, an assistant professor in the University’s Department of Psychiatry, studied the effects of the serotonin transporter gene in 740 medical students working in 13 hospitals across the country. To do this, he sequenced the DNA of the students and then monitored their depression symptoms during their first years of residency, which is considered to be the most stressful time in a medical student’s career. Published last June, Sen found that during residency, students with the less functional version of the serotonin transporter gene experienced more symptoms of depression.

Though the evidence supporting the link between the serotonin transporter gene and mental illness is strong, Burmeister noted that because genes work together, one gene alone doesn’t have a major impact on a person’s susceptibility to psychiatric disorders. Therefore, Sen is now looking at hundreds of genes that could have also affected the mental health of the medical students in the study, Burmeister said.

Watson said successful genomics research requires more than mere identification of the genes involved in an illness. When it comes to treatment, it’s very difficult to develop a drug that targets a specific gene, he said. Thus, in order to understand and treat mental illness, it is necessary to explore the other half of genomics research, which involves the actual physical processes that genes code for, Watson said.

However, genomics is not the only method available to explain and combat psychiatric disorders, Burmeister said.

“This idea that if something is genetic it’s deterministic is a misconception that we have to get over, because saying that genes are involved in depression does not necessarily mean that someone who has certain genetic variants is doomed to become depressed,” Burmeister said. “It just means that under certain circumstances, he or she may have to do certain things to help alleviate it, but it’s not unchangeable.”

A person’s genetics impact the brain, but so do the drugs he or she takes and the environment the person lives in, Burmeister said. This brings in the second area for understanding mental illness: neural circuitry.

The brain, especially with physical structures associated with memory or stress, can rewire itself, Watson said. The brain of a person with post-traumatic stress disorder changes slightly as a result of repeatedly remembering an event, he said.

“It might be just a matter of learning too strongly what the event was,” Watson said. “Sometimes the startled nature of a trauma is as fully important as what the trauma was, and the combination is really horrible.”

Some PTSD treatments aim to undo this rewiring by having patients remember the event under non-traumatic conditions or with medication. Similar to depression, there could be a precipitating factor that drives the initial depressive episode of PTSD, Watson said. Over time, the episodes occur more frequently, indicating that the brain has rewired toward the illness, and the person has essentially learned to be depressed.

Akil and her co-authors highlight some methods for understanding complex neural networks such as brain imaging and noninvasively shutting off different neurons in a neural circuit in the brain and observing the effects.

John Greden, executive director of the University’s Comprehensive Depression Center, said in addition to genomics and brain imaging, sleep research is key to understanding mental illnesses. People struggling with depression often have abnormal sleeping habits that exacerbate episodes of depression, he said.

“Sleep is probably the most predictable variable that changes when people get depressed,” Greden said. “In other words, most people with depression have alterations or unpleasant things happen with their sleep.”

Research at the Depression Center has revealed that monitoring the brain waves of adolescent girls as they sleep can reveal abnormalities in their brains that may make them vulnerable to depression, Greden said. He added that this is a finding that could lead to earlier detection and treatment of depression.

Greden said he thinks new personalized treatments that combine psychotherapy, brain stimulation and nutritional awareness to combat mental health issues will develop in the next three to five years.

Watson’s view is that developing a scientific methodology to treat mental illnesses will take a few more decades.

“I think you’re looking at a 20-year horizon,” he said. “That’s not so difficult to conceive of anymore. That number is actually built on real calculations.”

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