Using genetic testing to improve mental health, 1

Part 1 of a series on genes and mental health. Taken from an article published in Therapeutics Daily.

Two genes have been identified as associated with schizophrenia:

  • GCPII (glutamate carboxypeptidase II), which controls the absorption of folate and may be deficient in people with schizophrenia,
  • MTHFR (methylenetetrahydrofolate reductase), which activates folate for use in the brain

Donald C. Goff, MD, director of the Schizophrenia Clinical and Research Program at Massachusetts General Hospital and a leading researcher on the role of genetics in the development of new treatments for schizophrenia, pioneered research that identified a link between low blood levels of folate and negative schizophrenia symptoms. Folate, given routinely to pregnant women as folic acid and often recommended for maintaining brain health in the elderly, is (according to the article) "involved in many different chemical pathways in the brain, including keeping levels of the amino acid homocysteine low. When homocysteine levels are too high, this interferes with the functioning of receptors located all over the brain -- called NMDA ( N-methyl-D-aspartate) receptors -- that are critical to learning, memory, brain development, and general neural processing."

Dr. Goff and his colleagues are recruiting patients for a large trial to determine whether folate supplementation will help individuals affected by these genes, many of whom have treatment-resistant psychotic symptoms. Funded by the National Institute of Mental Health, this double-blind study will follow 150 patients with schizophrenia at three sites over a 16-week period.

"Schizophrenia is a prevalent and costly disorder and can be very difficult to treat. This is especially true for the estimated 30 percent of patients with treatment-resistant psychotic symptoms, who may also experience social withdrawal, apathy, and depression," reports Dr. Goff.

"Having these new data will validate whether folate, which is known to be very safe, is an effective way to improve outcomes for people with schizophrenia who now suffer from treatment-resistant psychotic symptoms.

Another researcher, Joshua Roffman, MD, is also working with people who have schizophrenia and a particular variant of the MTHFR gene that increases the severity of schizophrenia symptoms. In these patients, low folate intake was associated with symptoms that were especially severe. Dr. Roffman is hoping to identify people most likely to benefit from folate supplementation.

Now, Dr. Roffman's team is looking at the combination of MTHFR and another gene -- COMT (catechol-O-methyltransferase) -- that affects dopamine levels in the brain. Although the two genes have separately been associated with schizophrenia, Dr. Roffman's just completed study finds that when these genes interact, a specific subset of patients is at greater risk for cognitive impairment. In individuals who carry the risk variants of both MTHFR and COMT, lower-than-normal levels of dopamine in the part of the brain called the prefrontal cortex may cause problems with information processing and working memory. Using functional neuroimaging, Dr. Roffman and his colleagues also found that the same combination of MTHFR and COMT variants were associated with abnormally low activity in the prefrontal cortex.

"We now have the techniques to determine how genes combine to produce schizophrenia symptoms," Dr. Roff explains. "As we gain a better understanding of individual biogenetic pathways, we can identify high-risk groups and those most likely to benefit from specific treatments."

These two researchers, and their research teams, are using the results of genetic testing to find ways of improving the health of specific conditions found to be associated with certain genes.

Tomorrow: genes and depression

Marie Godfrey, PhD

 

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