Presented at NARSAD’s 3rd annual Boston Mental Health Research Symposium on May 30 at the Harvard Medical School, the studies shed new light on how specific genes contribute to the susceptibility to and pathology of schizophrenia, bipolar disorder and depression, some of the most severe, chronic and disabling mental illnesses that collectively affect an estimated 40 million Americans. Coming at a time when some treatments for mental illnesses are a matter of trial and error, these findings have relevance in the development of novel therapies targeted to specific patients and to specific genes.
Donald C. Goff, M.D., 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, moderated the discussion.
Folate as a Cause and Treatment for Schizophrenia: Who Will Benefit?
Do genes explain why some people with schizophrenia are helped when they take supplements of the common B vitamin, folate? The answer is yes and now, new NARSAD funded research is examining the reasons why.
According to Dr. Goff, whose pioneering research identified a link between low blood levels of folate and negative schizophrenia symptoms, folate is 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.
However, what causes low folate in people with schizophrenia is still open to question. One reason, confirmed by epidemiological studies, is poor dietary intake. Based on examining two major famines in the 20th century -- the Dutch Hunger Winter of 1944-45 brought about by the Nazi occupation in World War II and the Chinese famine in 1959-61 -- scientists found that the incidence of schizophrenia among children born to women who were pregnant during these famines increased two-fold.
But in most cases, starvation is not the problem. That is why Dr. Goff’s team looked for other causes, including two genes: GCPII (glutamate carboxypeptidase II), which controls the absorption of folate and may be deficient in people with schizophrenia, and MTHFR (methylenetetrahydrofolate reductase), which activates folate for use in the brain. Using this information, 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,” Dr. Goff
said. “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.”
Building on this landmark research, scientist and colleague, Joshua Roffman, M.D., is using NARSAD funds to go the next step -- identifying people with schizophrenia who are most likely to benefit from folate supplementation. Here, Dr. Roffman and his colleagues started with the MTHFR gene and found that one variant increases the severity of schizophrenia symptoms. Moreover, in patients with this variant, low folate intake was associated with symptoms that were especially severe.
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. Roffman explained. “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.”
Genes and Depression
If a better understanding of genes may lead to customized therapies for schizophrenia, can the same be true for new depression treatments? Answering this question is especially important now that a 2006 government study found that a significant number of people with clinical depression – more than half – are not helped by their initial course of antidepressant treatment, whether medication or talk therapy. In addition, antidepressant medications often come with troubling side effects, such as sleep changes, sexual problems, headaches and gastrointestinal problems, and an analysis by the Food and Drug Administration has shown that antidepressants may cause suicidal thinking and behavior in children, adolescents and adults ages 18 to 24.-NARSAD, The Mental Health Research Association
