Columbia University Medical Center (CUMC) investigators discovered valproate, a medication used to stabilize moods, is effective for treating negative symptoms in patients with two copies of the “Val” variant of the COMT gene. The medication breaks down dopamine in the brain.
Valproate is commonly prescribed to treat bipolar disorder and schizophrenia and can be an effective option for treating the debilitating “negative” symptoms of severe psychiatric disorders, which include slowed movement, blunted affect, and social withdrawal.
Researchers discovered that in roughly 40 percent of patients with this genotype, higher levels of proline (a neuromodulator that is increased by valproate), correlated with fewer negative symptoms.
In patients who have a “Met” variant of COMT, rising levels of proline appeared to do the exact opposite: these patients had more or worse negative symptoms, and the symptoms did not improve with valproate.
The results appear in the journal Translational Psychiatry.
Catherine Clelland, Ph.D., assistant professor of pathology and cell biology (in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) lead the research with colleagues at Columbia, the Nathan S. Kline Institute, and New York University School of Medicine.
Previous studies have demonstrated an interaction between elevated blood levels of proline and a gene called COMT, which makes an enzyme that helps maintain normal levels of neurotransmitters in the brain.
Proline is a modulator of neurotransmitters that, in higher amounts, is associated with psychiatric illnesses including schizophrenia.
One version of the enzyme contains the amino acid methionine (Met), while another type contains valine (Val). People may inherit one copy of each type (Val/Met) or two copies of the type (Val/Val or Met/Met).
Additional studies have suggested that COMT Val/Val has greater enzymatic activity, increasing its ability to lower dopamine levels in the brain.
In this study, the researchers compared the severity of negative symptoms and proline levels in 95 hospitalized schizophrenia patients with variants of the COMT gene.
In patients with COMT Val/Val, symptom severity decreased as proline levels rose. In contrast, higher proline levels were associated with greater negative symptom severity in patients with the Met/Met gene.
Among those patients who were being treated with valproate (approximately one-third of the schizophrenia patients), negative symptoms were more severe in those with the Met/Met gene than in those with the Val/Val gene.
“While longitudinal studies are needed to confirm our results, this study suggests that boosting proline levels in patients with the Val/Val gene may help address negative symptoms, whereas increasing proline in patients with the Met/Met gene may have the opposite effect,” said Dr. Clelland.
“This information may help to determine which patients may be most likely to benefit from treatment with mood stabilizers such as valproate that are known to modulate proline levels.”