The drug—a mood stabilizer called valproate—is commonly prescribed to treat bipolar disorder and schizophrenia, though its mechanism of action is poorly understood and only some patients respond to the treatment. Few options currently exist for treating the debilitating “negative” symptoms of severe psychiatric disorders, which include slowed movement, blunted affect, and social withdrawal. (Antipsychotic medications are used to treat hallucinations, delusions, and other “positive” symptoms of schizophrenia).
The authors conclude that valproate may be effective for treating negative symptoms in psychiatric patients with two copies of the “Val” variant of the COMT gene, which breaks down dopamine in the brain. In the 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 were published on September 13 in Translational Psychiatry by Catherine Clelland, PhD, assistant professor of pathology and cell biology (in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at Columbia University Medical Center and colleagues at Columbia, the Nathan S. Kline Institute, and NYU School of Medicine.
Previous studies have demonstrated an interaction between elevated blood levels of proline—a modulator of neurotransmitters that, in higher amounts, is associated with psychiatric illnesses including schizophrenia—and a gene called COMT, which makes an enzyme that helps maintain normal levels of neurotransmitters in the brain. 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.
The researchers also evaluated negative symptoms in 43 patients with bipolar disorder, about half of whom were treated with valproate. After one week of treatment, negative symptoms decreased for those with the Val/Val genotype, while symptoms increased or remained the same for those with the Met/Met genotype.
“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.”
The study is titled, “Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.” Additional authors included V. Drouet, K.C. Rilett, and J.A. Smeed (Columbia University Medical Center, New York, NY); R.H. Nadrich and A. Rajparia (New York University School of Medicine, New York, NY), L.L. Reads and J.D. Clelland (Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY).
This research was supported by the National Institute of Mental Health (grantsR21MH070601, R21MH082331, and R01MH100219). In addition, this research was supported in part by the National Center for Advancing Translational Sciences (CTSA grants UL1 TR000038 and KL2 RR024157).
C.L. Clelland and J.D. Clelland are inventors on two patent applications that are based in part upon this study data. If awarded, the patents will be owned by their respective institutions, and the inventors may benefit financially in the future if these patents are licensed.
The authors declare no other conflicts of interest.
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The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center and NewYork-Presbyterian Hospital brings together researchers and clinicians across disciplines to uncover the causes of Alzheimer’s, Parkinson’s, and other age-related brain diseases, and to discover ways to treat, prevent, and ultimately cure these diseases. In collaboration with the Departments of Pathology & Cell Biology and Neurology, research in the Taub Institute integrates genetic analysis, molecular and cellular studies, and clinical investigation to better understand complex neurodegenerative disorders. Funding for the Taub Institute’s Alzheimer’s Disease Research Center is provided by the NIH National Institute on Aging. In 2016, the Taub Institute was designated as a Center of Excellence for Alzheimer’s Disease by the New York State Department of Health. For more information, visit The Taub Institute at http://www.cumc.columbia.edu/dept/taub/.
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