McLean Hospital researchers have published a study in the journal Biological Psychiatry which suggests treatment for people who experience psychosis such as hallucinations and delusions as a result of psychiatric illness and the procedure can be targeted to a specific structural mutation.
Director of the Psychology Research Laboratory at McLean Hospital, the largest psychiatric affiliate of Harvard Medical School, Deborah L. Levy, Ph.D., was the leader of the study. The research offers a proof-of-principle demonstration of symptom relief by targeting a specific genotype and links an individual structural mutation to the pathophysiology of psychosis and treatment response.
The last decade had seen significant progress made in identifying genetic factors underlying schizophrenia, bipolar disorder, and other psychiatric disorders. Hundred, if not thousands, of common genetic variants, are common risk factors for schizophrenia and other psychotic disorders. The impact of each modification, however, is both quite small and indecisive in determining risk.
In this study, Levy described a variant that is characterized by an increase in the number of copies of specific genes (i.e., a copy number variant or CNV), is effectively due to the presence of a small extra chromosome. This CNV includes the gene encoding the enzyme glycine decarboxylase (GLDC). According to Levy, the compelling aspect is that this CNV can be linked to pathophysiology, and, as the new study shows, to treatment.
As a co-agonist at the NMDA receptor, a type of excitatory glutamate receptor, GLDC breaks down glycine. The participant in the survey has four, instead of the usual two, copies of the GLDC gene.
Uwe Rudolph, MD, former director of the Laboratory of Genetic Neuropharmacology at McLean Hospital, said that they then predicted that they would have increased glycine breakdown and thus less glycine available at the glycine modulatory site of the NMDA receptor. This results in NMDA receptor hypofunction.
For some time now, the NMDA receptor has been considered an essential factor in the pathophysiology of schizophrenia. Variants in genes associated with NMDA receptor function are overrepresented in schizophrenia. Levy noted that the presence of an increased number of copies of GLDC raised the question of whether this CNV is medically actionable in individuals with this mutation.
Explaining further, Levy said that starting with individual carriers of the mutation, meaning using a 'genotype-first' approach; they sought to determine whether the predicted reduced glycine availability attributable to the increased copy number could be potentially normalized with agents that increase glycine or D-serine availability. This approach contrasts the regular standard clinical practice of treating individuals based on clinical symptoms or diagnosis independent of specific genetic variants.
