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Researchers link response to treatments to a specific structural mutation

Published Date : 2019-08-26 Author : Anjali

Researchers from McLean Hospital and other institutions have found that treatment given to individuals experiencing psychosis, with symptomatic hallucinations and delusions associated with psychiatric illness can be targeted to a particular structural mutation. Deborah L. Levy, Ph.D., Director, Psychology Research Laboratory, McLean Hospital, affiliated to Harvard Medical School, led the study. The findings of the team have been published in Biological Psychiatry. The research demonstrates symptom relief by targeting a particular genotype and establishes a link on a single structural mutation to the pathophysiology of psychosis and response to treatments.

Levy’s research focuses on a variant characterized by a surge in the number of copies of specific genes i.e., a copy number variant or CNV. This CNV involves gene encoding the enzyme glycine decarboxylase (GLDC). Levy explains that there is compelling evidence that the CNV can be linked to pathophysiology, and consequently, to the treatment. GLDC breaks down glycine, a co-agonist at the NMDA receptor, which is a type of excitatory glutamate receptor. The patients included in the study have four, rather than the typical two, copies of the GLDC gene, which led Levy to question if the CNV is medically actionable in individuals with the mutation. The author showed that supplementation of standard psychotropic agents (including clozapine) with glycine or D-cycloserine improved the clinical symptoms. The researchers offered two independent demonstrations of symptom relief by focusing on the specific genotype.

Levy explains that with individual carriers of the mutation, or a ‘genotype-first’ approach, they sought to identify whether the predicted lower glycine availability attributed to the increased CNVs could be potentially normalized using agents that increase the availability of D-serine or glycine. This method contradicts with the usual clinical practice of treating individuals by examining clinical symptoms or diagnosis, rather than the specific genetic variants. Notably, the rare mutation was also visible in different clinical disorders like schizoaffective disorder and bipolar disorder with psychotic features, which indicates that the treatment response was dependent on the targeted mutation independent from clinical diagnosis.