Therapy Targeting Gene Associated with Psychosis Alleviates Symptoms

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Schizophrenia

Treating psychosis by targeting a genetic mutation alleviates symptoms. That’s according to a new, proof-of-principle study that just may pave the way for precision medicine in psychiatry. The study, published in the July issue of Biological Psychiatry, is one of the first to treat psychosis based on genetics rather than on symptoms.

“This approach contrasts with the standard clinical practice of treating individuals on the basis of clinical symptoms or diagnosis independent of specific genetic variants,” said Deborah Levy, Ph.D., of McLean Hospital, a psychiatric affiliate of Harvard Medical School in a press release.

Psychotic disorders are a group of mental illnesses that impact the way a person behaves and perceives reality. The milder symptoms include difficulty making decisions, responding emotionally and thinking clearly. Severe symptoms hallucinations, delusions and handling daily life. The most recognized of these disorders is schizophrenia. Approximately 5 percent of those with the diagnosis die by suicide.

It is difficult to gather statistics on schizophrenia because it is hard to diagnose, but the National Institutes of Health estimates that schizophrenia and related psychotic disorders affect approximately 1-2 million Americans.

In the current study, Levy and her colleagues identified a copy number variant (CNV) mutation in a mother and son. Both had psychosis diagnoses, but presented with different symptoms. Genetically, the two patients had four, instead of the usual two, copies of GLDC gene (glycine decarboxylase). The authors wrote that this mutation might reduce brain glycine, a key factor for proper glutamatergic functioning, which has already been shown to be disrupted in schizophrenia.

Glutamate, an excitatory neurotransmitter, is released by brain cells and is responsible for sending signals between nerve cells. Under normal conditions, it plays an important role in learning and memory.

The goal of the study was to assess whether this CNV could help guide treatment decisions by targeting the mutation to normalize its effects, a “genotype first” approach.The researchers conducted two double-blind, placebo-controlled studies involving the two patients. The treatment subjects received glycine or D-cycloserine, a metabolite of the metabolic pathway involving glycine, both of which were intended to restore glutamate function.

The results showed that the addition of two agents to restore glutamate function, glycine or D-cycloserine, to the patients’ standard medications improved psychotic symptoms in both patients beyond their usual treatment regimens. Each of the patients also saw some reductions in other symptoms, including mood symptoms and negative symptoms of schizophrenia, including enhanced emotional engagement and less social withdrawal.

“It is important to note that the two subjects studied here bore little clinical resemblance, with distinctly different symptom burdens, and highly dissimilar courses of illness,” noted first author J. Alexander Bodkin, M.D., of McLean Hospital in separate press release.

These kinds of genetic mutations that have a large effect on psychiatric disease are rare, with some known to occur in only one or a few families. Still, Levy said,“the compelling aspect is that this CNV can be linked to pathophysiology, and, as the new study shows, to treatment.”

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