Promising New Approach to Treat Symptoms of Psychosis

Psychotic symptoms such as delusions and hallucinations, which occur in schizophrenia and other psychiatric conditions may respond to treatment targeting specific mutations, according to a study led by Deborah L. Levy, PhD, director of the Psychology Research Laboratory at McLean Hospital, the biggest psychiatric center attached to Harvard Medical School.

The findings of the study appear in the journal Biological Psychiatry.

Rare Mutations and Disease Risk

Mutations can contribute to risk of disease in many ways

• For example, several common mutations may collectively increase disease risk but individually the risk of each mutation is very low and may not cause disease by itself
• On the other hand, mutations that have a huge impact by themselves individually are rare, and reported only in a few persons. Some of these genetic variants are so uncommon that they are termed "private" mutations, known to occur in a single-family such as the one described by Dr Levy in this study.

Key Pathways Impacted by Rare Mutation causing Psychosis

• The current study describes a rare mutation marked by a higher number of copies of certain genes (i.e., a copy number variant or CNV), caused in this instance due to the presence of an additional small chromosome
• In this case, the CNV affects the gene that codes for the enzyme glycine decarboxylase (GLDC)
• The function of GLDC is to breakdown glycine, which is a co-agonist at the N-methyl-D-aspartate (NMDA) receptor, a type of excitatory glutamate receptor. A co-agonist is a chemical or drug that can combine with a cellular receptor producing a response typical of a natural substance
• In the described mutation, patients have 4 instead of the usual 2 copies of the GLDC gene. This causes increased amounts of glycine to be destroyed
• As a result, glycine is not available to modulate the function of the NMDA receptor, resulting in NMDA receptor hypofunction
• NMDA receptor hypofunction has been shown to be a key factor in the pathophysiology of schizophrenia. Genetic mutations affecting NMDA receptor function have been found to be over-expressed in schizophrenia

Targeting Pathways Affected by NMDA Receptor Hypofunction

• The research team wondered if the presence of an increased number of copies of GLDC or CNV could be targeted medically in persons having a mutation causing NMDA receptor hypofunction
• This approach is different from the usual standard clinical practice of treating patients based on the clinical symptoms rather than targeting specific genetic variants
• Persons who took part in the study had four identical copies of the GLDC gene
• The team found that the addition of glycine or D-cycloserine (a partial selective agonist at the NMDA receptor) to standard psychiatric medications such as clozapine resulted in marked improvement of psychotic symptoms
• The scientists presented two separate proof-of-principle evidence of symptom reduction by targeting this specific mutation

Interestingly, during this study, the same rare mutation was observed in several psychiatric disorders with different symptoms (such as schizoaffective disorder and bipolar disorder with psychotic features), suggesting that symptom relief occurred by targeting the mutation, independent of symptoms or clinical diagnosis.

"It is important to note that the two subjects studied here bore a little clinical resemblance, with distinctly different symptom burdens, and highly dissimilar courses of illness," noted J. Alexander Bodkin, MD. Bodkin, the director of the Clinical Psychopharmacology Research Program at McLean, who supervised the psychiatric care of both patients throughout the open-label and blinded trials of glycine and d-cycloserine.

Scope of the Study

• If rare mutations associated with significant risk of illness could be identified in the clinical setting, therapy targeting the genetic variant could be offered to larger numbers of patients
• Since the positive effects of a targeted treatment can be huge, it is essential to conduct future studies on these lines even if only a small group of patients would derive benefit

In summary, targeting rare genetic variants that affect key metabolic pathways can be a potentially promising approach to reduce psychotic symptoms in patients with psychiatric conditions.

References :

1. Researchers Find Targeted Treatment That Reduces Symptoms of Psychosis - (https://www.mcleanhospital.org/news/researchers-find-targeted-treatment-reduces-symptoms-psychosis)
2. NMDA receptor function, memory, and brain aging - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181613/)

Source: Medindia