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