is a mental disorder that
affects a person's ability to think, feel, and behave clearly. Using post-mortem human brains, mice models, and schizophrenia patients,
the researchers identified that abnormally high levels of hydrogen sulfide in
the brain was linked to the pathogenesis of a subtype of schizophrenia. This abnormality
was associated with a DNA-modifying enzymatic reaction during development that
persisted throughout life. Importantly, the high level expression of this
hydrogen sulfide-producing enzyme could be used as a biomarker for this
particular subtype of schizophrenia called 'sulfide stress' induced
schizophrenia. Moreover, this discovery could open-up new avenues for the
development of novel psychiatric drugs.
published in the journal EMBO Molecular
, was led by Dr. Takeo Yoshikawa, MD, PhD, who is the Team Leader of the
Laboratory of Molecular Psychiatry at the RIKEN Center for Brain Science in
What are the Advantages of Biomarkers for
A biomarker for any
disease, including psychiatric disorders
schizophrenia, makes it much easier to diagnose the disease at an early stage.
In the case of schizophrenia, it has been known for over three decades that an
abnormal 'startle response'
is a good clinical
indicator of the condition. Interestingly, this startle response is not so
pronounced in normal individuals.
response generally doesn't occur if a loud sound is preceded by a weaker sound,
termed as a 'prepulse'
. This phenomenon
is known as 'prepulse
as the prepulse dampens the louder sound that follows, thereby
inhibiting the startle response. However, in case of schizophrenic patients,
PPI is decreased, as a result of which the startle response is not dampened.
Hence, these patients become startled upon exposure to a sudden loud sound.
This PPI test is a good behavioral diagnostic marker of schizophrenia, which is
conventionally used in clinical psychiatric practice.
How was the Research Conducted?
The scientists at
the RIKEN Center for Brain Science conducted the research in several stages,
with each preceding stage influencing subsequent stages. These stages of the
research are briefly described below: Mice Studies
"Nobody has ever
thought about a causal link between hydrogen sulfide and schizophrenia,"
- Differential protein expression in different
strains of mice was studied to identify those that were susceptible to
extremely low or extremely high PPI
- A protein enzyme called MPST (3-mercaptopyruvate sulfurtransferase) was
studied that is responsible for the production of hydrogen sulfide
- MPST was expressed at significantly higher levels
in the brains of mice with low PPI than in those with high PPI
- Measuring the levels of hydrogen sulfide in the
brains of the mice revealed that it was higher in the low-PPI mice
- In order to verify that MPST
expression was responsible for the generation of hydrogen sulfide, MPST gene knockouts of low-PPI mice
- It was revealed that PPI was
higher in the MPST gene knockout
mice than in regular low-PPI mice
- This indicated that reducing MPST
expression enabled the mice to become more normal
says Toshikawa. "Once we discovered this,
we had to figure out how it happens and if these findings in mice would hold
true for people with schizophrenia."
- Examination of the post-mortem
schizophrenic patients revealed that MPST expression was higher
in these brains than in those from people without schizophrenia
- MPST levels in schizophrenic
patient's brains were well correlated with the severity of symptoms
- Feasibility of using MPST as a
biomarker for schizophrenia was investigated by examining the hair
follicles of over 150 schizophrenic patients
- MPST mRNA (messenger ribonucleic
acid) expression was significantly higher in the hair follicles of
schizophrenic patients than in normal individuals
- This indicated that MPST levels in
hair follicles could be an excellent early biomarker of schizophrenia,
much before the appearance of clinical symptoms
- Elevated MPST levels were well
correlated with excessive production of hydrogen sulfide, leading to
'sulfide stress' induced schizophrenia
Implications & Future Prospects
Currently available treatments for schizophrenia use antipsychotic drugs
that are antagonists of the
serotonin-dopamine system in the brain. However, most of these drugs have
become ineffective and are also associated with a large number of side effects.
This has led to stagnation in the psychiatric drug development pipeline. This
new study has the potential to bring about a paradigm shift in drug
"A new paradigm is needed for the development of novel
Yoshikawa explains. "Currently,
about 30 percent of patients with schizophrenia are resistant to dopamine
D2-receptor antagonist therapy. Our results provide a new principle or paradigm
for designing drugs, and we are currently testing whether inhibiting the
synthesis of hydrogen sulfide can alleviate symptoms in mouse models of
- Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology - (https://www.embopress.org/doi/full/10.15252/emmm.201910695)