A certain subtype of schizophrenia could be diagnosed based on biomarkers in a patient’s hair, a new study found.

The team at the RIKEN Center for Brain Science (CBS) in Japan reports that a certain subtype of schizophrenia is related to very high levels of hydrogen sulfide in the brain. This mutation, caused by a DNA-modifying reaction during development, can also be detected by analyzing biomarkers in a patient’s hair.

A headful of markers

“Nobody has ever thought about a causal link between hydrogen sulfide and schizophrenia,” says team leader Takeo Yoshikawa, the paper’s corresponding author.

“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.”

The best way to diagnose a condition is to have a reliable, objective marker you can look for or compare a patient against. For schizophrenia, the most reliable such marker in use is an abnormal startle response test (the link between schizophrenia and abnormal startle responses has been documented since around 30 years ago).

Humans aren’t normally startled by a random burst of noise if it’s preceded by a smaller one — this latter one is called a prepulse. The whole phenomenon is known as prepulse inhibition (PPI); in people with schizophrenia, PPI is lowered, meaning such patients don’t experience a dampened startle response after the prepulse (or experience much lower dampening than normal). Because it’s pretty reliable and consistent, the PPI test is a strong tool used in diagnosing schizophrenia, even if it doesn’t tell us very much about the biology behind the condition.

The RIKEN CBS team set out to look for differences in protein expression between strains of mice that had either very low or very high PPI. They found that one protein (Mpst) was expressed much more in the brains of mice with low PPI than in those with high PPI. Knowing that this enzyme is involved in the synthesis of hydrogen sulfide, the team measured the concentration of this compound in the hairs of low-PPI mice — they found elevated levels.

To validate the findings so far, the team engineered some of the low-PPI mice in order to reduce the expression of the MPST gene (which governs the Mpst protein) — this helped make the mice behave more closely like their healthy kin. Next, the team established that MPST gene expression was higher (postmortem) in the brains of people with schizophrenia compared to healthy controls. The level of MPST protein seen in the brains also correlated well with the severity of the symptoms each patient experienced, they add.

After establishing that MPST expression can be used as a biomarker for schizophrenia, the team examined hair follicles from over 150 schizophrenia patients. The findings so far held firm: all of them had much higher expression of MPST mRNA than people without the condition. The results weren’t perfect, the team explains — which indicates that sulfide stress does not account for all cases of schizophrenia — but they did show that MPST levels in hair are a reliable biomarker for the disease, and can be tested before other symptoms become apparent.

Testing on postmortem mice’s brains showed that the high MPST levels were associated with changes in DNA that lead to permanently altered gene expression. The team hypothesized that inflammatory stress during early development might be the root cause (hydrogen sulfide can protect against inflammatory stress).

“We found that anti-oxidative markers—including the production of hydrogen sulfide—that compensate against oxidative stress and neuroinflammation during brain development were correlated with MPST levels in the brains of people with schizophrenia,” says Yoshikawa.

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 schizophrenia.”

The paper “Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology” has been published in the journal EMBO Molecular Medicine.