Despite some impressive research over the past decade, schizophrenia is still an incredibly mysterious disease. Diagnosis mostly comes through behavioral observation, and there is no agreed upon objective biomarker available to detect the condition. An impressive new study from a massive collaborative team of Japanese researchers is presenting a novel hypothesis as to the cause of a subtype of the condition. Alongside that, the study suggests a biomarker in human follicles could allow future diagnoses to be made using a single hair.
One of the most consistently deployed behavioral biomarkers used to diagnose patients with schizophrenia is called prepulse inhibition (PPI). The behavioral test essentially measures a person's startle response by observing the intensity of a reflex reaction to a startling external stimuli after receiving a smaller burst beforehand. In the majority of subjects suffering from schizophrenia, PPI is notably lower than normal, meaning a person has an inability to effectively filter sensory information correctly. The new research began by examining the brains of mice with extremely low PPI.
The researchers quickly homed in on a particular enzyme called Mpst, which was significantly more active in the brains of the low PPI mice. Mpst is known to help produce a chemical called hydrogen sulfide, and subsequent research affirmed high hydrogen sulfide levels in the brains of the low-PPI mice. Interestingly, the researchers then confirmed that suppressing Mpst activity in an animal’s brain seemed to result in their PPI rising to normal levels.
"Nobody has ever thought about a causal link between hydrogen sulfide and schizophrenia," says Takeo Yoshikawa, team leader on the research from Japan’s RIKEN research institute. "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."
Moving to human studies the researchers first examined a number of postmortem brain samples and discovered patients with schizophrenia did show higher expressions of the MPST gene. To test the hypothesis Mpst is an effective biomarker for schizophrenia, the researchers took hair samples from 150 patients with schizophrenia. While Mpst levels were not consistently raised in all schizophrenic subjects, the vast majority did display enhanced levels at a rate the researchers suggest make it a potentially useful diagnostic biomarker.
Exactly how increased hydrogen sulfide levels cause schizophrenia is not clear from this study, although the researchers do hypothesize a number of mechanisms that could explain the relationship. What the new study does clearly suggest, however, is that this whole process seems to originate in a person’s early developmental phases.
Hydrogen sulfide is generally produced in the brain as a protective agent against inflammatory stress. The new research discovered epigenetic changes to the MPST gene that seem to originate at the earliest stages of neurodevelopment.
"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.
So the hypothesis presented is that early stresses, either during fetal development or at very young ages, can prime the brain to overproduce hydrogen sulfide, resulting in epigenetic disruptions to the MPST gene. This excessive hydrogen sulfide production persists as one grows up, ultimately leading to what the researchers are classifying as a specific subtype of schizophrenia called "sulfide stress" induced schizophrenia.
Plenty of the findings in this new study are undoubtedly hypothetical but the researchers are confident there is enough prior research connecting excessive hydrogen sulfide production with cognitive impairments to justify the novel conclusion. Needless to say, more research is needed to clear up some of the hypothetical propositions raised by this study, but Yoshikawa suggests current schizophrenia treatments are so wildly inconsistent there is a pressing need for new ideas and research pathways.
"A new paradigm is needed for the development of novel drugs," explains 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 new study was published in the journal EMBO Molecular Medicine.
Source: RIKEN via ScienceDaily