New Clues to Schizophrenia Pathogenesis

As Dr Yolken observed, patients with schizophrenia in general have a higher rate of comorbid immunologic diseases.

In patients with schizophrenia in his own study, 9 of 17, or almost half of the cohort who had evidence of Lactobacillus phage phi-adh, also had a comorbid immunologic disorder.

Immunologic disorders included type 1 and type 2 diabetes and Crohn's disease.

Furthermore, none of the six patients with schizophrenia being treated with valproate had evidence of Lactobacillus phage phi-adh in their oral pharynx.

In contrast, 17 of 35 patients with schizophrenia who were not receiving valproate had evidence of the bacteriophage (P = .026).

"Valproate is clearly an effective medication in some patients with schizophrenia, even though the mode of action is not really well known,” Dr Yolken noted.

“So the possibility that medications that are changing the virome or the microbiome and altering behavior or having their effects based on these changes is an intriguing idea, because if we could figure out how they are affecting the microbiome, we could develop better drugs with lower degrees of toxicity than valproate.”

The primary host bacteria for Lactobacillus phage phi-adh is Lactobacillus gasseri.

Lactobacillus gasseri is a common component of the oral and gastrointestinal mucosa and is capable of binding to intestinal epithelium.

It is also a common component of foods and probiotic preparations.

Interventions directed at decreasing the carriage rate of Lactobacillus phage phi-adh and its host bacteria in patients with schizophrenia may include probiotic or prebiotic preparations or narrow-spectrum antibiotics, all of which can alter the microbiome, said Dr Yolken.

Intriguing Findings

Asked by Medscape Medical News to comment on the study, session chair James Kennedy, MD, director of molecular brain science, Centre for Addiction and Mental Health, Toronto, Ontario, called the findings “very intriguing” in that they suggest there is a balance between bacteria and viruses in the gastrointestinal tract in healthy individuals but an apparent imbalance in patients with schizophrenia, in light of the fact that a significant proportion of the study group harbored the Lactobacillus phage compared with very few control persons.

What needs to be looked at now is the relationship of this Lactobacillus phage to the life course of schizophrenia, because young people show no symptoms of the disorder until they reach their high school years,” Dr Kennedy suggested.

The strongest risk factor for schizophrenia is still genetics, he emphasized.

However, a working hypothesis for how an altered microbiome might affect the development of schizophrenia is that the bacteriophage sets up an inflammatory response in its bacterial host, and inflammatory molecules that arise from this interaction eventually cross the blood-brain barrier, as they have been shown to do in rodents.

If that process takes place in a genetically vulnerable adolescent, inflammatory molecules could interact with a person’s genetic susceptibility to foster the disorder.

“What we do know from human brain development is that just after puberty, the brain undergoes a pretty large-scale pruning of neurons that are not being used,” Dr Kennedy said.

So the adolescent brain starts to refine itself and take on its adult format, and if that process, which is rather delicate, is upset by changes in the microbiome that hit the brain with cytokines and other kinds of inflammatory molecules during adolescence, that could be one of the mechanisms by which the microbiome contributes to or, in the most extreme case, causes schizophrenia.”

The study was funded by the Stanley Research Medical Institute. Dr Yolken and Dr Kennedy report no relevant financial relationships.

12th World Congress of Biological Psychiatry. Abstract S-37:004. Presented June 17, 2015.

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