Increased microglial activity in schizophrenia

By Will Boggs MD

Individuals with schizophrenia and those at high risk of psychosis have elevated brain microglial activity, researchers report.

Several studies have implicated microglia, the resident immune cells of the central nervous system, in the pathology of psychosis.

Peter S. Bloomfield from Imperial College London and colleagues used the radioligand (11C)PBR28 to measure microglial activity in 14 persons with schizophrenia (and 14 age-matched healthy controls) and in 14 persons at ultra-high-risk of psychosis (and 14 age-matched controls).

The (11C)PBR28 distribution volume ratios in total gray matter and frontal lobe and temporal lobe gray matter were significantly increased in ultra-high-risk individuals and in patients with a diagnosis of schizophrenia, suggesting increased microglial activity compared with their matched comparison groups, the team reports in the American Journal of Psychiatry, online October 16.

Ultra-high-risk individuals and schizophrenia patients did not differ significantly from their respective control groups in cerebellar or brainstem distribution volume ratios.

(11C)PBR28 distribution volume ratios in total gray matter correlated positively with Comprehensive Assessment of the At-Risk Mental States symptom severity score in ultra-high-risk individuals but not with total Positive And Negative Syndrome Scale (PANSS) scores in patients with schizophrenia.

"Importantly, we found no relationship with depressive symptoms, suggesting elevated microglial activity is specific to the development of psychotic-like symptoms, rather than psychiatric symptoms in general," the researchers note.

"The elevations presented here might reflect a protective response triggered by associated pathology, such as glutamatergic excitotoxicity, or indicate a primary neuroinflammatory process linked to risk factors for psychosis and the development of subclinical symptoms," the authors suggest.

"When our findings are interpreted with evidence that anti-inflammatory drugs are effective in schizophrenia, particularly in addressing early negative symptoms, they suggest that a neuroinflammatory process is involved in the development of psychotic disorders," the researchers conclude. "While this indicates that anti-inflammatory treatment may be effective in preventing the onset of the disorder, further studies are required to determine the clinical significance of elevated microglial activity."

Liliana E. Laskaris and Dr. Maria Angelique Di Biase from The University of Melbourne and Melbourne Health in Carlton South, Victoria, Australia, recently reported on microglial activation and progressive brain changes in schizophrenia.

"The study adds to the mounting evidence of an overactive brain immune system in at least some individuals with schizophrenia," they told Reuters Health in a joint email. "The current study is important as it increases our understanding of the pathophysiology of schizophrenia and psychotic disorders and has implications for its clinical treatment. Specifically, it suggests that by reducing the activation of microglia then it may be possible to ameliorate or even prevent the development of psychosis in at-risk individuals."

"It should be noted that the evidence (both in vivo and post-mortem) for increased microglial activation in schizophrenia is mixed; thus further studies are warranted," said Laskaris and Dr. Di Biase, who were not involved in the new work. "This may be due to the existence of a subgroup of schizophrenia patients whose etiology is linked to increased inflammation."

"Although various anti-inflammatory agents have been trialed in psychosis, this study suggests that medication that solely targets microglial cells, rather than systemic inflammation, may be most effective," they said. "Such treatments will likely be most effective if targeted to a subgroup of UHR (ultra-high-risk) patients most susceptible to inflammation."

They added, "Further research is required to determine whether the increased activation of microglia is specifically associated with transition to psychosis by comparing the PET signal in at-risk subjects who did and did not go on to develop a full-blown psychotic disorder."

Bloomfield and coauthor Dr. Oliver D. Howes did not respond to a request for comments.


Am J Psychiatry 2015.

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