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ICOSR 2015—Is There an Infectious Flame in the Brain in Schizophrenia?

3 May 2015

As part of our ongoing coverage of the 2015 International Congress on Schizophrenia Research (ICOSR), held March 29 through April 1 in Colorado Springs, we bring you session summaries from some of the participants in the Young Investigator program. We are, as always, grateful for the gracious assistance of conference directors Carol Tamminga and Chuck Schulz, as well as meeting staff Cristan Tamminga and Dorothy Denton. For this report, we thank Golam Khandaker of the University of Cambridge in the United Kingdom.

May 4, 2015. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, recent studies have demonstrated complex interactions among the immune system, systemic inflammation, and the brain that can lead to changes in cognition, mood, and behavior. A symposium on Tuesday morning, March 31, brought together novel data from studies of mice and humans that offer new insights into the relationships among infection, immune response, cognition, and schizophrenia (for a recent review, see Khandakar et al., 2014). The session was chaired by Peter Jones of the University of Cambridge, UK.

The first speaker, Robert Dantzer from MD Anderson Cancer Center in Houston, Texas, presented findings from studies of inflammation-induced neuropsychiatric symptoms in mice that elucidate mechanistic bases for well-replicated epidemiological associations among infection, systemic inflammation, psychosis, and depression. Circulating inflammatory cytokines such as interleukin 6 (IL-6) can communicate with the brain in a number of pathways involving afferent neurons, and humoral and cellular mechanisms. Transduction of the peripheral cytokine signal to the brain leads to microglia activation, tryptophan metabolism along the kynurenine pathway affecting glutamatergic neurotransmission, an increase in oxidative stress, and activation of the HPA axis. These changes could be relevant for a number of neuropsychiatric symptoms seen in schizophrenia and other mental illnesses.

Golam Khandaker from the University of Cambridge followed with data suggesting that inflammatory immune response, especially elevated serum concentrations of cytokines such as IL-6, might contribute to the risks of psychosis and depression (Khandaker et al., 2014). This longitudinal study showed that higher serum concentrations of IL-6 in childhood at age nine years are associated with nearly twofold risks of psychosis and depression at age 18 years. These associations were not explained by concurrent infection, body mass, sex, social class, ethnicity, past psychological and behavioral problems, or history of maternal depression. This is one of the first longitudinal studies on this topic. The findings indicate a potentially causal role of inflammatory immune response in schizophrenia that are consistent with those of many previous studies reporting elevated levels of IL-6 and other proinflammatory cytokines in acutely unwell patients with schizophrenia and depression.

The next speaker, Robert Yolken from Johns Hopkins University in Baltimore, Maryland, presented an analysis of the microbiome in schizophrenia patients, which provides important clues to the potential causes of immune activation in schizophrenia (Yolken et al., 2015). Compared with non-psychiatric controls, schizophrenia patients had increased streptococci, pathogenic bacteria, and bacteriophage viruses, specifically the Lactobacillus phage phi adh, in their pharyngeal microbiome. The presence of streptococci was associated with elevated serum C-reactive protein and specific auto-antibody levels in schizophrenia, for example, anti-gliadin IgG. Pharyngeal bacteriophage was associated with immunological disease and valproate treatment. The findings indicate that oropharyngeal microbiome composition in schizophrenia differs from that of controls and may be related to concurrent immunological abnormalities.

Inflammation could contribute to cognitive deficits and decline seen in schizophrenia. Exposure to members of the Herpesviridae family is associated with risk of schizophrenia as well as cognitive dysfunction in schizophrenia and healthy controls.

Vishwajit Nimgaonkar from the University of Pittsburgh presented a longitudinal study comparing schizophrenia cases and healthy controls from India over a one-year period that shows seropositivity to herpes simplex virus type 1 (HSV1) is associated with decline in certain cognitive domains over time, irrespective of schizophrenia diagnosis. These findings indicate a potentially important role of HSV1 in cognition that might be relevant for schizophrenia and other cognitive disorders.—Golam Khandaker.