Inflammation and stress combine in bipolar and schizophrenia subtypes

By Lucy Piper, Senior medwireNews Reporter

Researchers have found that some individuals with bipolar disorder or schizophrenia have combined stress response and immune dysfunctions.

They suggest that these inflammatory and stress interactions may explain some of the heterogeneity between schizophrenia and bipolar disorder and provide novel molecular targets for treatment.

“Our study builds on the mounting evidence suggesting that a subset of individuals with psychotic illness have increased expression of immune-related genes in the brain, cerebrospinal fluid, and blood,” says the team, led by Cyndi Shannon Weickert (Neuroscience Research Australia, Randwick, New South Wales).

“By showing that the immune changes are often concomitant with alterations in the stress signalling system, we have expanded the understanding of possible molecular mechanisms involved in the pathophysiology and of the therapies targeting these systems.”

The researchers examined expression of eight inflammatory-related genes in the Stanley Array Cohort of 35 mentally healthy individuals, 35 patients with schizophrenia and 34 patients with bipolar disorder.

Of these genes, SERPINA3 messenger(m)RNA was significantly increased in individuals with schizophrenia compared with those with bipolar disorder and controls, while interleukin (IL)8 mRNA was significantly decreased in schizophrenia patients relative to the other two groups.

IL1β, IL18, tumour necrosis factor (TNF), and PTGS2 mRNAs showed no differences according to diagnosis and IL1RL1 and IL6 mRNAs were not significantly changed but were higher than median values in both psychosis groups.

The researchers suggest in Translational Psychiatry that the upregulation of SERPINA3 in patients with schizophrenia may reflect a compensatory role to attenuate a chronic inflammatory response.

By contrast, for bipolar disorder patients, evidence of an inflammatory effect was only seen in clustering analyses of the eight inflammatory markers alongside 11 mRNAs from the glucocorticoid receptor (GR) stress signalling pathway.

Clustering of 12 of the 19 genes and four demographic factors revealed two groups: a high inflammation/stress group (n=32) and a low inflammation/stress group (n=68).

The researchers note that the high inflammation/stress group comprised a significantly greater number of individuals with schizophrenia (n=15) and a trend towards a higher number of individuals with bipolar disorder (n=11), compared with mentally healthy individuals (n=6).

“In schizophrenia and bipolar disorder it is possible that chronic hypercortisolemia, in a portion of patients with greater negative symptoms, may cause a chronic decrease in the expression and function of GR protein leading to attenuation of the natural inhibition of the immune system by stress,” the investigators remark.

Conducting a pathway analysis, the team found that the gene networks that distinguished between the schizophrenia and bipolar disorder patients in the high inflammation/stress subgroup and controls in the low inflammation/stress group involved growth factor, immune, inhibitory signalling, cell death and signalling, AMPA receptor and nuclear factor functions.

“In combination, the inflammatory/stress dysfunction may integrate previously independent observations about the pathophysiology of the disorders and provide additional targets for novel, individually or biological subgroup-targeted treatment interventions,” Weickert et al conclude.

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