Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses

Abstract

Inflammation is a natural defence response of the immune system against environmental insult, stress and injury, but hyper- and hypo-inflammatory responses can trigger diseases. Accumulating evidence suggests that inflammation is involved in multiple psychiatric disorders. Using inflammation-related factors as biomarkers of psychiatric disorders requires the proof of reproducibility and specificity of the changes in different disorders, which remains to be established. We performed a cross-disorder study by systematically evaluating the meta-analysis results of inflammation-related factors in eight major psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depression disorder (MDD), post-trauma stress disorder (PTSD), sleeping disorder (SD), obsessive–compulsive disorder (OCD) and suicide. A total of 43 meta-analyses involving 704 publications on 44 inflammation-related factors were included in the study. We calculated the effect size and statistical power for every inflammation-related factor in each disorder. Our analyses showed that well-powered case–control studies provided more consistent results than underpowered studies when one factor was meta-analysed by different researchers. After removing underpowered studies, 30 of the 44 inflammation-related factors showed significant alterations in at least one disorder based on well-powered meta-analyses. Eleven of them changed in patients of more than two disorders when compared with the controls. A few inflammation-related factors showed unique changes in specific disorders (e.g., IL-4 increased in BD, decreased in suicide, but had no change in MDD, ASD, PTSD and SCZ). MDD had the largest number of changes while SD has the least. Clustering analysis showed that closely related disorders share similar patterns of inflammatory changes, as genome-wide genetic studies have found. According to the effect size obtained from the meta-analyses, 13 inflammation-related factors would need <50 cases and 50 controls to achieve 80% power to show significant differences (p < 0.0016) between patients and controls. Changes in different states of MDD, SCZ or BD were also observed in various comparisons. Studies comparing first-episode SCZ to controls may have more reproducible findings than those comparing pre- and post-treatment results. Longitudinal, system-wide studies of inflammation regulation that can differentiate trait- and state-specific changes will be needed to establish valuable biomarkers.

Functional Neuroimaging in Psychiatry—Aiding in Diagnosis and Guiding Treatment. What the American Psychiatric Association Does Not Know

“…Furthermore, the role of inflammation in depression is now supported by a wealth of evidence. Experts now believe that inflammatory processes underlie and contribute to depressive pathophysiology in a significant proportion of cases (68)(69)(70)(71). These concepts grew from observations that medications which reduced inflammatory processes had antidepressant properties.…”

“…Briefly, cytokines are elevated in a portion of patients suffering from depression. In particular, tumor necrosis factor alpha (TNFa), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-13 (IL-13), interleukin-18 (IL-18), Creactive protein (CRP), chemokine-2 (CCL2), and chemokine-11 (CCL11) are elevated in depression based on multiple metaanalyses (68,71,73). But how inflammatory cytokines induce depressive symptoms remain incompletely understood.…”

Commentary: Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

“…While promising studies have begun to identify subpopulations of patients with MDD likely to respond to anti-inflammatory therapy (15), results of immune phenotyping in other disorders have been variable. A recent systematic review found that meta-analyses for MDD, ASD, bipolar disorder, and schizophrenia have consistently reported changes in only 16, 7, 8, and 7 individual inflammation-related factors in peripheral blood, respectively (16). The single metaanalysis of immune phenotyping studies in OCD was filtered out because of insufficient statistical power (16).…”

“…A recent systematic review found that meta-analyses for MDD, ASD, bipolar disorder, and schizophrenia have consistently reported changes in only 16, 7, 8, and 7 individual inflammation-related factors in peripheral blood, respectively (16). The single metaanalysis of immune phenotyping studies in OCD was filtered out because of insufficient statistical power (16). Longitudinal data were lacking and state versus trait markers difficult to distinguish, markers were restricted to a few per study based on a biased candidate gene/cytokine approach, and the contribution of confounding factors-including childhood adversity, diet, and smoking-was potentially significant (16).…”

“…The single metaanalysis of immune phenotyping studies in OCD was filtered out because of insufficient statistical power (16). Longitudinal data were lacking and state versus trait markers difficult to distinguish, markers were restricted to a few per study based on a biased candidate gene/cytokine approach, and the contribution of confounding factors-including childhood adversity, diet, and smoking-was potentially significant (16). Ultimately, longitudinal clinical characterization combined with a broad approach to immune phenotyping-as employed in a recent analysis of microarray data in MDD (17)-is likely a higher-yield approach both for biomarker discovery and for improving our understanding of how peripheral inflammation reflects or perpetuates psychiatric symptoms.…”