Neuroinflammatory biomarkers in suicidal behavior

Immune dysregulation is of importance in the pathophysiology underlying psychiatric disorders including major depression, bipolar disorder, and schizophrenia. Neurobiological alterations such as a dysregulated stress-hormonal axis and serotonergic alterations have been reported in suicide attempters at risk for subsequent suicide. Immune dysregulation in suicidal behavior is less well studied, but with some evidence for elevated proinflammatory cytokines and decreased levels of neurotrophins, such as brain-derived neurotrophic factor. The aim of this thesis was to study neuroinflammatory biomarkers with regard to suicidal behavior in patients with mood disorders.

For the first part of this thesis (Studies I-III) we studied a high-risk cohort of patients with a recent suicide attempt. All were thoroughly assessed diagnostically and rated with regard to personality traits, severity of depression and suicidal intent. We did a follow-up on all patients regarding cause of death. 20 healthy controls were used for comparison. Patients were sampled for blood (n = 58) and cerebrospinal fluid (CSF) (n= 43). Samples were assayed using immune-based assay-systems for immune markers and growth factors.

Seven patients who at follow-up, had completed suicide had lower plasma levels of vascular endothelial growth factor (VEGF). Furthermore, we found that the patients had lower CSF levels of both VEGF and interleukin- (IL-) 8 compared to the healthy comparison group. Lastly, we found that IL-6 levels in both plasma and CSF correlated with personality traits of impulsivity in suicide attempters.

For the second part of this thesis (Study IV) we investigated the effects of physical activity on immune markers implied to be of importance in the pathophysiology of depression and suicidal behavior. The participants were completely healthy both somatically and psychiatrically. We studied the effects of an acute intensive exercise challenge during four days (n = 14), and a moderate exercise challenge during four weeks (n = 13). Paired sampling from blood and CSF before and after exercise intervention was compared. All rated mood before and after intervention.

We found that CSF IL-8 was significantly elevated in both groups as a result of physical exercise. Serum IL-6 and IL-8 were significantly elevated in the total group, as well as IL-6 in the intensive group and IL-8 in the moderate group. We found no significant correlation between serum and CSF levels in the assayed analytes, suggesting that the effects of physical activity were segregated between the compartments. Furthermore, we found a negative correlation regarding mood ratings and CSF IL-8, suggesting relevance of CSF IL-8 as a state marker for mood.

We propose that low VEGF may be a marker for treatment resistance and suicide risk, while high IL-6 seems to be related to impulsivity and violent methods of attempted suicide, both of which are important endophenotypes of suicidal behavior. Physical exercise is also an important confounder in immune biomarker studies.

List of scientific papers

I. Isung, J., F. Mobarrez, P. Nordström, M. Asberg, and J. Jokinen. “Low Plasma Vascular Endothelial Growth Factor (VEGF) Associated with Completed Suicide.” The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of Biological Psychiatry 13, no. 6 (September 2012): 468–73.
https://doi.org/10.3109/15622975.2011.624549

II. Isung, J., S. Aeinehband, F. Mobarrez, B. Mårtensson, P. Nordström, M. Asberg, F. Piehl, and J. Jokinen. “Low Vascular Endothelial Growth Factor and Interleukin-8 in Cerebrospinal Fluid of Suicide Attempters.” Translational Psychiatry 2 (2012): e196.
https://doi.org/10.1038/tp.2012.123

III. Isung, J., S. Aeinehband, F. Mobarrez, P. Nordström, B. Runeson, M. Asberg, F. Piehl, and J. Jokinen. “High Interleukin-6 and Impulsivity: Determining the Role of Endophenotypes in Attempted Suicide.” Translational Psychiatry 4 (2014): e470.
https://doi.org/10.1038/tp.2014.113

IV. Isung, J., M. Granqvist, J. Jokinen, and F. Piehl. “Immune Marker Variability in Plasma and Cerebrospinal Fluid after Physical Exercise: Implications for Biomarker Research in Psychiatry.” [Manuscript]