Inflammation, Psychosis, and the Brain

By Tatiana Falcone, MD, Erin Carlton, MS, Kathleen Franco, MD, and Damir Janigro, PhD | July 10, 2009

Dr Falcone is associate professor of psychiatry in the department of psychiatry and neurology at the Cleveland Clinic Neurological Institute. Erin Carlton is a medical student at the University of Toledo. Dr Franco is a consultation liaison psychiatrist at the Cleveland Clinic and associate dean of admissions and student affairs, and professor of medicine and psychiatry at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr Janigro is the director of cerebrovascular research at Cleveland Clinic and professor of molecular medicine at the Cleve-land Clinic Lerner College of Medicine.

Drs Falcone and Franco and Ms Carlton report no conflicts of interest concerning the subject matter of this article. Dr Janigro reports that he has a US patent on S100ß.

When comparing hematological results of these patients with those of controls, monocytosis was the most common and statistically significant finding (P < .01) (Figure 2).

In the psychotic group, most patients had monocyte counts that were well above what is considered normal for children. The percentage of monocytes was particularly high. These findings did not correlate with drug use before admission or with therapeutic and pharmacological interventions.

Prospective study of inflammatory markers in children with psychosis
To further assess the role of inflammation in the pathogenesis of psychosis, we studied the relationship between S100b serum concentrations and acute psychosis in children and adolescents. Participants had been admitted to the child and adolescent inpatient psychiatry unit with a diagnosis of acute psychosis. (Psychosis NOS, schizophreniform disorder, or schizophrenia had been diagnosed in the past 6 months.) Parent(s) or guardian(s) gave consent for us to obtain blood samples.

Our hypothesis was that proinflammatory changes were responsible for observed differences in the monocyte counts of the psychotic patients and that a downstream effect of monocytosis was damaging to the endothelial cells constituting the BBB. Serum samples of 10 psychotic children were compared with those of 9 healthy children. In the healthy control group, a preliminary interview had ruled out psychosis, any neurodegenerative disorder, fever, current infection, or current use of antibiotics.

S100b levels were significantly higher in children with psychosis than in controls (P < .05) (Figure 3). Most psychotic children had S100b levels above normal. Nonetheless, S100b is a nonspecific measure of BBB permeability. Elevated S100b does not give insight into the mechanism of BBB disruption, and it does not prove a causal link to psychotic symptoms. Psychosis may precede elevations of S100b and BBB dysfunction. From this standpoint, S100b can still serve as a biomarker of BBB disruption.

Future research may determine whether serum factors are causally related or only associated with transendothelial leakage of S100b.

Conclusion
First-episode psychosis in children is associated with evidence of increased inflammation (eg, monocytosis) and elevated serum concentrations of S100b. Several cytokines—TNF-a, IL-1b, and IL-6, among others—have been reported to be elevated in patients with schizophrenia. These inflammatory mediators are often associated with BBB leakage, which is consis-tent with animal models of schizophrenia.^21-24 Curiously, some antipsychotic medications have immunomodulatory effects.²⁵

Our results support the inflammatory theory of schizophrenia that was formulated over a 100 years ago and perhaps offer hope that prevention of chronicity can occur if the first episode of psychosis is rapidly and effectively controlled.²⁶ Although there are mixed results in 6 studies using anti-inflammatory medications in schizophrenic patients, Müller and colleagues^27,28 believe that these agents are more likely to be effective in first-episode patients than in those with chronic schizophrenia.

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Drug Mentioned in This Article
Lithium (Eskalith, Lithane, Lithobid)

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