Inflammation, Psychosis, and the Brain

Cytokines, or cellular hormones, include neurotrophins, neuropoietic factors, interleukin (IL)-1 and IL-6, interferons (IFNs), colony-stimulating factors, growth factors, and thymic hormones that are released following stress. Perivascular macrophages, microglial cells, astrocytes, and cerebral endothelial cells can produce cyto-kines on activation.¹⁰ Cytokines influence the transport of compounds into the brain by altering the permeability of the BBB. In vitro studies reveal that the administration of IL-1, IL-6, tumor necrosis factor (TNF)-a, and IFN-g increases endothelial permeability.^11-14 TNF-a can induce the production of matrix metalloproteinases—in particular gelatinase B—that attack the basal lamina macromolecule-like type 4 collagen(Drug information on collagen) that surrounds the brain microvessels. Modulation of adhesion molecules may promote leukocyte adhesion to the cerebral endothelium and permit the migration of lymphocytes across the BBB via a transcellular route (Figure 1).

Serum and cerebrospinal fluid S100b protein, inflammation, and schizophrenia
There is increasing interest in the brain-specific protein S100b and its physiological roles and behavior in various neuropathological conditions. Levels of S100b, a small astrocytic calcium-binding protein, are increased in some neurological conditions, such as brain trauma, ischemia, epilepsy, and brain tumors. Increased serum levels of S100b help rule out BBB disruption as reliably as contrast-­enhanced MRI and can be identified in seconds to minutes after BBB disruption. Elevated serum levels of S100b also predict the presence of neoplasms in the CNS. S100b thus serves as a noninvasive measurement of BBB function in patients and healthy persons.

S100b levels are elevated in first-episode psychosis, chronic schizophrenia, and acute psychosis (Table). In 14 studies that evaluated 399 adults with schizophrenia and 389 controls, S100b concentrations were above nor­­mal: average levels were 0.158 ng/mL in patients who have schizophrenia and 0.02 ng/mL in healthy controls. In a larger sample, Rothermundt and colleagues³ demonstrated the association of negative symptoms of schizophrenia with continuously elevated S100b for 24 weeks after an acute episode. Findings indicate that patients with initially elevated S100b concentrations show significantly slow­er improvement.

Monocytosis in patients with schizophrenia
Monocytosis has been reported in 5 studies. In their original observations of catatonia, Bruce and Peebles¹⁵ reported 12 cases of adolescents with psychosis and leukocytosis—particularly monocytosis. Zorrilla and colleagues16 reported monocytosis in symptomatic schizophrenic patients. Nikkila and associates¹⁷ compared cerebrospinal fluid samples obtained from schizophrenic patients and controls. The proportion of mononuclear/macrophages was signficantly higher in samples taken from patients who had schizophrenia. Wilke and coworkers18 detected a statistically significant increase in leukocyte numbers, particularly monocytes (P < .05), in patients compared with controls. Kowalski and colleagues¹⁹ demonstrated activation of monocytes in 20 patients with paranoid schizophrenia and an increased serum concentration of IL-1b and TNF-a that normalized with antipsychotic treatment.

Infections with different pathogens, viruses, retroviruses, and bacteria are increased across the life span of schizophrenic patients with a specific genotype. Fellerhoff and colleagues⁹ reported that Chlamydia stimulated the transmigration of monocytes through the BBB in 40.3% of 72 schizophrenic patients. This is a possible mechanism for monocyte activation and the inflammatory cascade.²⁰ For example, the presence of this infection activates the inflammatory response and increases production of cytokines associated with schizophrenia. It is perhaps genotype HLA-A10 in addition to the infection that may be associated with psychotic symptoms in some schizophrenic patients.

In our pilot study to analyze white blood cell abnormalities in children with psychosis, conducted from 2003 through 2006, we enrolled 102 inpatients admitted to the Cleveland Clinic Child and Adolescent Psychiatry unit. Sixteen patients who were taking anti-biotics or lithium(Drug information on lithium), who had a fever on admission, or who had bipolar disorder were excluded from the sample. A total of 86 patients with a median age of 14 years participated in the study. In those patients, 2 child psychiatrists diagnosed psychosis using DSM-IV-TR criteria for psychosis not otherwise specified (NOS), schizophreniform disorder, schizoaffective disorder, or new-onset schizophrenia. Active psychosis included hallucinations, delusions, or peculiar fantasies. A group of 86 nonpsychotic patients, recruited from the same inpatient unit, served as controls.