Letter to the Editor

Cytokines in schizophrenia: Methodological Issues

A role for immune processes in the pathogenesis of schizophrenia has been suggested by genetic and epidemiological studies, as well as cross-sectional studies on blood and brain samples. However, results are heterogeneous, which is likely caused by low samples sizes, insufficient control of confounders that influence immune processes, and potentially publication bias. Large hypothesis-free ‘omic’ studies partially circumvent these problems and could provide further evidence for a role of immune pathways in schizophrenia. In this review we assessed whether the largest genome, transcriptome and methylome studies in schizophrenia to date support a link with the immune system. We constructed an overview of the schizophrenia-associated genes and transcripts that were identified in these large ‘omic’ studies. We then performed a hypothesis-driven analysis to examine the association and enrichment of immune system-related genes and transcripts in these datasets. Additionally, we reviewed secondary analyses that were previously performed on these ‘omic’ studies. Except for the link between complement factor 4 (C4), we found limited evidence for a role of microglia and immune processes among genetic risk variants. Transcriptome and methylome studies point towards alterations in immune system related genes, pathways and cells. This includes changes in microglia, as well as complement, nuclear factor-κB, toll-like receptor and interferon signaling pathways. Many of these associated immune-related genes and pathways have been shown to be involved in neurodevelopment and neuronal functioning. Additional replication of these findings is needed, but once further conformation is provided, these findings could be a potentially interesting target for future therapies.

Increased rates of exposure to Toxoplasma gondii have been found in patients with psychiatric disorders globally, but there is scarce information about the epidemiology of T. gondii infection in psychiatric patients in Zhejiang Province, Southeastern China. In a case-control survey, we measured IgG and IgM class antibodies against T. gondii in 798 patients from a public psychiatric hospital in the city of Wenzhou, Zhejiang Province, and in 681 non-psychiatric controls from the general population in the same region. Subjects in each group were matched by sex and age with an enzyme-linked immunoassay. Seroprevalence of anti-Toxoplasma IgG antibodies in psychiatric patients (13.3%, 106/798) was significantly higher than in the control population (9.4%, 64/681) (P =  0.022). Anti-Toxoplasma IgM antibodies were also significantly higher in the psychiatric patients (4.1%, 33/798) than in the control group (1.9%, 13/681) (P =  0.016). Additionally, we found significantly elevated seropositive rates of anti-Toxoplasma IgG and IgM in patients with schizophrenia, as well as those with bipolar disorder. The identification of specific anti-Toxoplasma antibodies in psychiatric patients may be useful for assessing infection and timely initiation of treatment.

Previous studies have identified elevations in antibodies to Toxoplasma gondii in individuals with a history of suicide attempts but studies have not measured the association between suicide attempts and a panel of antibody markers. We assessed 162 patients receiving treatment for schizophrenia, bipolar disorder, or major depression on the Columbia Suicide Severity Rating Scale for suicide attempt history and other clinical measures. All participants had a blood sample drawn from which were measured antibodies to Toxoplasma gondii and other neurotropic infectious agents. A total of 72 (44%) of participants had a lifetime suicide attempt; these individuals had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV). We also found an association between the levels of these antibodies and the number of suicide attempts. There was a particularly strong odds of a suicide attempt history in individuals who had elevated levels of IgM antibodies to both Toxoplasma gondii and to CMV suggesting an additive risk associated with the antibodies. These findings remained significant when adjusting for current cigarette smoking and history of drug/alcohol use which were also associated with suicide attempts. We did not find an association between a suicide attempt history and IgG class antibodies to Toxoplasma gondii, CMV, or IgM or IgG antibodies to the Epstein Barr Virus or other antigens tested. The identification of blood-based antibody markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.