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Original Investigation
September 18, 2019

Association of Cytomegalovirus and Toxoplasma gondii Antibody Titers With Bipolar Disorder

Author Affiliations
  • 1Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota
  • 2Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 3Department of Psychiatry and Behavioral Neuroscience, Lindner Center of HOPE, University of Cincinnati, Cincinnati, Ohio
  • 4Stanley Laboratory of Developmental Neurovirology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 5Department of Psychiatry, University of Minnesota, Minneapolis
  • 6Department of Psychiatry & Psychology, Mayo Clinic, Jacksonville, Florida
JAMA Psychiatry. 2019;76(12):1285-1293. doi:10.1001/jamapsychiatry.2019.2499
Key Points

Question  Is bipolar disorder associated with exposure to infectious agents with immune activation?

Findings  In this case-control study of 1952 patient cases, cytomegalovirus IgG was significantly increased and toxoplasma IgG was significantly decreased among patients with bipolar disorder compared with control individuals. Patients with bipolar disorder who received drug treatment with antitoxoplasma activity had significantly lower toxoplasma IgM titers compared with those not receiving this treatment.

Meaning  Increased and decreased long-term antibody response to cytomegalovirus and toxoplasma, respectively, were associated with bipolar disorder in this sample; further work appears to be needed to better understand genetic vs environmental risk of the disease and how infection or immune activation contributes to overall disease pathogenesis with particular reference to disease onset.

Abstract

Importance  Infection-associated immune activation and inflammation are increasingly recognized in the pathophysiology of bipolar disorder.

Objective  To determine whether antibodies to common infectious agents, including cytomegalovirus (CMV), Toxoplasma gondii, and measles, as well as the inflammatory marker C-reactive protein, in serum samples differ between patients with bipolar disorder and control individuals without bipolar disorder.

Design, Setting, and Participants  In this case-control study, antibody titers were measured in serum samples from 1207 patients with bipolar disorder and 745 controls that were obtained from biobanks with participating sites in Rochester and Minneapolis, Minnesota (n = 1537), and Cincinnati, Ohio (n = 415), from January 5, 2009, through May 12, 2014. A subset of case patients and controls from Minnesota were matched by age, sex, and educational level. Bipolar type, age at onset, and history of psychosis were assessed for case patients as well as current drug treatment at the time of blood sample obtainment from the biobank. Data were analyzed from February 5, 2018, to January 4, 2019.

Exposures  The CMV and T gondii antibodies with IgM titers were expressed as z scores and IgG titers dichotomized into seropositive and seronegative based on expected prevalence in the US population and further classified based on the joint CMV-positive/T gondii–negative IgG status, C-reactive protein z score, and drug treatments with antitoxoplasma activity.

Main Outcomes and Measures  Patients were stratified by bipolar disorder type I or type II, nonearly (>19 years of age) and early (≤19 years of age) onset, and history of psychosis during mania or no psychosis.

Results  Of 1207 patients with bipolar disorder (mean [SD] age, 43.2 [15.1] years; 742 [61.5%] female), the CMV-positive/T gondii–negative IgG status was significantly higher (odds ratio [OR], 1.33; 95% CI, 1.09-1.62; P = .004) compared with that in the 745 controls (mean [SD] age, 44.5 [15.5] years; 444 [59.6%] female). The CMV-positive/T gondii–negative IgG status was associated with bipolar cases type I (OR, 1.41; 95% CI, 1.14-1.75; P = .001), nonearly age at onset (OR, 1.41; 95% CI, 1.16-1.72; P = .001), and history of manic psychosis (OR, 1.46; 95% CI, 1.13-1.88; P = .004). Patients with bipolar disorder who received drug treatment with antitoxoplasma activity (n = 272) had significantly lower T gondii IgM titers (median, 1.59; interquartile range, 1.30-2.07) compared with those (n = 900) who did not receive this treatment (median, 1.69; interquartile range, 1.35-2.25) (P = .03).

Conclusions and Relevance  In this sample, increased long-term antibody response to CMV and decreased long-term antibody response to T gondii were associated with bipolar disorder and the subphenotypes of bipolar type I, nonearly disease onset, and manic psychosis. Further work appears to be needed to better understand genetic vs environmental disease risk and infection or immune activation contribution to overall disease pathogenesis with particular reference to disease onset.

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    1 Comment for this article
    EXPAND ALL
    Cytomegalovirus Antibody Titers as an Indicator of Immunossenesce in Bipolar Disorder
    Elisa Brietzke, MD, PhD. | Queen's University
    We read with interest the article from Frye et al. demonstrating that patients with bipolar disorder (BD), especially those with some subphenotypes, have higher Cytomegalovirus (CMV) titers compared to healthy subjects. Literature indicates an association between persistent low-grade activation of inflammatory response and bipolar disorder, which may contribute to BD pathophysiology. Cytomegalovirus infection may be an environmental factor for inflammation; the chronicity of the infection is a longstanding immune challenge, requiring that the organism endanger its immune system by maintaining a long-term response. This response is characterized by the periodic expansion of a large population of CMV-specific CD8, and to a lesser extent, CD4 T cells produced in response to cycles of viral reactivation (aptly called memory inflation). Constant inflammation can undermine the immune system, as it results in its overload and consequent immunosenescence. The presence of a chronic low-grade inflammation profile, increased senescent T and B cells subpopulations, and diminished function of mature cells, related to immune aging in healthy subjects, suggests that BD might be an accelerated immunosenescence disorder. However, what might be the cause? Could immunosenescence be involved in BD pathophysiology, or is the cyclical characteristic of BD that results in an immune overload? Could differential CMV exposure be a cause of immunosenescence in BD?
    In one study, Rizzo and colleagues (2018) demonstrated the existence of a latent Immunological Aging (IA) trait contributing to several cellular immunosenescence markers observed in patients with BD, especially in those exhibiting multiple mood episodes. However, in this study CMV infection was considered a possible bias to be controlled and not an intrinsic abnormality from the psychiatric condition. While a large study such as the one conducted by Frye et al. could benefit from the perspective of CMV increased titers as evidence of premature immune aging, other studies assessing inflammation in BD should advance the research of, or at least take into account, the presence of CMV infection and the organism response to the virus.
    Both types of studies bring to light important and novel information in order to develop new treatment strategies, such as the use of immunomodulators, anti-inflammatories antiviral treatments, or lifestyle changes, which would ultimately prevent or promote the removal of senescent and functionally exhausted cells. Creating additional “immunological space” could be beneficial in BD; however, requires a better understanding into the functionality of the immune system in psychiatric diseases, a field as exciting as it is unknown.

    Andrea Wieck PhD1, Alice Carvalhal Schoffel MsC2 , Elisa Brietzke MD, PhD3.
    1. Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.
    2. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
    3. Department of Psychiatry, Queen’s University School of Medicine, Kingston, ON, Canada.
    CONFLICT OF INTEREST: None Reported
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