Association of Cytomegalovirus and Toxoplasma gondii Antibody Titers with Bipolar Disorder

Mark A. Frye, Brandon J. Coombes, Susan L. McElroy, Lori Jones-Brando, David J. Bond, Marin Veldic, Francisco Romo-Nava, William V. Bobo, Balwinder Singh, Colin Colby, Michelle K. Skime, Joanna M. Biernacka, Robert Yolken

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1285-1293
Number of pages9
JournalJAMA psychiatry
Volume76
Issue number12
DOIs
StatePublished - Dec 2019

Bibliographical note

Funding Information:
receiving grants from the Marriott Foundation during the conduct of the study; receiving grants from the National Institute of Alcohol Abuse and Alcoholism and National Institute of Mental Health, National Institutes of Health, Assurex Health, Myriad, and Pfizer; being a consultant to Janssen Global Services LLC; receiving other support from Mitsubishi Tanabe Pharma Corporation, Myriad, Sunovion, and Teva Pharmaceuticals; receiving travel and hotel honoraria from CME Outfitters to give a lecture for continuing medical education credit and receiving support for a presentation from Sunovian. Dr McElroy reported receiving grants and personal fees from Allergan, Avanir, Myriad, Shire, and Sunovion; receiving grants from Brainsway, Marriott Foundation, Medibio, Neurocrine, and Novo Nordisk; receiving personal fees from Bracket, F. Hoffmann-LaRoche Limited, Mitsubishi Tanabe Pharma America, and Opiant; being a consultant to or member of the scientific advisory boards of Bracket, MedAvante, Naurex, Shire, and Sunovion; being a principal or co-investigator on studies sponsored by the Agency for Healthcare Research & Quality, AstraZeneca, Cephalon, Forest, Marriott Foundation, the National Institute of Mental Health, Orexigen Therapeutics Inc, Shire, and Takeda Pharmaceutical Company Ltd; being an inventor on US Patent 6 323 236 B2; and receiving payments from Johnson & Johnson, which has exclusive patent rights. Dr Bond reported receiving grants form Myriad Genetics outside the submitted work. Dr Romo-Nava reported receiving grants from the Marriott Foundation during the conduct of the study; receiving nonfinancial support from Soterix Medical outside the submitted work; and having patent 62 581 968 pending. Dr Bobo reported receiving other support from Marriott Foundation during the conduct of the study, receiving other support from UpToDate outside the submitted work, and receiving research support from the National Institutes of Health, the Agency for Healthcare Research & Quality, and the Mayo Foundation for Medical Education and Research. Dr Singh reported receiving other support from Medibio outside the submitted work. Dr Biernacka reported receiving grants from Marriott Foundation during the conduct of the study. No other disclosures were reported.

Funding Information:
Funding/Support: Funding for this study was provided by the Marriott Foundation.

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