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 D Veldic, Francisco Romo-Nava, William V Bobo, Balwinder Singh, Colin Colby, Michelle K. Skime, Joanna M Biernacka, Robert Yolken

Research output: Contribution to journalArticle

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)
JournalJAMA Psychiatry
DOIs
StateAccepted/In press - Jan 1 2019

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Toxoplasma
Cytomegalovirus
Bipolar Disorder
Antibodies
Psychotic Disorders
Immunoglobulin G
Odds Ratio
Age of Onset
C-Reactive Protein
Antibody Formation
Immunoglobulin M
Pharmaceutical Preparations
Measles
Therapeutics
Infection
Serum
Case-Control Studies
Joints
Outcome Assessment (Health Care)
Inflammation

ASJC Scopus subject areas

  • Psychiatry and Mental health

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Association of Cytomegalovirus and Toxoplasma gondii Antibody Titers with Bipolar Disorder. / Frye, Mark A; Coombes, Brandon J.; McElroy, Susan L.; Jones-Brando, Lori; Bond, David J.; Veldic, Marin D; Romo-Nava, Francisco; Bobo, William V; Singh, Balwinder; Colby, Colin; Skime, Michelle K.; Biernacka, Joanna M; Yolken, Robert.

In: JAMA Psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Frye, Mark A ; Coombes, Brandon J. ; McElroy, Susan L. ; Jones-Brando, Lori ; Bond, David J. ; Veldic, Marin D ; Romo-Nava, Francisco ; Bobo, William V ; Singh, Balwinder ; Colby, Colin ; Skime, Michelle K. ; Biernacka, Joanna M ; Yolken, Robert. / Association of Cytomegalovirus and Toxoplasma gondii Antibody Titers with Bipolar Disorder. In: JAMA Psychiatry. 2019.
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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..",
author = "Frye, {Mark A} and Coombes, {Brandon J.} and McElroy, {Susan L.} and Lori Jones-Brando and Bond, {David J.} and Veldic, {Marin D} and Francisco Romo-Nava and Bobo, {William V} and Balwinder Singh and Colin Colby and Skime, {Michelle K.} and Biernacka, {Joanna M} and Robert Yolken",
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TY - JOUR

T1 - Association of Cytomegalovirus and Toxoplasma gondii Antibody Titers with Bipolar Disorder

AU - Frye, Mark A

AU - Coombes, Brandon J.

AU - McElroy, Susan L.

AU - Jones-Brando, Lori

AU - Bond, David J.

AU - Veldic, Marin D

AU - Romo-Nava, Francisco

AU - Bobo, William V

AU - Singh, Balwinder

AU - Colby, Colin

AU - Skime, Michelle K.

AU - Biernacka, Joanna M

AU - Yolken, Robert

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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..

AB - 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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