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. 2020 Jul 30;147(13):1577–1586. doi: 10.1017/S0031182020001183

Infection with Toxoplasma gondii increases the risk of psychiatric disorders in Taiwan: a nationwide population-based cohort study

Hsin-An Lin 1,2, Wu-Chien Chien 3,4,5, Kuo-Yang Huang 6, Chi-Hsiang Chung 3,7, Lih-Chyang Chen 8, Hsin-Chung Lin 9,✉, Jong-Long Guo 2,✉
PMCID: PMC10317747  PMID: 32729456

Abstract

This study aimed to evaluate associations between toxoplasmosis and psychiatric disorders in Taiwan based on the National Health Insurance Research Database, Taiwan (1997–2013). Patients newly diagnosed with toxoplasmosis formed the case group (n = 259), and the control group included propensity-score matched patients without toxoplasmosis (n = 1036). The primary outcome was incidence of psychiatric disorders. Cox proportional hazards regression and stratified analyses were performed to examine risk of developing specific psychiatric disorders between patients with and without toxoplasmosis. Patients with toxoplasmosis had significantly higher incidence of psychiatric disorders than those without toxoplasmosis (P = 0.016). A significant difference was found in numbers of psychiatric disorders between the two groups during 14 years of follow-up (log-rank P < 0.001). Those with toxoplasmosis had significantly higher risk of bipolar disorder [adjusted hazard ratio (aHR = 3.60, 95% confidence interval (CI) = 2.07, 7.26), depression (aHR = 4.94, 95% CI = 2.15, 11.80) and anxiety (aHR = 5.36, 95% CI = 2.98, 25.88), but no significant between-group differences were found for schizophrenia and other psychiatric disorders. In conclusion, the present nationwide population-based analysis revealed that Toxoplasma gondii infection in Taiwan significantly increases the risk for developing bipolar disorder, depression and anxiety, but not for schizophrenia and other psychiatric disorders.

Key words: Anxiety, bipolar disorder, depression, schizophrenia, Toxoplasma gondii

Introduction

Toxoplasma gondii is a zoonotic parasite that causes opportunistic infection globally. Although roughly one-third of the world's population is affected by T. gondii infection, seroprevalence of anti-T gondii immunoglobulin G (IgG) and IgM antibodies varies greatly by geographic regions and countries, with lower seroprevalence in European countries and the United States (Pappas et al., 2009). Regional differences in seroprevalence can range from 10 to 80% (Robert-Gangneux and Darde, 2012), but the lack of systematic reporting of seropositivity makes it difficult to understand associated risk factors (Pappas et al., 2009). Although T. gondii infection is found in many warm-blooded animals, domestic cats are the definitive host (Chiang et al., 2014; Achaw et al., 2019; Ybanez et al., 2019). Numerous studies demonstrated that all cats in the world can shed T. gondii oocytes in feces, leading to environmental contamination and public health threats (Dabritz and Conrad, 2010; Berger-Schoch et al., 2011; Lilly and Wortham, 2013; Zulpo et al., 2018). Human are likely to be infected via ingestion of T. gondii oocyte-contaminated soil and water, and/or consumption of raw or undercooked meat containing T. gondii tissue cysts (Elmore et al., 2010; Berger-Schoch et al., 2011; Chiang et al., 2014). Stray cats with increased exposure to pathogens are more likely to be infected by T. gondii than domestic cats (Hartmann et al., 2013; Chalkowski et al., 2019; Khodaverdi and Razmi, 2019; Palerme et al., 2019). Domestic cats, however, can transmit T. gondii to their owners, so having a cat is an independent risk factor for T. gondii seropositivity in Ethiopia and Taiwan (Chiang et al., 2014; Achaw et al., 2019).

A survey revealed that among 1783 Taiwanese healthy blood donors, 161 (9.0%) donors were seropositive for anti-T. gondii IgG only and 5 (0.28%) donors were seropositive for both IgM and IgG, suggesting previous T. gondii infection (Chiang et al., 2012). In healthy individuals, T. gondii infection is typically mild with flu-like symptoms and lymphadenopathy (Hill et al., 2005), whereas central nervous system (CNS) disorders and ocular disease are also noted in congenital T. gondii infection (Chiang et al., 2014). However, immunocompromised individuals such as those with HIV/AIDS (Hung et al., 2005), those undergoing chemotherapy or transplant recipients (Dubey and Jones, 2008) and neonates (Hu et al., 2006), may develop serious complications such as seizures, encephalitis or lung disease resembling tuberculosis. Notably, studies from around the world have reported associations between toxoplasma seropositivity and psychiatric disorders, such as psychosis, schizophrenia, bipolar disorder, major depression and anxiety (Lindgren et al., 2018; Achaw et al., 2019; Palerme et al., 2019; Stepanova et al., 2019; Ybanez et al., 2019). However, inconsistent and even controversial results were reported.

A recent cross-sectional survey found significant associations between T. gondii seropositivity and psychotic-like symptoms, but not schizophrenia, in Finland (Lindgren et al., 2018). Although, patients diagnosed with schizophrenia had a higher incidence of latent toxoplasmosis than healthy controls in Russia (Stepanova et al., 2019). Results of a review and meta-analysis (Sutterland et al., 2015) concluded higher odds of anti-toxoplasma IgG in patients with schizophrenia and bipolar disorder, but not in those with major depression. Clearly, there is still much to be learned about associations between T. gondii and specific mental disorders. We hypothesized that infection with T. gondii may increase the probability of developing psychiatric disorders. The comprehensive data from the National Health Insurance Research Database (NHIRD) of Taiwan may help to test our hypothesis. Therefore, the present nationwide population-based, longitudinal cohort study aimed to evaluate associations between infection with T. gondii and specific psychiatric disorders in a large population-based sample from the NHIRD.

Patients and methods

Data sources

In the present longitudinal cohort study, the data analysed were derived from the NHIRD of Taiwan, which covers 99.9% of the Taiwanese population (Wu et al., 2010). The NHIRD includes all demographic and clinical information on outpatient and inpatient claims data. All clinical diagnoses and procedures are recorded based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).

Ethical considerations

The present study protocol was approved by the Institutional Review Board (IRB) of Tri-Service General Hospital, Taiwan (TSGHIRB No.: B-109-23). Because all patient data were anonymized in the NHIRD, informed consent was waived.

Study population

The case group consisted of patients newly diagnosed with toxoplasmosis (T gondii infection), who were identified from the NHIRD (1997–2013) based on ICD-9-CM 130. The date when toxoplasmosis was diagnosed was defined as the index date, and patients diagnosed with psychiatric disorders before the index date were excluded to ensure the temporal order between T. gondii infection and psychiatric disorders. In addition, patients younger than 18 years were excluded. In addition, the non-toxoplasmosis control group was established by propensity score matching for age, gender and index year with a 4-fold ratio of the case group (ratio 4:1), thereby reducing selection bias.

Primary outcome

In the case group, the patients with psychiatric disorders were tracked from the index date to the onset of all recorded psychiatric disorders, whereas the patients without psychiatric disorders were followed from the index date to the end of the study period. The primary outcome was the incidence of psychiatric disorders, consisting of schizophrenia (ICD-9-CM 295), bipolar disorder (ICD-9-CM 296.0, 296.4–296.8), depression (ICD-9-CM 296.2–296.3, 300.4, 311), anxiety (ICD-9-CM 300) and other psychiatric disorders (ICD-9-CM 295–312), while excluding overlapping codes. Eligible patients with the following other psychiatric disorders were identified in the present study, such as unspecified affective psychoses (296.90), other specified affective psychoses (296.99), unspecified psychosis (298.9), acute alcoholic intoxication, continuous (303.01), other and unspecified alcohol dependence (303.90), other and unspecified alcohol dependence, continuous (303.91), opioid type dependence, unspecified (304.00), alcohol abuse (305.0), alcohol abuse, unspecified (305.00), tobacco use disorder (305.1), psychogenic respiratory malfunction (306.1), tension headache (307.81), unspecified adjustment reaction (309.9) and postconcussion syndrome (310.2).

Covariates

The sociodemographic variables of the case and control groups, included age, insurance premium, season of diagnosis, place of residence, urbanization level and hospital level. The eligible patients were divided into three age groups: 18–44 years, 45–64 years and ⩾65 years. Insurance premiums in New Taiwan Dollars (NTD) were classified into three groups: <18 000, 18 000–34 999 and ⩾35 000. Regarding place of residence, Taiwan was divided into five regions, such as northern, middle, southern and eastern Taiwan, as well as outlying islands. Urbanization levels of residences were categorized into four levels: from the highest urbanization (level 1) to the lowest urbanization (level 4). The levels of hospital care were classified into three groups: local hospitals, regional hospitals and medical centres.

Statistical analysis

Categorical variables are expressed as counts and percentages; continuous variables are expressed as mean and standard deviation (mean ± s.d.). Differences in categorical variables between case and control groups were examined by χ2 test or Fisher's exact test, whereas continuous variables were examined by t-test. Differences in the incidence of psychiatric disorders between the two groups were assessed by the Kaplan–Meier method with a log-rank test, and the result was presented as a survival curve. Univariate and multivariate Cox proportional hazards regression analyses were performed to examine the risk of developing psychiatric disorders. In addition, stratified analyses were performed based on the demographics and psychiatric disorders to explore the hazard ratios (HRs) between patients with and without toxoplasmosis. All P values were two-sided and P < 0.05 was considered statistically significant. All statistical analyses were conducted using the statistical software package SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

In the present longitudinal cohort study, 259 patients with toxoplasmosis were included in the case group, and 1036 patients without toxoplasmosis were included in the control group based on propensity score matching at a 1:4 ratio (Fig. 1). The demographic and clinical characteristics of the total population, case group and control group are summarized in Table 1. No significant differences were found in age, age group, gender, insurance premium and season of diagnosis between the case and control groups. In contrast, level of hospital care, urbanization level and place of residence were significantly different between patients with and without toxoplasmosis (all P < 0.001). Furthermore, patients with toxoplasmosis had significantly higher Charlson comorbidity index (CCI) scores than those without toxoplasmosis (P < 0.001) (Table 1).

Fig. 1.

Fig. 1.

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Flowchart of patient selection.

Table 1.

Demographic and clinical characteristics of the total population, case group and control group

Variables Total population, n = 1295 With toxoplasmosis, n = 259 (case group) Without toxoplasmosis, n = 1036 (control group) P
Age (years) 44.36 ± 16.40 44.10 ± 16.21 44.43 ± 16.45 0.779
Age group (years) 0.999
≧65 165 (12.7) 33 (12.7) 132 (12.7)
45–64 375 (29.0) 75 (29.0) 300 (29.0)
18–44 375 (29.0) 151 (58.3) 604 (58.3)
Gender 0.999
Female 500 (38.6) 100 (38.6) 400 (38.6)
Male 795 (61.4) 159 (61.4) 636 (61.4)
Insurance premium (NTD) 0.364
<18 000 1268 (97.9) 255 (98.5) 1013 (97.8)
18 000–34 999 19 (1.5) 4 (1.5) 15 (1.4)
≧35 000 8 (0.6) 0 8 (0.8)
Season of diagnosis 0.415
Spring (March–May) 324 (25) 60 (23.2) 264 (25.5)
Summer (June–August) 323 (24.9) 75 (29.0) 248 (23.9)
Autumn (September–November) 321 (24.8) 62 (23.9) 259 (25.0)
Winter (December–February) 327 (25.3) 62 (23.9) 265 (25.6)
Level of hospital care <0.001
Local hospital 370 (28.6) 11 (4.2) 359 (34.7)
Regional hospital 396 (30.6) 63 (24.3) 333 (32.1)
Hospital centre 529 (40.8) 185 (71.4) 344 (33.2)
Urbanization level <0.001
4 (lowest) 175 (13.5) 17 (6.6) 158 (15.3)
3 106 (8.2) 8 (3.1) 98 (9.5)
2 522 (40.3) 108 (41.7) 414 (40.0)
1 (highest) 492 (38) 126 (48.6) 366 (35.3)
Place of residence <0.001
Northern Taiwan 557 (43.0) 146 (56.4) 411 (39.7)
Middle Taiwan 351 (27.1) 48 (18.5) 303 (29.2)
Southern Taiwan 295 (22.8) 44 (17.0) 251 (24.2)
Eastern Taiwan 87 (6.7) 20 (7.7) 67 (6.5)
Outlying islands 5 (0.4) 1 (0.4) 4 (0.4)
CCI 1.16 ± 2.35 2.76 ± 3.36 0.75 ± 1.81 <0.001
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Categorical variables are presented as counts (percentages); continuous variables are presented as mean ± s.d.

Significant P values are shown in bold.

Patients with toxoplasmosis had a significantly higher incidence of psychiatric disorders than those without toxoplasmosis (P = 0.016). Thirty out of 259 (11.6%) patients in the case group were diagnosed with psychiatric disorders, and 73 out of 1036 (7.0%) patients in the control group were diagnosed with psychiatric disorders (Table 2). Particularly, the incidence of anxiety was significantly higher in patients with toxoplasmosis than in those without toxoplasmosis (P = 0.002) (Table 2). In addition, Kaplan–Meier analysis of the cumulative incidence of psychiatric disorders over 14 years of follow-up demonstrated a significant difference in incidence of psychiatric disorders between the case group and control group (log-rank P < 0.001), and a significant difference was observed as early as the first year of follow-up (Fig. 2).

Table 2.

Incidence of psychiatric disorders in the total population, case group and control group

Variables Total population, n = 1295 With toxoplasmosis, n = 259 (case group) Without toxoplasmosis, n = 1036 (control group) P
Psychiatric disorders 103 (8.0) 30 (11.6) 73 (7.0) 0.016
Schizophrenia 12 (0.9) 2 (0.8) 10 (1.0) 0.772
Bipolar disorder 8 (0.6) 2 (0.8) 6 (0.6) 0.664
Depression 27 (2.1) 9 (3.5) 18 (1.7) 0.072
Anxiety 26 (2.0) 12 (4.6) 14 (1.4) 0.002
Other psychiatric disorders 30 (2.3) 5 (1.9) 25 (2.4) 0.664
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Values are presented as counts (percentage).

Significant P values are shown in bold.

Fig. 2.

Fig. 2.

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Kaplan–Meier for cumulative incidence of psychiatric disorders stratified by Toxoplasmosis using log-rank test.

The risk factors for psychiatric disorders in the total population were identified by univariate and multivariate Cox regression analyses (Table 3). After adjusting for age, gender, insurance premium, season of diagnosis, level of hospital care, urbanization level and CCI, multivariate Cox proportional hazards regression analyses revealed that in the total population, patients with toxoplasmosis had a significantly higher adjusted HR (aHR) for psychiatric disorders [aHR = 3.79, 95% confidence interval (CI) = 2.37, 6.07] compared to those without toxoplasmosis. Younger patients also had significantly higher HRs for psychiatric disorders (45–64 vs ⩾65: aHR = 2.23, 95% CI = 1.14, 4.36; 18–44 vs ⩾65: aHR = 5.50, 95% CI = 2.89, 10.44). Male patients had a significantly higher risk for psychiatric disorders than female patients (aHR = 2.44, 95% CI = 1.52, 3.89). Medical visits in the autumn were significantly associated with a lower risk for psychiatric disorders compared to medical visits in the spring (aHR = 0.47, 95% CI = 0.26, 0.86). Compared to seeking medical help in local hospitals, seeking medical assistance in regional hospitals and hospital centres were significantly associated with higher HRs for psychiatric disorders (regional hospital vs local hospital: aHR = 1.67, 95% CI = 1.37, 2.22; hospital centre vs local hospital: aHR = 1.82, 95% CI = 1.49, 2.37). Patients with more severe comorbidities had a significantly higher risk for psychiatric disorders (aHR = 1.08, 95% CI = 1.02, 1.15) (Table 3).

Table 3.

Risks of psychiatric disorders in the total population evaluated by Cox regression analyses

Variables Univariate Multivariate
HR (95% CI) P aHR (95% CI) P
Toxoplasmosis 3.98 (2.56, 6.20) <0.001 3.79 (2.37, 6.07) <0.001
Age group (years)
⩾65 Reference Reference
45–64 2.35 (1.21, 4.56) 0.012 2.23 (1.14, 4.36) 0.019
18–44 4.68 (2.5, 8.74) <0.001 5.50 (2.89, 10.44) <0.001
Gender
Female Reference Reference
Male 1.72 (1.11, 2.66) 0.016 2.44 (1.52, 3.89) <0.001
Insurance premium (NTD)
<18 000 Reference Reference
18 000–34 999 0.83 (0.16, 5.93) 0.85 0.73 (0.1, 5.32) 0.752
⩾35 000 NA NA
Season of diagnosis
Spring Reference Reference
Summer 0.88 (0.52, 1.47) 0.611 0.79 (0.47, 1.34) 0.38
Autumn 0.5 (0.27, 0.9) 0.021 0.47 (0.26, 0.86) 0.015
Winter 0.84 (0.49, 1.42) 0.504 0.83 (0.48, 1.43) 0.501
Level of hospital care
Local hospital Reference Reference
Regional hospital 1 (0.64, 1.57) 0.228 1.67 (1.37, 2.22) 0.002
Hospital centre 1.08 (0.65, 1.8) 0.262 1.82 (1.49, 2.37) 0.005
Urbanization level
4 (lowest) Reference Reference
3 0.92 (0.5, 1.71) 0.797 0.99 (0.58, 2.38) 0.852
2 0.89 (0.38, 2.1) 0.788 0.81 (0.45, 2.24) 0.546
1 (highest) 1 (0.56, 1.79) 0.993 1.17 (0.65, 2.6) 0.66
Place of residence
Northern Taiwan Reference
Middle Taiwan 0.81 (0.49, 1.35) 0.413
Southern Taiwan 1.02 (0.62, 1.68) 0.935
Eastern Taiwan 1.59 (0.86, 2.97) 0.143
Outlying islands NA
CCI 1.06 (1.01, 1.12) 0.047 1.08 (1.02, 1.15) 0.014
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aHR, adjusted hazard ratio; CI, confidence interval; NA, not applicable.

Significant P values are shown in bold.

Table 4 summarizes the risk of developing psychiatric disorders in patients with or without toxoplasmosis stratified by demographic variables. After adjusting for significant variables identified in univariate Cox regression analyses shown in Table 3, multivariate Cox regression analyses revealed that the risk of developing psychiatric disorders was significantly higher in patients with toxoplasmosis than in those without toxoplasmosis, regardless of being stratified by almost all demographic and clinical variables. Although patients who had insurance premiums less than NTD18 000 were significantly associated with an elevated risk of psychiatric disorders (aHR = 3.78, 95% CI = 2.36, 6.10) (Table 4), only one event occurred in patients with an insurance premium higher than NTD18 000.

Table 4.

Multivariate Cox regression analysis for psychiatric disorders in patients with or without toxoplasmosis stratified by demographics

Stratified variables With toxoplasmosis Without toxoplasmosis With vs without
Events Person-years Events Person-years aHR (95% CI) P
Gender
Female 12 1427.04 23 4346.23 3.35 (2.09, 5.30) <0.001
Male 18 1351.98 50 7804.81 4.38 (2.75, 7.02) <0.001
Age group (years)
⩾65 2 573.66 11 3897.94 2.58 (1.23, 4.01) 0.001
45–64 8 937.68 24 4428.95 3.20 (1.99, 5.12) <0.001
18–44 20 1267.68 38 3824.15 3.36 (2.10, 5.40) <0.001
Insurance premium (NTD)
<18 000 30 2764.89 72 11 878.48 3.78 (2.36, 6.10) <0.001
18 000–34 999 0 1 159.36 NA NA
⩾35 000 0 0 NA NA
Season of diagnosis
Spring 9 486.38 22 2701.64 4.80 (3.00, 7.44) <0.001
Summer 8 724.05 24 3285.96 3.20 (1.94, 5.10) <0.001
Autumn 3 768.16 11 3271.45 2.44 (1.50, 3.98) <0.001
Winter 10 800.43 16 2891.99 4.63 (2.87, 6.99) <0.001
Urbanization level
4 (lowest) 4 180.06 15 1748.74 5.27 (3.17, 8.78) <0.001
3 2 223.41 6 1010.50 3.12 (1.90, 5.12) <0.001
2 11 1172.46 38 5709.56 2.77 (1.45, 4.64) <0.001
1 (highest) 13 1203.08 14 3682.24 5.79 (3.65, 9.54) <0.001
Level of hospital care
Local hospital 5 457.46 20 2763.70 3.12 (1.89, 5.25) <0.001
Regional hospital 11 912.35 33 5355.89 4.04 (2.12, 6.03) <0.001
Hospital centre 14 1409.20 20 4031.46 4.30 (2.64, 6.79) <0.001
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aHR, adjusted hazard ratio; CI, confidence interval; NA, not applicable.

Significant P values are shown in bold.

Furthermore, Cox proportional hazards regression model was applied to estimate the risk for developing each psychiatric disorder in patients with toxoplasmosis in relative to those without toxoplasmosis (Table 5). After adjusting for significant variables identified in univariate Cox regression analyses shown in Table 3, multivariate Cox regression analyses revealed that compared to the control group, the case group had significantly higher risk of bipolar disorder (aHR = 3.60, 95% CI = 2.07, 7.26), depression (aHR = 4.94, 95% CI = 2.15, 11.80) and anxiety (aHR = 5.36, 95% CI = 2.98, 25.88). In contrast, no significant differences in the HRs of developing schizophrenia and other psychiatric disorders between the two groups were observed (Table 5).

Table 5.

The risk for specific psychiatric disorders between the case and control groups evaluated by Cox regression analyses

Psychiatric disorders Case group vs control group (reference)
aHR 95% CI P
Schizophrenia 1.14 0.20, 6.59 0.897
Bipolar disorder 3.60 2.07, 7.26 0.001
Depression 4.94 2.15, 11.80 <0.001
Anxiety 5.36 2.98, 25.88 <0.001
Other psychiatric disorders 1.36 0.49, 3.79 0.560
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aHR, adjusted hazard ratio; CI, confidence interval.

Significant P values are shown in bold.

Discussion

In the present Taiwanese population-based cohort study, patients with toxoplasmosis had a significantly higher risk for psychiatric disorders than the non-toxoplasmosis control population, demonstrated by consistently higher aHR, regardless of stratification by demographic variables. In particular, compared to patients without toxoplasmosis, those with confirmed toxoplasmosis had significantly higher risk of bipolar disorder, depression and anxiety. However, no significant differences were found in the risk of schizophrenia and other psychiatric disorders between the patients with and without toxoplasmosis.

To our best knowledge, the present study is the first to explore associations between toxoplasmosis and several psychiatric disorders using a national population sample in Taiwan. Notably, we found no significant differences in the risk of schizophrenia between patients with and without T. gondii infection. In consistent with our findings, no significant association between T. gondii seropositivity and risk of schizophrenia was reported by two population-based studies conducted in Finland and New Zealand (Sugden et al., 2016; Lindgren et al., 2018) and a case-control study carried out in the Netherlands (de Witte et al., 2015).

Nevertheless, overwhelming evidence suggests otherwise. A recent large internet-based cohort study revealed that toxoplasmosis was significantly associated with schizophrenia in Czechia (Flegr and Horáček, 2020), and such association has been previously documented via systemic review and meta-analysis (Torrey et al., 2012; Sutterland et al., 2015). Latent toxoplasmosis incidence, evidenced by anti-T. gondii IgM and IgG concentrations, was significantly higher in patients with schizophrenia than healthy controls in Russia (Stepanova et al., 2019). Comparably, elevated serum levels of anti-T. gondii IgG and IgM in patients with schizophrenia in relative to those of controls were found in China (Chen et al., 2019). Furthermore, an analysis of the Danish Blood Donor Study suggested that T. gondii infection was a possible causative factor for schizophrenia due to the temporality of pathogen exposure (Burgdorf et al., 2019).

Regarding the discrepancies among previous studies examining the relationship between T. gondii infection and schizophrenia, Yolken et al. (2017) hypothesized that the timing of patient evaluation might be one of possible explanations in a nested case-control study. They found that patients, who were diagnosed with recent onset psychosis and took a serologic test soon after psychosis manifested, had elevated odds of seropositivity for IgG antibodies against T. gondii; however, patients with established schizophrenia did not have significantly higher odds of T. gondii IgG seropositivity (Yolken et al., 2017). Several schizophrenia medications were demonstrated to possess anti-T. gondii activity in cell culture (Jones-Brando et al., 2003), which may partially explain non-reactivity of anti-T. gondii IgG antibodies in established schizophrenia. In addition, serum levels of anti-T. gondii antibodies were suggested to decline in the absence of persistent exposure to T. gondii (Rougier et al., 2017). In the present population-based study, toxoplasmosis was defined based on ICD diagnostic code without serological evidence. The ICD-9-CM coding system does not contain a specific code for recent onset psychosis. Hence, additional prospective longitudinal cohort studies are required to further investigate T. gondii infection in schizophrenia patients relying on antibody titres and T. gondii exposure history.

In the present study, patients with confirmed toxoplasmosis had significantly higher risk of bipolar disorder, and other recent studies have also reported associations between T. gondii infection and bipolar disorder (Wu et al., 2010; Sutterland et al., 2015). In addition, Del Grande et al. (2017) demonstrated the link between T. gondii and bipolar disorder, emphasizing the human immune response, the presence of latent toxoplasmosis and an increased risk of bipolar disorder and suicidal/aggressive behaviour. Findings of this report suggest that re-exposure to the parasite could modify the individual's immune response and reactivate latent toxoplasmosis (Del Grande et al., 2017), as has been suggested for schizophrenia (Sutterland et al., 2015). Furthermore, the potential of latent toxoplasmosis to provoke the development of bipolar disorder has been suggested (Afifi et al., 2018).

The present study showed that both depression and anxiety were more likely to occur in patients with toxoplasmosis than in those without, whereas varying results have been found in the literature. The elevated levels of T. gondii IgG antibodies were correlated with depression and anxiety in pregnant women (Groër et al., 2011), but another study reported no association between T. gondii seropositivity and prenatal depression (Alvarado-Esquivel et al., 2017). A community-based study found that T. gondii seropositivity was associated with anxiety, but not depression (Markovitz et al., 2015), and a cohort study indicated that toxoplasmosis was associated with anxiety (Flegr and Horáček, 2020). Two meta-analyses concluded that T. gondii infection was not associated with depression (Wang et al., 2014; Nayeri Chegeni et al., 2019). Notably, a Danish study found that T. gondii seropositivity was associated with moderate–severe depression, but not mild–severe (Bay-Richter et al., 2019a; Nayeri Chegeni et al., 2019); therefore, severity of depression may be one possible reason for conflicting relationships between T. gondii infection and depression reported in the literature.

Vector-borne parasitic diseases have been noted previously for associations with mental disorders. Our previous nationwide population-based cohort study (Lin et al., 2019), demonstrated a higher risk for psychiatric disorders among women with Trichomonas vaginalis infection, specifically a higher likelihood of trichomoniasis in psychiatric patients. Although cats act as a reservoir for T. gondii infections (Lilly and Wortham, 2013; Zulop et al., 2018), the vectors only pose a risk in the initial cystic stage when cats shed oocytes (Hartmann et al., 2013). If sheep, cattle and pigs ingest T. gondii oocyte-contaminated soil and water, tissue cysts will develop, and humans are likely to be infected if they consume undercooked meat (Berger-Schoch et al., 2011). Actual clinical disease does not occur often in T. gondii positive cats, manifesting mainly in immunosuppressed cats that may display CNS effects if disease symptoms finally do appear (Hartmann et al., 2013). This pattern may present clues about the mental effects of T. gondii infection in humans.

Toxoplasma gondii has a tropism for muscle and brain tissue, where it may establish chronic infection through cyst formation (Weiss and Dubey, 2009). The intracellular parasite T. gondii can alter dopamine metabolism within neurons; such metabolic fluctuation may cause behavioural changes in the host (Parlog et al., 2015). In a mouse model of T. gondii infection, degenerating neurons shown upregulated complement proteins and were surrounded by activated microglia, which are both signs of neurodegeneration typical of psychiatric disorders (Li et al., 2019). Changes in neuronal connectivity and synaptic plasticity also have been suggested as part of the mechanism responsible for psychiatric disorders upon T. gondii infection (Parlog et al., 2015).

Genetic background is also suggested to be an important influence on the response to latent toxoplasmosis (Bay-Richter et al., 2019b; Torrey and Yolken, 2019). Supportive of the role of gene-mediated immune response to T. gondii, Wang et al. (2019) identified two schizophrenia-related genes with significant toxoplasmosis-associated variants. Kano et al. (2018) found that the specific mental health-relate gene (disrupted in schizophrenia, or DISC1) activated transcription factors against T. gondii infection, and that the genotype DISC1 Phe/Phe was associated with higher titres of T. gondii antibodies in sera. Furthermore, via a comprehensive system analysis of T. gondii-infected human brains, Ngô et al. (2017) identified several susceptibility genes for congenital toxoplasmosis and suggested that T. gondii modulates critical signalling pathways, which contributes to the development of epilepsy, neurodegeneration and cancer.

Strengths and limitations

One of the main strengths of the present study is the utilization of the NHIRD, which contains nationwide longitudinal data of 99.9% of Taiwan's population, and minimizes discrepancies and biases. Hence, the NHIRD is an excellent data source for population-level analysis. However, because only data from Taiwanese patients are used, the current findings may not be generalizable to other populations or other countries. The use of secondary retrospective data does not support inferences of causation and only indicates associations. The NHIRD does not provide data of individual patients' lifestyle, family history, the date when T. gondii infection occurred, and serological data, which limits the analysis of potential influencing factors. The diagnoses of toxoplasmosis and psychiatric disorders were identified in the present study based on ICD-9 codes from the NHIRD database, and it is possible that coding errors and misclassification may exist, as noted in a previous study (Kern et al., 2006). Although one-third of the world population was estimated to be infected by T. gondii (Montoya and Liesenfeld, 2004), latent T. gondii infection was not indicated in the NHIRD.

Conclusions

The present nationwide population-based analysis revealed that T. gondii infection in Taiwan significantly increases risk for developing bipolar disorder, depression and anxiety, but not schizophrenia or other psychiatric disorders. The epidemiologic role of T. gondii in the development of psychiatric disorders is an urgent public health issue that may benefit from increasing the awareness of this association and its prominent risk factors among the general public, healthcare professionals and public health agencies.

Acknowledgements

We would like to thank the National Health Insurance programme of Taiwan for making the comprehensive research database, the NHIRD, accessible. Moreover, we would like to thank the National Defense Medical Center team for support.

Financial support

This work was supported by the Tri-Service General Hospital Songshan Branch, Taiwan (TSGHSB-C108-10, TSGH-SS-E-109035) to Hsin-An Lin, and the Tri-Service General Hospital, Taiwan (TSGH-B-109010) to Wu-Chien Chien.

Ethical standards

The current study protocol was reviewed and approved by the Institutional Review Board of Tri-Service General Hospital, Taiwan. Because all patient data were deidentified in the National Health Insurance Research Database (NHIRD) of Taiwan, informed consent was waived.

Conflict of interest

None.

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