Abstract: Previous studies suggest that Toxoplasma gondii may be a causative agent of bipolar disorder. The aim of the current study was to examine the association between T. gondii infection and risk for bipolar I disorder. A total of 117 individuals with bipolar I disorder and 200 healthy controls participated in the study. They tested for the presence of anti- Toxoplasma gondii antibodies; they also completed demographic questionnaires. Data were analyzed using the Chi-square test, Fisher exact test and t-test. Results showed that there were no significantly elevated IgG seroprevalence among patients with bipolar I disorder compared to healthy individuals (p = 0.3). The difference between two groups also wasn’t significant when analyzed separately for men (p = 0.5) and women (p = 0.4). Furthermore when comparing the sero-prevalence adjusted by age, the difference between patients and healthy participants wasn’t significant in none of age subgroups (p>0.05). In conclusion, no significant association was found between T. gondii seropositivity and Bipolar I disorder.
INTRODUCTION
Bipolar disorder is a kind of mood disorder, in which pathological mood manifest as episodes of hypomania, mania, or mixed episodes. The life time prevalence of bipolar spectrum disorders has been reported to be 3-8% (Akiskal, 2009). People in late adolescence and early adulthood have an increased risk of being diagnosed with bipolar disorder (Almeida, 2004). The patients encounter with difficulties which are related to job, social activities, interpersonal relationships and other important areas. The disorder may lead to unrepairable harms in different aspects of person’s health and her/his personal-socio-economical achievements (University of Leeds, 2009).
Therefore, it is essential to provide some Strategies for prevention and treatment of the disorder. Because of ambiguities in the pathogenesis of Bipolar disorder, effectiveness of existing pharmacological and non pharmacological interventions is relative, So that 40% of patients with bipolar I disorder end up in chronic phase; moreover, bipolar II disorder is described as a chronic illness (Sadock and Sadock, 2007). Scientists believe that multiple factors including genetic, neurobiological, intra-psychic, interpersonal and environmental factors interact with each other to produce the disorder or increase risk (Akiskal, 2009). Discussing the environmental factors, studies have indicated that infectious agents may be involved in the pathogenesis of bipolar disorder and recently has been pointed to the role of Toxoplasma gondii (University of Leeds, 2009; Torrey et al., 2000; Webster et al., 2006; Jones-Brando et al., 2003).
Toxoplasmosis is a common parasitic infections in human and some warm blooded animals (Suzuki, 2002; Dubey, 2010). The humans commonly become infected by consumption of undercooked or raw meat containing tissue cysts, or food or water that is contaminated with T. gondii oocysts (Kijlstra and Jongert, 2008). After a short phase of acute toxoplasmosis, the infection turn into latent phase and is encysted in the CNS and muscular tissue, probably for the whole life of infected host (Dubey and Jones, 2008; Miller et al., 2009). The parasite forms cysts in neurons, glial cells and astrocytes throughout the brain (Sabah and Mahfoth, 2009) and have the ability to alter the host behavior to increase their transmission (Kristina and Fittipaldi, 2008). Researches have indicated that infected individuals experience psychotic symptoms (Hamidinejat et al., 2010), changes in personality (Flegr and Havlicek, 1999; Flegr et al., 2000, 1996; Novotna et al., 2005; Khademvatan et al., 2013), or may suffer from psychiatric and neurological disorders (Prandovszky et al., 2011). Infected rodents also have been found to experience behavioral changes and cognitive dysfunction (Webster, 2007; Novotna et al., 2005).
Some indirect evidences pointed to the role of T. gondii infection in the etiology of Bipolar disorder. Haloperidol which is an effective antipsychotic drug for the acute phase of mania, as has been found, could reduce the behavioral changes related to T. gondii (Webster et al., 2006). Besides, in vitro studies also have indicated that valporic acid (a first-line mood stabilizer drug) and haloperidol are able to inhibit the T. gondii republication in fibroblast cells of human (Jones-Brando et al., 2003). But the controversial results have been achieved in some other studies (Xiao et al., 2009; Arling et al., 2009).
Due to the few number of studies about the role of T. gondii in causation of bipolar disorder and existence of controversial results in general and lack of the studies in Iran in particular-in spite of high prevalence of toxoplasmosis (approximately 50% of the publication (Assmar et al., 1997). The present study was performed in order to evaluate the Toxoplasma contamination in patients with bipolar I disorder and compare it to the healthy controls. Proving the role of T. gondii in pathogenesis of Bipolar disorder might lead to a new approach to the prevention and treatment of both toxoplasmosis and Bipolar disorder.
MATERIALS AND METHODS
The present study was conducted over a period of 12 months from 2011 to 2012. The study was done on a total of 317 subjects who were divided into 2 groups, as follows:
Group I
Patients with bipolar disorder: one hundred seventeen patients (59 men
and 58 women) with bipolar I disorder who were attending the Golestan educational
hospital in Ahvaz/Iran, were studied. The mean age of the subjects was 33.93
years (SD = 11.87, range: 16 to 69). The patients’
diagnosis was made through structured clinical interview for Diagnostic and
Statistical Manual of mental disorders, 4th edition (DSM-IV-TR) by at least
two psychiatrists.
Group II
Healthy individuals: The control group consisted of 200 matched healthy
volunteers including 96 men and 104 women with a mean age of 33.88 years (SD
= 11.45, range: 16 to 63), who admitted to Golestan educational hospital in
Ahvaz/Iran. They had no history of bipolar disorder.
The subjects of two groups were not immune-deficient and did not have any other major psychiatric disorder or neurological disease. All subjects singed informed consent before participation in the study and completed the questionnaire that was designed to obtain demographic data about ethnicity, gender, age, level of education, marital status and occupational status.
There was no statistically significant differences among the patients and control subjects with respect to age (p = 0.1), gender (p = 0.7) and residence (p = 0.07) and two groups were matched with respect to these variables.
Serological test for toxoplasmosis: The subjects provided 5 mL of blood for serological analysis. Blood samples were centrifuged and then were kept on -20°C until the analysis. Anti-Toxoplasma antibody (IgG and IgM) concentrations were measured by the enzyme-linked immunosorbent assay (ELISA) method (IgG and IgM: Trinity Biotech Captia™, USA).
Statistical analysis: Data were analyzed using Chi-square test, Fisher’s exact test and t-test. Odds ratios (OR) with 95% confidence intervals (95% CI) were also determined. The probability level of 0.05 was accepted statistically significant. Statistical analyses were carried out using SPSS software, version 16.
RESULTS
In this study, seroprevalence of anti-T. gondii IgG antibodies were evaluated in 317 subjects. Latent toxoplasmosis was diagnosed in 90(28.39%) subjects and 227(71.6%) participants were Toxoplasma-negative. Among the sero-positive subjects, 51.1% (n = 162) were female and 48.89% (n = 155) were male. Frequencies of the participants’ demographic features have been listed in Table 1.
IgG antibodies were detected in 31.6% of cases with bipolar disorder and 26.5% of healthy individuals. No significant difference was found between IgG levels in two groups (p>0.05) (Table 2). Hence there was no correlation between T. gondii infection and bipolar disorder.
Anti-Toxoplasma IgM antibodies were positive in 4 patients and 2 healthy individuals. The difference in between was not significant (p>0.05) (Table 2).
Prevalence of T. gondii infection in two groups with respect of gender, residence and age was analyzed.
The sero-prevalence of the males and females were 35.5 and 27.5%, respectively in patients (p = 0.4) and were 32.2 and 21.1%, respectively in healthy individuals (p = 0.08).
| Table 1: | Frequencies of the participants’ demographic features |
| Table 2: | Analysis of anti-Toxoplasma gondii IgG and IgM antibodies in bipolar patients and control group |
| Sig: Significance, OR: Odd ratio, CI: Confidence interval | |
There was no significant difference in prevalence of anti-T. gondii IgG antibody between male and female in both of patients and healthy groups. But in healthy group the difference is near the formal level of statistical significance (p = 0.08) (Table 3).
The prevalence of T. gondii infection in individuals living in urban and rural areas was 29.7 and 36.3%, respectively in patients (p = 0.3) and were 27.6 and 21.6% in healthy individuals (p = 0.3).The differences were not significant (Table 4).
The participants were divided into 5 groups based on the age (<20, 20-29, 30-39, 40-49 and >50 years). The seroprevalence of T. gondii infection in the five age groups were 42.8, 29.1, 20.8, 41.6 and 35.7%, respectively in patients; And in the healthy individuals were 33.3, 24.7, 24, 30.4 and 28.5% in respect. The difference in infection rate among age subgroups was not statistically significant in each of the sample groups (p>0.05).
| Table 3: | Seroprevalence of anti-T. gondii IgG antibodies in bipolar patients and control group in respect of gender |
| Sig: Significance, OR: Odd ratio, CI: Confidence interval | |
| Table 4: | Seroprevalence of anti-T. gondii IgG antibodies in bipolar patients and control group in respect of residence |
| Sig: Significance, OR: Odd ratio, CI: Confidence interval | |
| Table 5: | Distribution of latent toxoplasmosis according to the age, gender and residency in bipolar patients and healthy control group |
| Sig: Significance, OR: Odd ratio, CI: Confidence interval | |
When comparing the sero-prevalence adjusted by age, the difference between patients and healthy participants wasn’t significant in none of age subgroups (Table 5). The difference in sero-positivity between the bipolar group and the control group also wasn’t significant when analyzed separately for men and women (Table 5).
DISCUSSION
The present study was conducted to evaluate the association between Toxoplasma infection and bipolar disorder. To the authors knowledge, this is the first written study in Iran about the relation between these two disorders and a few studies were conducted elsewhere in this field.
The study demonstrated that there was no significant difference between patients with Bipolar I disorder and healthy subjects in IgG antibodies. However, a larger number of patients with bipolar I disorder (31.62%) manifested IgG reactivity compared to healthy controls (26.5%).
The findings are in contrast to the intervention studies (Webster et al., 2006; Jones-Brando et al., 2003). According to these studies, growth of T. gondii can be inhibited by some anti psychotic and mood stabilizer drugs (Saraei-Sahnesaraei et al., 2009; Xiao et al., 2009).
But the findings replicate the results of the study conducted by Xiao et al. (2009) which have shown no correlation between T. gondii infection and psychiatric disorders including bipolar disorder. They did not find significantly increased sero-prevalence among individuals with affective disorder compared to patients with physical disease and healthy controls. However similar to our study, prevalence of toxoplasmosis in patients with affective disorder (6.7%) was more than healthy controls (3.0%) and those with physical disease (4.5%) (Xiao et al., 2009).
Arling et al. (2009), also didn’t find significant association between T. gondii seropositivity and recurrent mood disorder diagnosis.
In our study there were no differences between patients and healthy participants in IgG antibodies when comparing the seroprevalence adjusted by gender.
It seems that one of the reasons for the findings is the different prevalence of two disorders. About 50% of publication are infected with T. gondii (Assmar et al., 1997) but the prevalence of bipolar I disorder is approximately up to 3% (Akiskal, 2009). Therefor, considering the stronger role of genetics in etiology of BD and the possible role of some infectious and environmental factors in etiology of the disorder, the results of epidemiological examinations about the association between bipolar disorder and T. gondii may be confusing. Considering the finding that many of patients with bipolar disorder were sero-negative and many of individuals infected with T. gondii, didn’t have symptoms of bipolar disorder, the genetic hypothesis stated hear in etiology of BD.
The possible reason for different findings obtained from the studies of T. gondii and bipolar disorder may be related to the genotype of T. gondii. This protozoan has genotypes that are various in terms of virulence and their geographical replication may be different (Saraei-Sahnesaraei et al., 2009). The distinct neuropathogenic potential has been known in different genotypes of T. gondii (Xiao et al., 2009).
The results didn’t show significant difference between males and females with bipolar for IgG positivity. The finding is in line with the study conducted by Xiao et al. (2009) which demonstrated that seroprevalance of anti-T. gondii IgG is not statistically significant in men and women with psychiatric disorders including bipolar disorder.
But higher seropositivity in males than females was found in control group (31.2% in men versus 21.1% in women). Although the difference wasn’t significant, but it was near to formal level of statistical significance (p = 0.08). The finding may have occurred because of the relation between raise Toxoplasma infection and testosterone increase (Shirbazou et al., 2011). Similar to the finding, Lindova et al. (2006) reported increased seroprevalance of anti-T. gondii IgG in male compared to female students. The opposite result i.e., higher prevalence of T. gondii infection in men than women (10.5% in men versus 14.3% in women) was found by Xiao et al. (2009).
No significant difference in seroprevalance of anti-T. gondii IgG between individuals living in urban and rural areas was detected in the present research. Based on the result, living places has no effect on the risk of the toxoplasmosis.
In the research of Xiao et al. (2009), individuals living in urban and rural areas in the North part of China, similarly, didn’t have significant difference in the infection rate. By contrast, Yuksel et al. (2010) reported the association between residences in a small town/village and having toxoplasmosis.
In the current study, the differences in latent toxoplasmosis weren’t statistically significant among five age subgroups, in any of the patient and healthy groups. However, higher seroprevalence was detected in 20-29-year age individuals in both of them.
There weren’t significantly differences between the patients group compared to the healthy controls in anti-toxoplasmosis IgG antibodies in each different age subgroups.
Xiao et al. (2009) found that anti-toxoplasmosis IgG antibodies were more prevalent in 40-49 years old individuals in any of the psychiatric patients group and healthy controls. But the differences in infection rate among age groups (<20, 20-29, 30-39, 40-49 and >50 years) were not statistically significant.
CONCLUSION
The present study does not support the contamination with Toxoplasma gondii as a risk factor for bipolar disorder. However, the hypotheses of association between bipolar disorder and Toxoplasma gondii is not rejected and further investigations are suggested to determine the precise relationship between these two disorders by using more reliable methods, larger study samples and better controlled studies.
It is also recommended that participation of patients with bipolar II disorder be the focus of future researches. Other beneficial suggestion would be the Study of influence of the different parasite genotypes on increased risk of bipolar disorder.
LIMITATIONS
There are some limitations in this study that could be addressed : because of limited data, relationship between T. gondii seroprevalence and bipolar II disorder could not be assessed. Moreover, this study was cross-sectional.
ACKNOWLEDGMENT
This study is conducted and financially supported by grants No U-90044 from Ahvaz Jundishapur university of Medical sciences and approved in the ethical committee by NO: ETH-172. We should appreciate all staff of Protozoology laboratory of Ahvaz Jundishapur Medical sciences.