Potential Association Between Latent Toxoplasma gondii Infection and Suicide Attempts: A Case

Abstract

Toxoplasma gondii is a ubiquitous parasitic protozoan that may be an important cause of neurological and psychiatric diseases. The purpose of this case–control registry-based study was to evaluate the prevalence of T. gondii infection and related risk factors among subjects who attempted suicide by drug use and a control group at the Iranian National Registry Center for Toxoplasmosis in Mazandaran Province, northern Iran. Baseline data were collected from participants using a questionnaire, and a blood sample was taken from each individual. The plasma was prepared for serological analysis, whereas the buffy coat was used for molecular analysis. Out of 282 individuals (147 cases with suicide attempters [SA] and 135 controls), 42.9% of patients and 16.3% of control subjects were positive for anti-Toxoplasma immunoglobin G (IgG), but all participants were negative for T. gondii DNA and anti-Toxoplasma immunoglobin M. Based on multiple logistic regressions, IgG seropositivity in SA in the age group of 20–30 years was 3.22 times higher than that in the control group (p < 0.001). These findings suggest that latent T. gondii infection among SA is significantly higher than that in healthy individuals, indicating a potential association between latent toxoplasmosis and SA at least in the studied area. Further research is needed to shed light on the potential association between T. gondii and suicide among different populations and areas of the world.

Introduction

Toxoplasma gondii, the cause of toxoplasmosis, is a neurotropic protozoan parasite of the phylum Apicomplexa that infects up to one-third of the human population in both developed and developing countries (Montoya and Liesenfeld, 2004). Humans can acquire the infection through the ingestion of T. gondii tissue cysts or oocysts excreted by cats and congenital infection with tachyzoites (Moncada and Montoya, 2012; Sepúlveda-Arias et al., 2014). This ubiquitous parasitic protozoan has a complex life cycle. The proliferative stage, tachyzoite, converts into a latent stage, bradyzoite, which encysts in various bodily organs such as the brain, muscles, lungs, and eyes (Di Cristina et al., 2008). Stage conversion from bradyzoites to tachyzoites plays an important role in maintaining latent infection and reactivating chronic infections (Weiss and Kim, 2000). In immunocompromised individuals, bradyzoites are released from tissue cysts, reproduce, and spread to other organs, especially the brain and muscles, causing severe morbidity and mortality (Luft and Remington, 1992).

Suicide and intoxication are major public health issues worldwide, particularly among adolescents, young people, and middle-aged adults, likely because of socioeconomic and behavioral factors (Cluver et al., 2015; ElHak et al., 2009). The World Health Organization (WHO) reports that approximately 450,000 individuals died because of illegal drug ingestion, with approximately 165,000 deaths directly caused by drug use (WHO, 2016).

Over the past few years, numerous studies have reported a potential association between latent toxoplasmosis and suicide rates (Akgul, 2019; Bak et al., 2018; Burgdorf et al., 2019). As Mazandaran Province in Iran has the highest prevalence of T. gondii infection in the country (Foroutan et al., 2018), this study is aimed to investigate, for the first time, the seroprevalence and common risk factors for T. gondii infection among suicide attempters (SA) by drug use admitted to two training hospitals (Imam Khomeini and Razi) in Mazandaran Province, north of Iran.

Patients and Methods

Study design and study populations

This study was approved by the Mazandaran University of Medical Science Ethics Committee (No: IR.MAZUMS.REC.1400.9232) and carried out in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants. The case–control study included individuals of all ages and genders who attempted suicide by drug poisoning and were referred to two training hospitals (Imam Khomeini and Razi) in Mazandaran Province, northern Iran, between January 2021 and April 2021. Apparently, healthy individuals who visited the blood bank to donate blood were considered a matched control group. Inclusion criterion for the case group was attempted suicide by drug poisoning of any age or gender. The exclusion criterion was the unwillingness to participate in the study. Demographic information such as gender, age, place of residence, occupation, level of education, marital status, type of drug used, contact with cats, history of eating raw meat, oral contraceptive pill use, smoking status, history of depression disorder, and prior SA were collected through a questionnaire. Blood samples (approximately 3 mL) were collected from each participant in tubes containing di‐potassium ethylene diamine tetraacetic acid (K2-EDTA) as an anticoagulant and sent to the Iranian National Registry Center for Toxoplasmosis. The samples were centrifuged at 3000 rpm for 3 min, and the plasma and buffy coat were stored at −20°C for further examination (serological and PCR assay, respectively).

Laboratory Tests

Serological assay

The existence of anti-Toxoplasma immunoglobin G (IgG) and immunoglobin M (IgM) was distinguished using a commercially available enzyme-linked immune sorbent assay (ELISA) kit (Pishtaz Teb), based on the manufacturer’s protocol. The status of toxoplasmosis was determined based on the kit. The results greater than 1.1 were considered positive. Also, the sensitivity and specificity of the commercial ELISA diagnostic kit were approximately 100%.

PCR assay

T. gondii DNA was extracted from the specimens according to the phenol–chloroform isoamyl alcohol method (Hezarjaribi et al., 2021). Then, conventional PCR (PCR) was done by forward primer F 5′-CGCTGCAGGGAGGAAGACGAAAGTTG-3′ and reverse primer R 5′-CGCTGCAGACACAGTGCATCTGGATT-3′, amplifying a 529-bp fragment of gene RE with a master mix (12.5 μL; Fermentas) mixed with 4 μL of the extracted DNA to yield an ultimate content of 25 mL, comprising 7.3 μL distilled water and 0.6 μL of each primer at a concentration of 1 pmol/μL. Then, 32 cycles were performed in a thermocycler (Corbett Research) at 94°C, for 3 min by 1 cycle (initiation denaturation), 94°C for 30 s (denaturation), 55°C for 30 s (annealing), 72°C for 20 s (extension), 30 cycles, and 72°C for 7 min, 1 cycle (final extension). Subsequently, the PCR product was evaluated by electrophoresis on 1% (w/v) agarose gel in Tris-borate-EDTA at 85 V for 25 min and observed using ultraviolet transillumination after staining with Safe View™ DNA Stains (Applied Biological Materials, Inc.). As positive and negative controls, T. gondii DNA extracted at a dilution of 1:10⁵ and distilled water were used.

Data Analysis

Statistical analysis was conducted using statistical package for the social sciences (SPSS) software (version 23.0). The frequency of the data was shown in percentage (%). For parametric data, the analysis of variance (ANOVA) and chi-square tests were used to look for statistically significant differences. A p value of less than 0.05 was considered statistically significant. Furthermore, to determine the risk factors related to T. gondii infection, a univariate logistic model was fitted, and the variables that had p < 0.25 were included in the multiple model.

Results

In total, 282 subjects were evaluated in the current study, including 135 controls and 147 patients who attempted suicide because of drug toxicity. The patients in the case group were 95 females and 52 males, and their mean age was 25.3 ± 4.8 (range 12–80). Participants in the control group were 90 females and 45 males, and their mean age was 23 ± 5.2 (range 12–70). In the current study, 42.9% (63/147) of patients with SA and 16.3% (22/135) of control subjects tested positive for anti-Toxoplasma IgG, whereas all participants tested negative for T. gondii DNA and anti-Toxoplasma IgM. In this study, out of 147 patients with SA, anti-T. gondii IgG was detected in 63 patients, more common in females (59%) than in males (41%), in 20–30-year-old patients (32%), and in rural populations (50.8%) (Table 1).

Table 1.

Comparison of the Baseline and Clinical Characteristics of Suicide Attempters and Controls

Characteristics	Suicide attempters (n = 147)		Controls (n = 135)	p
Characteristics	IgG negative (%)	IgG positive (%)	IgG positive (%)	p
Gender
Male	26 (31)	26 (41)	8 (36.4)	0.22
Female	58 (69)	37 (59)	14 (63.6)
Age-group (years)
<20	33 (40)	5 (8)	0 (0)
20–30	33 (39)	20 (32)	8 (36.4)
31–40	12 (14)	19 (30)	7 (31.8)	0.01^*
41–50	5 (6)	10 (16)	2 (9.1)
51–60	1 (1)	4 (6)	3 (13.6)
>60	0 (0)	5 (8)	2 (9.1)
Residence
Urban	50 (59.5)	31 (49.2)	12 (54.5)	0.24
Rural	34 (40.5)	32 (50.8)	10 (45.4)
Job
Housewife	27 (32.1)	29 (46)	8 (36.4)
Employee	0 (0)	2 (3.2)	3 (13.6)	0.03^*
Self-employment	12 (14.3)	13 (20.6)	7 (31.8)
Manual worker	0 (0)	1 (1.6)	2 (9.1)
Unemployed	19 (22.6)	9 (14.3)	1 (4.5)
Other occupations	26 (31)	9 (14.3)	1 (4.5)
Education
Illiterate	3 (3.6)	7 (11.1)	2 (9.1)	0.01^*
Elementary	9 (10.7)	13 (20.6)	2 (9.1)
Guidance	21 (25)	11 (17.5)	5 (22.7)
Diploma	47 (56)	22 (34.9)	7 (31.8)
Postdiploma	2 (2.4)	2 (3.2)	5 (22.7)
Bachelor	1 (1.2)	7 (11.1)	1 (4.5)
Master	0 (0)	1 (1.6)	0 (0)
PhD	1 (1.2)	0 (0)	0 (0)
Drugs used
Benzodiazepines	19 (22.6)	14 (22.2)	0 (0)
Antipsychotics	6 (7.1)	1 (1.61)	0 (0)
Antidepressants	1 (1.2)	0 (0)	0 (0)
Narcotics	11 (13.1)	4 (6.3)	0 (0)
Analgesics	10 (11.9)	5 (7.9)	0 (0)	0.18
Agricultural pesticides	5 (6)	11 (17.5)	0 (0)
Other drugs	9 (10.7)	7 (11.1)	0 (0)
Multidrugs	23 (27.4)	21 (33.3)	0 (0)
Marital status
Single	42 (50)	16 (25.4)	4 (18.2)	0.004^*
Married	42 (50)	47 (74.6)	18 (81.8)
Cats at home
Yes	41 (48.8)	38 (60.3)	5 (22.7)	0.18
No	43 (51.2)	25 (39.7)	17 (77.3)
Raw meat consumption
Yes	0 (0)	3 (4.8)	3 (13.6)	0.07
No	84 (100)	60 (95.2)	19 (86.3)
History of OCP use
Yes	20 (23.8)	14 (22.2)	5 (22.7)	0.84
No	64 (77.6)	49 (77.8)	17 (77.3)
History of smoking
Yes	13 (15.5)	8 (12.7)	8 (36.4)	0.81
No	71 (84.5)	55 (87.3)	14 (63.6)
History of depression
Yes	50 (59.5)	36 (57.1)	3 (13.6)	0.86
No	34 (40.5)	27 (42.9)	19 (86.4)
Past history of suicide
Yes	35 (41.7)	28 (44.4)	0 (0)	0.74
No	49 (58.3)	35 (55.6)	22 (100)

Significant at level of 0.05, values are reported as frequency (%).

IgG, immunoglobin G.

Patients taking multidrug combinations and benzodiazepines had the highest seroprevalence rates of T. gondii infection (p > 0.05). Moreover, seropositivity was higher in patients who had contact with cats at home (60.3%). The majority of IgG seropositives had a diploma (34.9%), were housewives (46%), and were married (74.6%). Only 4.8% of seropositive patients consumed raw meat. In addition, 22.2%, 12.7%, 57.1%, and 44.4% of seropositive patients had a history of oral contraceptive pill (OCP) consumption, smoking, depression, and suicide (p > 0.05). There were statistically significant differences between IgG seropositive patients and these factors in terms of age, job, marital status, and education (p < 0.05) (Table 1).

Multiple logistic regressions showed that there is a significant relationship between anti-T. gondii IgG and SA in the 20–30-year age group (p < 0.05). So, IgG seropositivity in the 20–30-year age group was 2.31 times higher than that in other groups (p = 0.001) (see Table 2). Furthermore, based on multiple logistic regression, significant differences were observed in the level of IgG antibody between the SA and the control groups (p < 0.05). So, IgG seropositivity in SA in the age group of 20–30 years was 3.22 times higher than that of the control group (p < 0.001).

Table 2.

The Adjusted Odds Ratios of Risk Factors in the Suicide Attempters and Controls Based on Multiple Logistic Regression Models

Characteristics	Odds ratio (95% CI)	p
Toxoplasma gondii seropositivity
Cases	3.22 (2.1, 17.8)	<0.001^*
Controls
Age-group (years)
<20
20–30	2.31 (1.7, 10.2)	0.01^*
31–40
41–50
51–60
>60
Job
Housewife
Employee	2.20 (1.4, 12.34)	0.03^*
Self-employment
Manual worker
Unemployed
Other occupations
Education
Illiterate		0.01^*
Elementary	1.84 (1.1, 19.54)
Guidance
Diploma
Postdiploma
Bachelor
Master
PhD
Marital status
Single	3.11 (0.1.8, 20.01)	0.004^*
Married

Significant at level of 0.05.

Discussion

In our study, we found that 42.9% of individuals with a history of suicide attempt and 16.3% of control subjects tested positive for anti-Toxoplasma IgG. Notably, none of the participants showed evidence of T. gondii DNA or anti-Toxoplasma IgM. These findings are consistent with previous research linking T. gondii infection to suicide. Akgul (2019), Bak et al. (2018), Burgdorf et al. (2019), and Sutterland et al. (2019) have all reported similar associations between T. gondii infection and suicide. Moreover, a recent meta-analysis by Postolache et al. (2021) indicated a positive relationship specifically between suicide attempts (but not suicidal ideation) and T. gondii IgG seropositivity and serointensity. The results of our study suggest that there may be a potential connection between T. gondii infection and suicidal behavior. It is worth noting that a higher percentage of individuals who had attempted suicide tested positive for anti-Toxoplasma IgG compared with the control group. However, it is important to acknowledge that further research is needed to establish a definitive causal relationship between T. gondii infection and suicide. Nonetheless, our findings contribute to the growing body of evidence supporting this potential association, adding to the existing literature on the topic.

Based on our results, toxoplasmosis was more common in females (59%) than in males (41%), although a significant difference was not detected based on gender. Evidence has revealed that the psychiatric genetic risk factor DN-DISC1 controls the neurobehavioral process of chronic toxoplasmosis in a sex-dependent manner (Kannan et al., 2018). Therefore, the gene–environment interaction between genetic variation and T. gondii infection may play a role in the occurrence of suicidal intentions (Wu and Chen, 2021).

According to a recent systematic review and meta-analysis study conducted by Asadiyun and Daliri (2023), findings indicate that the highest proportion of suicide attempts in Iran is observed among individuals aged 15–24 years, accounting for 50% of the total cases. Following closely, the age group of 25–34 years comprises 27.4% of suicide attempts in the country. These statistics shed light on the importance of addressing mental health issues within these specific age ranges and implementing targeted interventions to prevent suicide attempts among young individuals in Iran. The comparison of the T. gondii seropositivity in the different ages of SA indicated statistically significant differences (p < 0.05). In this study, patients aged 20–30 years had the highest seroprevalence rates of T. gondii (p = 0.001). In the light of our results, IgG seropositivity in suicide attempt patients in this age group was 3.22 times higher than that in the control group (p < 0.001). Presumably, age at T. gondii exposure is a main risk factor for the development of various behavioral and neurobiological abnormalities (Kannan et al., 2016). In contrast to our findings, age had no statistically significant association with T. gondii IgG seropositivity among psychiatric outpatients in the Achaw et al. study conducted in Northwest Ethiopia (Achaw et al., 2019). These contradictory results may be due to the differences in study populations. In our study, out of the 147 patients who had suicide attempts, 36% (53 individuals) were aged between 20 and 30 years. This suggests that young adults in their 20s are particularly vulnerable to suicide attempts. It highlights the importance of focusing on mental health support and suicide prevention efforts for this age group. Thus, further comprehensive studies with appropriate sampling are required for a better understanding of the causal relationship.

According to studied results, job and marital status were also significant risk factors for SA. Housewives and marital patients had the highest seroprevalence rates of T. gondii infection (p < 0.05). It seems that owing to the availability of drugs in housewives’ and married individuals’ households, the rate of poisoning in these groups is high. In the current study, most of the attempted suicide patients with drug used were individuals who had a diploma or less of education, and only 9.5% of the cases had a university education. Also, patients without a university education had the highest seroprevalence rates of T. gondii infection (p < 0.05). Programs that focus on increasing public knowledge about the adverse effects of drug abuse can decrease drug-related morbidity and mortality (Shahbazi et al., 2017).

Generally, most of the suicide attempt cases evaluated in this study used multiple drugs and benzodiazepines, which could possibly be because of their low price and easy supply. The patients in these groups had the highest seroprevalence rates of T. gondii infection (p > 0.05). Ahmadi et al. (2010) evaluated the pattern of acute chemical poisoning in Sari, northern Iran, between April 2006 and March 2008, where the most common agents were drugs (77.7%), such as benzodiazepines and opioid analgesics. Also, organophosphate and carbamate insecticides were the third and fourth main agents (Ahmadi et al., 2010). According to Shayeste et al. (2018), between 2008 and 2014, benzodiazepines were the most common cause of drug poisoning (37.2%) in Gorgan, north of Iran.

According to studied results, 57.1% and 44.4% of seropositive patients had a history of depression and SA, respectively. Arling et al. (2009) evaluated 218 subjects with depression and reported that patients with SA had a higher seroprevalence of T. gondii seropositivity than patients without a suicide history (Arling et al., 2009). Bak et al. (2018) reported that subjects with T. gondii IgG antibodies and SA had more severe depressive symptoms, anxiety, and suicidal behavior (Bak et al., 2018). The T. gondii parasite could induce the production of interferon gamma, interleukin (IL)-6, and IL-12 by activating macrophages and lymphocytes. These proinflammatory cytokines cause an increase in the activity of the enzymes kynurenine monooxygenase and indoleamine 2,3-dioxygenase that improve the metabolism of tryptophan, leading to decreased serotonin synthesis in the brain (Miller et al., 2009). Indeed, the decrease in serotonin synthesis in the brains of SA may increase the susceptibility to depression in these individuals (Mann, 2003).

In addition to conventional serological assays, molecular assays are used for the diagnosis of T. gondii infection (Liu et al., 2015). According to the data, patients and control groups showed no evidence of acute T. gondii infection by PCR or IgM ELISA. Although this class of antibodies mostly rises in acute infections (Villard et al., 2013), these results were in accordance with the results of Yucel et al., who did not detect T. gondii IgM antibodies in any of the adolescents who had attempted suicide (Yucel et al., 2021). Moreover, according to studied results, 60.3% of seropositive SA have a cat at home. A previous study showed that the overall prevalence of T. gondii IgG antibodies in stray cats in this region, north of Iran, was 40% (Sharbatkhori et al., 2014). Cats are the main animals that can excrete resistant oocysts, particularly in warm and moist areas, and thus play an essential role in the epidemiology of T. gondii infection (Egorov et al., 2018).

One significant drawback is that we did not evaluate the mechanisms of pathogenesis of T. gondii infection in SA. In future research, it would be valuable to conduct prospective studies with larger sample sizes to examine these mechanisms and their potential application as a clinical tool. By understanding the underlying mechanisms, we could develop more targeted interventions and therapies for individuals with SA who are also infected with T. gondii.

Conclusion

Given that latent T. gondii infection among SA is significantly higher than healthy individuals, it supports that there is a potential association between latent toxoplasmosis and SA at least in studied area. As a whole, our findings suggest that the potential association between T. gondii and suicide needs to be clarified further among different populations and areas of the world.

Footnotes

Authors’ Contributions

M.F. and Z.Z. designed the study and wrote the article. M.N., M.M., and M.S. were involved in writing, editing, and preparing the final version of the article. Z.Z., A.A., and E.S. were involved in interpretation of and editing the article and analyzed and interpreted the data. All authors reviewed the article and approved the final version of the article.

Disclosure Statement

The authors declare no competing interests.

Availability of Data and Materials

The data are available to the corresponding author and can be obtained upon request.

Funding Information

The study was funded by the Mazandaran University of Medical Sciences. The funder has no role in the design of the study and collection, analysis, and interpretation of data and in writing the article.

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Potential Association Between Latent Toxoplasma gondii Infection and Suicide Attempts: A Case–Control Registry-Based Study