Toxoplasmosis and Other Diseases
It appears that increased antibodies to T. gondii are not specific to schizophrenia. A study of 199 patients with bipolar disorder reported an increased prevalence compared to controls (Fekadu A, Shibre T, Cleare AJ. Toxoplasmosis as a cause for behaviour disorders—overview of evidence and mechanisms. Folia Parasitol. 2010;57:105–113). This finding was subsequently replicated in a smaller American sample (n=41) (Pearce BD, Kruszon-Moran D, Jones JL. The relationship between Toxoplasma gondii infection and mood disorders in the third National Health and Nutrition survey. Biol Psychiatry. 2012;72:290-295). It was also replicated in a French sample of 110 bipolar disorder patients and 106 healthy controls (OR=2.2, p=0.028) (Hamdani N, Daban-Huard C, Lajnef M, et al. Relationship between Toxoplasma gondii infection and bipolar disorder in a French sample. J Affect Disord. 2013;148:444-8). In this French sample seropositivity to T. gondii correlated with cognitive deterioration and elevated levels of interleukin-6 (Hamdani N, et al. Cognitive deterioration among bipolar disorder patients infected by Toxoplasma gondii is correlated to interleukin 6 levels. J Affect Disord. 2015; 179: 161-166.) Yet another study from Brazil reported a significant increase in T. gondii seropositivity in a small sample of patients with mood disorder (n=28, including 24 bipolar and 14 major depression) compared to healthy controls (n=95) (Nascimento FS, de Rosalmeida Dantas C, Netto MP, et al. Prevalence of antibodies to Toxoplasma gondii in patients with schizophrenia and mood disorders. Schizophr Res. 2012;142:244-5). In a small study, maternal T. gondii IgG antibodies were not associated with bipolar disorder in the offspring. [Freedman D, et al. Maternal T. gondii, offspring bipolar disorder and neurocognition. Psychiatry Research. 2016; 243: 382-389.]
Studies examining the possible relationship between infection with T. gondii and bipolar disorder date to at least 1980 [Delgado G, Rodriguez PE. Ractivity of toxoplasma intradermal test in neurotic and manic-depressive patients. Rev Cubana Med Trop. 1980; 32: 35-9]. In recent years, two meta-analyses have been published, including the above studies. Sutterland et al identified 11 studies with a total of 1,163 bipolar patients and reported a significant OR of 1.52 (95% CI 1.06-2.18, p = 0.02) . (Sutterland AL, et al. Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systemic review and meta-analysis. Acta Psychiatr Scand. 2015; 1-19. Doi: 10.1111/acps.12423). There was no significant publication bias but heterogeneity was high. The second meta-analysis, by de Barres et al, included 8 studies, 3 of which had not been included in the first meta-analyses. They included 797 bipolar patients with an OR of 1.26 (95% CI 1.08-1.47). Also of interest is an impressive case study describing “a relationship between ocular manifestations [of toxoplasmosis] and the clinical course of bipolar disorder, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG” [Del Grande C, et al. Bipolar disorder with psychotic features and ocular toxoplasmosis. 2017. J Nervous Ment Dis. 2017; 205: 192-195]. Also of interest are two studies looking at the intersection of genes with T. gondii in causing bipolar disorder; in both studies the samples were too small. [Avramopoulos D, et al. Infection and inflammation in schizophrenia and bipolar disorder: a Genome wide study for interactions with genetic variation. PLosONE. 2015; doi: 10.1371/journal.pone.0116696; Oliveira J, et al. Toxoplasma gondii exposure may modulate the influence of TLR2 genetic varation on biopolar disorder: a gene-environment interaction study. International Journal of Bipolar Disorders. 2016; 4: 11]
Major Depression and Suicide Attempts
Sutherland et al [same] carried out a meta-analysis of 9 studies with 1,462 subjects that examined antibodies to T. gondii in individuals with major depression. They reported a non-significant association (OR 1.21; CI 0.86-1.70) with high heterogeneity. The heterogeneity was largely due to a Chinese study that had an OR of 2.41; Sutherland et al speculated that the Chinese study was different because it included subjects with depression with psychotic features [Zhou]. Sutherland’s negative findings regarding toxoplasmosis and major depression are supported by two population-based studies involving 484 [Markovitz AA, et al. Toxoplasma gondii and anxiety disorders in a community based sample. Brain Behav Immun. 2015; 43: 192-7.]] and 1846 subjects [Gale SD, et al. Association between laten toxoplasmosis and major depression, generalized anxiety disorder and panic disorder in human adults. Folia Parasitol. 2014; 61: 285-92.]; both failed to find any association between toxo seropositivity and depressive symptoms. Since the 2012 publication of the Sutherland et al meta-analysis, three additional studies involving 70 [Duffy AR, et al. Relationship between Toxoplasma gondii and mood disturbance in women veterans. Military Medicine. 2015; 6: 621-625.]; 325 [Alvador-Esquicol C, et al. Toxoplasma gondii infection and mixed anxiety and depressive disorder: A case-control seroprevalence study in Durango, Mexico. J Clin Med Res. 2016; 8: 519-523.]] and 414 [Groer MW, et al. Prenatal depression an anxiety in Toxoplasma gondii-positive women. American Journal of Obstetrics and Gynocology. 2011; 204” 433/e1-7.] ] subjects all reported significant associations between toxo seropositivity and symptoms of depression but another study [Alvardo-Esquivel C, et al. Lack of association between Toxoplasma gondii exposure and depression in pregnant women: a case-control study. BMC Infectious Diseases. 2017; 17] did not.
Eight studies have assessed serological status to T. gondii in individuals who have attempted or completed suicide. Yagmur et al (n=400), Zhang et al (n = 84), and Okusaga et al (n = 950) all reported significantly higher toxo seropositivity rates in suicide attempters compared to controls, although in the latter study that was only true for younger individuals [Yagmur F, et al. May Toxoplasma gondii increase suicide attempt-preliminary results in Turkish subjects? Forensic Science International. 2010; 199: 15-17; Zhang Y, et al Toxoplasma gondii immunoglobulin G antibodies and nonfatal suicidal self-directed violence. J Clin Psychiatry 2012; 73: 1069-1076; Okusaga O, et al. Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia. Schizophrenia Research. 2011; 133: 150-155]. Dickerson et al (n= 162) reported an elevated rate for those with toxo IgM but not IgG antibodies (Dickerson F et al. Suicide attempts and markers of immune response in individuals with serious mental illness. Journal of Psychiatric Research. 2017; 87: 37-43.) Three other studies (n=320, 283, and 108) reported that the rate of seropositivity between suicide attempters and controls did not differ but rather that those who had attempted suicide had significantly higher T. gondii IgG titres [Arling TA, et al. Toxoplasma gondii antibody titres and history of suicide attempts in patients with recurrent mood disorders. The Journal of Nervous and Mental Disease. 2009; 197: 905- 952.; Alvaredo-Esquicel C. Toxoplasma gondii infection and suicide attempts. J of Nerv Ment Dis. 2013; 201: 948-952.; Coryell W, et al. Toxoplasmosis titres and past suicide attempts among older adolescents initiating SSRI treatments. Archives of Suicide Research. 2016; 20: 605-613.] In Denmark individuals who had had congenital toxoplasmosis, as assessed by having antibodies at birth, were significantly more likely to attempt and complete suicide as adults [Pedersen MG, et al. Toxoplasma gondii infection and self-directed violence in mothers. Arch Gen Psychiatry. 2012; 69: 1123-1130.]. And in Poland a postmortem study found higher rates of toxo seropositivity among individuals ages 38 to 58 who died by suicide compared to those who died from various medical conditions [Sanojlowicz D, et al. Prevalence of Toxoplasma gondii parasite infection among people who died due to sudden death in capital city. Przegl Epideiol. 2013; 67: 29-33.]. Finally, two studies have reported a correlation between national rates of suicide and rates of toxo seropositivity [Lester D. Brain parasites and suicide. Psychological Reports. 2010; 107: 2749-2755; Ling VJ, et al. Toxoplasma gondii seropositivity and suicide rates in women. J Nerv Ment Dis. 2011; 199: 440-444].
Two studies examined antibodies to T gondii in individuals diagnosed with obsessive compulsive disorder (OCD). In Turkey 42 individuals with OCD had a significantly higher prevalence of IgG antibodies than 100 controls (p<0.01) [Miman O, Mutlu EA, Ozcan O, et al. Is there any role of Toxoplasma gondii in the etiology of obsessive-compulsive disorder? Psychiatry Res. 2010;177:263–265]. In China a study comparing 29 individuals with OCD and 445 controls reported no significant difference [Cong W, et al. Seroprevalence and associated risk factors of Toxoplasma gondii infection in psychiatric patients: a case-control study in eastern China. Epidemiol. Infect. 2015; 143: 3103-3109]. A study in the Czech Republic used questionnaire information from 1,275 individuals to link self-reported toxo seropositivity to a higher score on an OCD inventory [Flegr J and Horacek J. Toxoplasma-infected subjects report an obsessive-compulsive disorder diagnosis and socre higher in obsessive-compulsive inventory. European Psychiatry. 2016; 40: 82-87.]. Case reports also linked OCD to acquired toxoplasmosis in two children [Brynska A, et al. Obessive-compulsive disorder and acquired toxoplasmosis in two children. European Child and Adolescent Psychiatry. 2001; 10: 200-204].
A study of a large community cohort in Detroit reported that T. gondii seropositivity was associated with a diagnosis of general anxiety disorder but not with PTSD or depression (Markovitz et al, Toxoplasma gondii and anxiety disorders in a community-based sample. Brain Behav Immun. 2015; 43: 192-7 ). Another study of 414 pregnant women reported that the 44 women with antibodies to T. gondii were more likely to be depressed and anxious (Groër MW, Yolken RH, Beckstead JW, et al. Prenatal depression and anxiety in Toxoplasma gondii positive women. Am J Obstet Gynecol. 2011;204:433.e1-7). However, a study of 1,846 American adults reported no significant association between T. gondii seropositivity and general anxiety disorder, panic disorder, or major depressive disorder (Gale SD, et al. Association between latent toxoplasmosis and major depression, generalized anxiety disorder and panic disorder in human adults. Folia Parasitol. 2015; 61(4):285-92).
Three studies have reported the prevalence of toxo seropositivity among substance abusers. Studies of IV drug users in Vietnam (n = 300) and Spain (n = 647) both reported an elevated IgG antibodies [Buchy P et al. Etude serologique de la toxoplasmose au Vietnam, dans une population de toxicomanes (Ho Chi Minh vile) et de gemmes encenties (Nha Trang) 2002.; Gutierrez J. et al. Seroprevalence of human toxoplasmosis. Microbios. 1996; 85: 73-75]. However a Mexican study of 149 alcohol and drug abusers and 149 controls reported no significant difference in T. gondii antibodies [Alvarado-Esquival C, et al. Toxoplasma gondii exposure in patients suffering from mental and behavioral disorders due to psychoactive substance use. BMC Infectious Diseases. 2015; 15: 172].
Intermittent Explosive Disorder
A study of 110 individuals with intermittent explosive disorder reported that 22% had antibodies to T. gondii compared to 9% of controls (p=0.05) (Coccaro EF, et al. Toxoplasma gondii infection: relationship with aggression in psychiatric subjects. J Clin Psychiatry. 2016; 77:334-341).
In 1953 Kozar was the first to report a high prevalence of antibodies to T. gondii in individuals with epilepsy [Kozar, previous]. Since 1995 six studies have been published looking for an association between toxoplasmosis and epilepsy. A 2015 meta-analysis of these studies, with a total of 1,280 subjects with epilepsy and 1,608 controls, reported a positive association with an OR of 2.25 (95% CI 1.27-3.90), p = 0.005. The authors concluded that “despite the limited number of studies, and lack of high quality data toxoplasmosis should continue to be regarded as an epilepsy risk factor [Ngoungou EB, et al. Toxoplasmosis and epilepsy—systematic review and meta-analysis. PLoS Neglected Tropical Diseases. 2015; doi: 10.1371/journal.pntd.0003525]. A previous meta-analysis, that included only the first three studies, had reported an OR of 4.8 (CI 2.6-7.8) [Palmer BS. Meta-analysis of three case controlled studies and an exological study into the link between cryptogenic epilepsy and chronic toxoplasmosis infection. Seizure. 2007; 16: 657-663].
The first study of T. gondii exposure and brain neoplasms, published in 1967, reported that 71 of 126 individuals (56%) with brain tumors were dye-test positive compared to 52 of 126 (41%) controls (p = 0.02). The highest rate of positivity was among gliomas [Schuman L. et al. Relationship of central nervous system neoplasma gondii infection. American Journal of Public Health. 1967; 57: 848-856.]. In 1993 an attempt to replicate this using ELISA to assess T. gondii antibodies in 117 individuals with gliomas, 53 with meningioma, and 415 controls failed to replicate the association in gliomas but reported a positive association in meningiomas (p=0.02) [Ryan P, et al. Tumor of the brain and presence of antibodies to Toxoplasma gondii. International Journal of Epidemiology. 1993; 22: 412-419.]. More recently two epidemiological studies have been carried out comparing rates of T. gondii seropositivity with the incidence of brain cancers. The first reported a positive association across 37 countries (p<0.0001) [Thomas F, et al. Incidence of adult brain cancers is higher where the protozoan parasite Toxoplasma gondii is common. Biology Letters. 2012; 8: 101-103] and the second reported similar findings for 22 administrative regions in France, more pronounced in men and in older people [Vittecoq M, et al. Brain cancer mortality rates increase with Toxoplasma gondii seroprevalence in France. Infection, Genetics and Evolution. 2012; 12: 496-498.].
A small study of Alzheimer’s disease in Turkey reported a significantly higher seropositivity for T. gondii among patients than controls (Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S. Could Toxoplasma gondii have any role in Alzheimer disease? Alzheimer Dis Assoc Disord. 2011;25:1-3). A second study in Iran also reported a positive association but there were questions regarding the proper interpretation of the data [Mahami-Oskoues, et al Toxoplasmosis and Alzhemier: can Toxoplasma gondii really be introduced as a risk factor in etriology of Alzheimer? Parasitol Res. 2016; 115: 3169-3174.; Abdeli. Toxoplasma gondii infection in patients with Alzheimer’s disease and health individuals: strange molecular results. Int J Geriatric Psychiatry. 2016; 32: 582-586] Another study from Iran was negative [Rashno MM, et al. Alzheimer’s disease and Toxoplasma gondii infection; seromolecular assess the possible link among patients. Int J Geriatr Psychiatry. 2017; 32: 231-234.]
One study of patients with Parkinson’s disease reported an increase in T. gondii antibodies (Miman O, Kusbeci OY, Aktepe OC, et al. The probable relation between Toxoplasma gondii and Parkinson’s disease. Neurosci Lett. 2010;475:129–131), but three other studies did not (Celik T, Kamisli O, Babur C, et al. Is there a relationship between Toxoplasma gondii infection and idiopathic Parkinson’s disease? Scand J Infect Dis. 2010;42:604–608). [ Mahsmi-Orkeuoue, et al The correlation between Toxoplasma gondii infection and Parkinson’s disease: a case-control study. J Parasit Dis. 2016; 40: 872-876.; Alvarado-Esquivale et al. Toxoplasma gondii exposure and Parkinson’s disease: a case-control study. BMJ Open. 2017; 7: e013019]
Still other neurological studies have linked T. gondii antibodies to migraine (Koseoglu E, Yazar S, Koc I. Is Toxoplasma gondii a causal agent in migraine? Am J Med Sci. 2009;338:120–122).
A study of 163 individuals with MS reported no association with T. gondii antibodies (Stascheit F. et al. Toxoplasma gondii seropositivity is negatively associated with multiple sclerosis. Journal of Neuroimmunology. 2015; 285: 119-124).
In a Finnish study of 874 individuals with autism, it was reported that women who had a high maternal T. gondii IgM level had a significantly decreased odds of having a child with autism [Spann NM, et al. Prenatal toxoplasmosis antibody and childhood autism. Autism Res. 2017; 10: 769-777]
Perhaps the most interesting association of T. gondii with other diseases is with rheumatoid arthritis. Six studies have reported an increased prevalence of T. gondii antibodies in individuals with this disease (Tomairek HA, Saeid MS, Morsy TA, Michael SA. Toxoplasma gondii as a cause of rheumatoid arthritis. J Egypt Soc Parasitol. 1982;12:17-23; Mousa MA, Soliman HE, el Shafie MS, Abdel-Baky MS, Aly MM.Toxoplasma seropositivity in patients with rheumatoid arthritis. J Egypt Soc Parasitol. 1988;18:345-51; Shapira Y, Agmon-Levin N, Selmi C, et al. Prevalence of anti-toxoplasma antibodies in patients with autoimmune diseases.J Autoimmun. 2012;39:112-6; Fischer S, Agmon-Levin N, Shapira Y, et al.Toxoplasma gondii : bystander or cofactor in rheumatoid arthritis. Immunol Res. 2013;56:287-92). [El Sayed NM, et al. The current status of Toxoplasma gondii infection among Egyptian rhemetoarid arthritis patients. Asian Pac J Trop Dis. 2016; 6: 797-801. El-Henaway AA, et al. Anti-toxoplasma antibodies in Egyptian rheumatoid arthritis patients. Theumatol Int. 2017. Doi: 10.1007/s00296-017-3703-8] Another study reported that individuals with rheumatoid arthritis compared to controls have had more exposure to cats (Gottlieb NL, Ditchek N, Poiley J, Kiem IM. Pets and rheumatoid arthritis. An epidemiologic survey. Arthritis Rheum. 1974;17:229-34). This association is especially interesting because rheumatoid arthritis and schizophrenia share many epidemiological features and it has been noted in many studies that the two diseases are mutually exclusive, i.e., once you get either rheumatoid arthritis or schizophrenia, you almost never get the other (Torrey EF, Yolken RH. The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain Behav Immun. 2001;15:401-10). This suggests that T. gondii or another pathogen may cause both diseases with the clinical outcome differing because of genetic predisposition, timing of the initial infection, strain difference, or other.