Toxoplasmosis and Schizophrenia: A Systematic Review and Meta‐Analysis of Prevalence and Associations and Future Directions

We analyzed 66 studies published over the past 2 decades with 11,540 patients with SCZ and 69,491 controls, exploring the association between toxoplasmosis and SCZ or SCZ phenotypes. This large accumulated research agenda reflects the great interest of the scientific community for the identification of potentially preventable and/or treatable risk factors for SCZ (40). Although there was large heterogeneity across studies in the types of toxoplasmosis exposures and SCZ outcomes targeted, on average, 45% of patients with SCZ were Toxoplasma IgG (or IgG/IgM) seropositive versus 30% of controls. Toxoplasma IgG (or IgG/IgM) seropositivity increased the odds of SCZ by 1.91‐fold. This is similar to the estimate from an earlier meta‐analysis by Sutterland et al. in 2015 (OR = 1.81; 95% CI 1.52–2.17) (19).

Most studies targeted only Toxoplasma IgG (or IgG/IgM) seropositivity in SCZ. In contrast, the association with specific SCZ phenotypes was targeted in less than half of the studies. A positive association between Toxoplasma IgG (or IgG/IgM) seropositivity and at least one SCZ phenotype was reported in only a third of the analyzed studies. We did not perform a meta‐analysis for the association between toxoplasmosis and SCZ phenotypes as a meta‐analysis for this association was recently published by Sutterland et al. (25) in 2020. In this meta‐analysis no overall association was seen between Toxoplasma IgG seropositivity and severity of total, positive or negative SCZ symptoms (25). A significant association was only detected in the subgroup of patients with SCZ with a shorter duration of illness (less than 10 years), with Toxoplasma IgG seropositivity being associated with more severe positive symptoms (25).

We identified important methodological biases in the analyzed studies. Approximately 75% of the studies did not perform adjustments for important confounders such as age and socioeconomic status, or place of residence. Moreover, only four studies (41, 42, 43, 44) had addressed whether the Toxoplasma infection preceded the diagnosis of SCZ. In the absence of temporality assessment, causality is uncertain. Toxoplasma infections may be the cause or the result of SCZ (e.g., due to common environmental exposures during hospitalization of patients with SCZ). Three out of 4 studies properly addressing temporality documented a positive association between Toxoplasma infection and SCZ. Burgdorf et al. 2019, a large prospective cohort study in Denmark, showed increased rates of Toxoplasma infection preceding the diagnosis of SCZ (41). Another prospective population cohort study from Denmark by Pedersen et al. of 45,609 women also showed that high Toxoplasma IgG levels before delivery were associated with a significantly increased risk of developing SCZ spectrum disorders subsequently (44). Furthermore, a study among US military personnel in whom Toxoplasma IgG levels were obtained before the diagnosis of SCZ also showed an association between higher Toxoplasma IgG levels and SCZ (43).

Schizophrenia has traditionally been assumed to be largely a genetic condition, with high heritability (45). However, there is concern that the genetic etiology of SCZ might have been overestimated given the inability to detect large genetic effects (45). Schizophrenia may result from a complex interplay between genetic and environmental factors (46). For example, HLA genes of the major histocompatibility complex (MHC) have the strongest genetic predisposition for SCZ in genome‐wide association studies (47). Similarly, MHC genes may affect susceptibility to Toxoplasma infections (48, 49). Certain HLA alleles (e.g., HLA C*04:01 allele) have been shown to decrease susceptibility to T. gondii infection in patients with SCZ but not in controls (49). Interactions between genetic and environmental risk factors merit further investigation (46). Environmental factors may be extremely complex and heterogeneous regarding infections by different strains and timing of infection.

Although most studies studied the role of chronic latent toxoplasmosis (IgG seropositivity) with SCZ, approximately a quarter of the studies also studied the potential association of acute toxoplasmosis (IgM seropositivity) with SCZ. On average, 5% of patients with SCZ were Toxoplasma IgM seropositive, versus 0% of controls. A significant association between Toxoplasma IgM seropositivty and SCZ was shown in less than 5% of the studies. An earlier meta‐analysis by Monroe et al. (21) showed that Toxoplasma IgM seropositivity was associated with an increase in the odds of acute psychosis. However, positive Toxoplasma IgM results with commercially available tests are often false positive and thus, they cannot be used to diagnose acute Toxoplasma infection (50, 51). Positive Toxoplasma IgM results in commercial labs should always be confirmed with additional tests before the diagnosis of acute toxoplasmosis is made. Studies claiming an association between acute Toxoplasma infection and SCZ based only on positive Toxoplasma IgM results, without additional confirmatory testing, should be viewed with caution.

There is speculated biological plausibility for the role of toxoplasmosis in SCZ. Several experimental lines of research addressing parasite‐induced anatomical, histological, and physiological changes have been published; however, there is heterogeneity in reported results (14). During the chronic latent stage of the infection, formation of bradyzoites in the brain could directly alter the dopamine biosynthesis and cause dopaminergic disturbances involved in psychotic disorders (52, 53). The elicited anti‐T. gondii immune responses may cross‐react with host N‐methyl‐D‐aspartate receptors (NMDAR), causing disruption of neural circuits and cognitive deficits (13). Autoantibodies that bind to the NMDARs may underlie glutamate receptor dysfunction and cognitive impairment found in SCZ (54). Latent Toxoplasma infection has been associated with upregulation of the complement C1Q classic immune pathway, which aids in the clearance of the parasite from the central nervous system with subsequent consequences for the connectivity of neighboring cells and synapses, suggested to be involved in SCZ onset (10). Moreover, complement C4 genes have been proposed in gene‐environment interaction studies as potential susceptibility loci for SCZ and infections (including T. gondii infections) (55). Patients with SCZ have increased plasma levels of complement C4 protein activation products, causing increases in blood brain barrier permeability (56). However, there is heterogeneity in the animal studies about the proposed underlying pathophysiologic mechanisms (e.g., alterations in neurotransmitter release, cyst location, and neuroinflammation) for the association of toxoplasmosis with SCZ (14, 17, 57, 58). This heterogeneity may arise from differences in the behavioral assays used, the timing of the behavioral assays, the T. gondii and mice strains utilized, and the route of infection (14). If T. gondii influences human behavior or disease, the effect may depend on the genetic background of the individual and the context of the T. gondii infection (14).

Several neuroleptic antipsychotic and mood stabilizers have been tested for their ability to inhibit replication of T. gondii (59). Among those, the antipsychotic haloperidol and the mood stabilizer valproic acid have been shown to most effectively inhibit T. gondii growth in vitro (60). McFarland et al. (61) and Neville et al. (62) recently reviewed experimental compounds (61) and clinical approved drugs (62) with anti‐Toxoplasma activity. Chorlton et al. (63) identified four published RCTs (64, 65, 66, 67) testing different medications in patients with SCZ. Several important limitations were identified that likely biased the results towards the null; including failure to target specifically Toxoplasma seropositive patients with SCZ (in 2/4 of these trials) and selecting not clinically appropriate medications. The medications tested in those trials included azithromycin (64), trimethoprim (TMP) monotherapy (65), artemisin therapy (66) and artemether therapy (67). These medications are not considered first line anti‐Toxoplasma treatments (64) and most of those are not even considered acceptable anti‐Toxoplasma treatments (65, 66, 67) and have not been used in other clinical settings (e.g., for treatment or prophylaxis of high‐risk Toxoplasma seropositive patients) (68, 69). Four additional small RCTs are currently listed in ClinicalTrials.gov, testing pyrimethamine monotherapy (70), artemisin plus risperidone (71), valproate (72) and L‐tetrahydropalmatine (73) in patients with SCZ. These trials similarly do not use first line medications and are not targeting only Toxoplasma seropositive patents with SCZ.

Further association studies are unlikely to offer more solid evidence at this point. We believe that randomized double‐blind placebo‐controlled clinical trials are urgently needed to test the role of anti‐Toxoplasma primary prophylaxis (with first line anti‐Toxoplasma prophylaxis medications) in Toxoplasma seropositive patients with SCZ. These trials should be ideally simple in design, pragmatic, multicenter, and with few clinically important endpoints. The COVID‐19 era has taught us that only well designed, large, RCTs are able to provide solid clinical evidence in a timely fashion and to change our clinical practices (74, 75).

The hypothesis underlying a study testing a first line anti‐Toxoplasma prophylaxis medication in Toxoplasma seropositive patients with SCZ is that prevention of local intermittent subclinical reactivations of Toxoplasma cysts in the brain of these patients may positively impact their SCZ course. Currently, there are no clinically available medications for the eradication of bradyzoite tissue cysts (the T. gondii tissue form in chronic latent Toxoplasma infection) (76). The goal of such a study in patients with SCZ should be the prevention of intermittent subclinical reactivation rather than eradication of latent T. gondii infection. This has been the strategy for prophylaxis of immunocompromised patients who are Toxoplasma seropositive (69, 77, 78). The proposed mechanism on how anti‐Toxoplasma prophylaxis may help SCZ is that prevention of subclinical reactivations of Toxoplasma cysts may prevent secondary alterations in neurotransmitters' release and/or neuroinflammation and subsequent worsening of SCZ clinical course. A proof‐of‐concept for such prophylaxis study will require at least 1 year of prophylactic drug since reactivations may be periodical and spaced over time.

The preferred first line anti‐Toxoplasma primary prophylaxis regimen is TMP/sulfamethoxazole (TMP/SMX; one double‐strength or one single strength tablet once daily) (69, 77, 78). Long‐term experience exists for the safety and efficacy of TMP/SMX prophylaxis in several high‐risk immunocompromised patients, for example, Toxoplasma seropositive transplant patients (69, 77) or patients with acquired immune deficiency syndrome (78). The majority of these patients tolerate TMP/SMX without toxicities altering the benefit/risk ratio. Primary prophylaxis in Toxoplasma seropositive hematopoietic stem cell transplant patients is routinely recommended for at least 6 months or even longer for certain patients considered significantly immunosuppressed‐requiring prophylaxis‐for more prolonged periods (69, 77). Prolonged secondary prophylaxis with TMP/SMX is also recommended in patients with recurrent toxoplasmic eye disease in vision threatening areas (e.g., for 12–20 months for certain patients) (79, 80) and for Pneumocystis jiroveci prophylaxis in severely immunocompromised patients (e.g., up to 6–12 months for certain transplant patients) (81).

We propose that Toxoplasma IgG seropositive patients with SCZ should be randomized to primary prophylaxis with a first line anti‐Toxoplasma medication such as TMP/SMX versus placebo. The selection of an appropriate first line anti‐Toxoplasma medication, similar to what is routinely used for primary prophylaxis in other clinical settings, is critical. Moreover, the duration of the prophylactic therapy (e.g., at least 1 year) would be an additional key factor to allow for proper assessment of clinically important impact on SCZ course. Multidisciplinary collaboration between psychiatrists, infectious diseases experts, and research methodologists in the design of such a pragmatic clinical trial should be a priority.

We would like to thank Dr. Anita Koshy for her critical comments on our paper, which helped significantly improve our work. There was no funding for this project.