**5. Studies based on** *Toxoplasma gondii* **nucleic acid detection**

Studies of animal brain biopsies have shown *T. gondii* to have high neurotropism, with the capacity to infect glial cells (especially microglia and astrocytes) and neurons, forming per‐ sistent cysts in brain tissue [69]. Although no tropism for specific brain regions has been observed, with cysts being detected in many areas, the most frequently parasitized regions are the hippocampus, thalamus, cerebral cortex, cerebellum, olfactory bulb, and, especially, the amygdala [70–73].

However, the presence of brain cysts can only be detected in *postmortem* biopsies, explaining the few studies of this type and the predominance of serological techniques for the detec‐ tion of chronic infection by *T. gondii* in humans. The presence of glial anomalies, including a reduced amount of astrocytes, has been reported in the brains of schizophrenic patients [74], and it has been speculated that these may possibly result from infection by *T. gondii* [31]. Imaging techniques have revealed a lower density of gray matter in certain brain regions of schizophrenic patients [75], which may be directly related to the infection, given that non‐ parasitized schizophrenic patients were found to have the same brain morphology as healthy controls [76].

ence of antibodies in newborns and their later development of schizophrenia. Among the for‐ mer, Brown et al. [60] and Blomström et al. [61] demonstrated associations between increased anti‐*Toxoplasma* IgG levels in pregnant mothers and risk of schizophrenia in their offspring, although other researchers published discrepant results [62]. Xiao et al. [63] observed a signif‐ icant association between the presence of maternal antibodies against type I *T. gondii* (but not against types II or III) and the onset of psychotic disorders in the offspring. Among the latter group of studies, Mortensen et al. [59] demonstrated that newborn levels of anti‐*T. gondii* IgG levels (from the mother) were significantly higher in individuals who developed schizophre‐

Published data suggest that schizophrenia risk in offspring is associated with persistent maternal infection by *T. gondii* but is not directly related to acute maternal infection [64]. If this were the case, a significant association could be expected between the presence of IgM in the serum of mothers and/or newborns and the presence of the disease, which has not been demonstrated [60]. However, this relationship may be masked by the low frequency of

As noted above, increased maternal IgG levels can cross the placenta (unlike IgM antibod‐ ies) and may damage fetal brain development by molecular mimicry [60, 64]. However, the presence of maternal IgG may indicate a reactivation of latent infection due to the impact of immune system disorders on protozoan replication control during pregnancy [66]; hence, brain development could also be impaired by transplacental transmission and/or the passage

The majority of schizophrenic patients do not have anti‐*Toxoplasma* antibodies, and the major‐ ity of seropositive patients are not schizophrenic. Therefore, *T. gondii* would only explain a minority of cases. Other factors under investigation that may explain why only some parasit‐ ized individuals develop schizophrenia include genetic susceptibility, the infective genotype of the parasite, the existence of different infection pathways, and the timing of toxoplasmosis

Studies of animal brain biopsies have shown *T. gondii* to have high neurotropism, with the capacity to infect glial cells (especially microglia and astrocytes) and neurons, forming per‐ sistent cysts in brain tissue [69]. Although no tropism for specific brain regions has been observed, with cysts being detected in many areas, the most frequently parasitized regions are the hippocampus, thalamus, cerebral cortex, cerebellum, olfactory bulb, and, especially,

However, the presence of brain cysts can only be detected in *postmortem* biopsies, explaining the few studies of this type and the predominance of serological techniques for the detec‐ tion of chronic infection by *T. gondii* in humans. The presence of glial anomalies, including a reduced amount of astrocytes, has been reported in the brains of schizophrenic patients [74], and it has been speculated that these may possibly result from infection by *T. gondii* [31].

**5. Studies based on** *Toxoplasma gondii* **nucleic acid detection**

anti‐*Toxoplasma* IgM detection in pregnant women [24, 65].

of inflammatory cytokines to the fetus [67, 68].

nia in adulthood.

64 Schizophrenia Treatment - The New Facets

onset [20, 33, 63].

the amygdala [70–73].

One of the few studies of *postmortem* brain biopsies found no parasite DNA in any subject (14 schizophrenic patients and 26 healthy controls) [77]. There appear to be three possible expla‐ nations: first, there was truly no association with the infection; second, the biopsies missed infected brain areas; and finally, the sensitivity of the nucleic acid detection technique might be inadequate. In addition, the detection of parasite DNA only demonstrates the presence of the parasite not its possible effect on the parasitized individual and would not establish an etiological relationship with schizophrenia. Thus, the detection of parasite DNA in brain tis‐ sues does not distinguish between asymptomatic patients with latent parasitization and those with encephalitis [17].

A study of blood samples detected parasite DNA in 33 out of 101 samples from schizophrenic patients *versus* 2 out of 55 samples from controls, a significant difference [46]. In contrast, Gutiérrez‐Fernández et al. [32] detected parasite DNA in only 1 out of 128 blood samples from schizophrenic patients and in none of 143 samples from controls (nonsignificant difference). However, although the presence of parasite DNA in blood indicates acute infection [17], it does not necessarily signify infection of the brain, and no relationship was found between anti‐*Toxoplasma* IgM and schizophrenia in the aforementioned study [46].
