**11. Is there an etiological association between** *Toxoplasma gondii* **infection and schizophrenia development?**

Numerous studies have contributed evidence on the involvement of toxoplasmosis in the pathogenesis of numerous CNS diseases, including bipolar disorder, depression, Alzheimer's disease, Parkinson's disease, and epilepsy [49, 202–204]. However, the main advances over the past few years have been achieved by research on deciphering the molecular mechanisms underlying the physiopathology of schizophrenia.

This chapter analyzes data from *in vitro* and animal and human *in vivo* studies in order elu‐ cidate points of connection between *T. gondii* and schizophrenia. It can be concluded that infection by *T. gondii* is highly likely to be a cause of the disease for the following reasons: it is a neurotropic microorganism that persistently invades glial cells and neurons; it gener‐ ates brain development anomalies; it reduces brain gray matter density; it elicits an inflam‐ matory and immune response that alters neurotransmission systems; it affects cognitive function and behavior; and its replication is inhibited by some antipsychotics. All disor‐ ders reported for the parasite are associated with the development of psychotic symptoms. Furthermore, specific genetic polymorphisms linked to an increased risk of schizophrenia have also been associated with a higher likelihood of infection by this parasite. Nevertheless, despite all of the above evidence on this possible pathogenic association, one important

**Figure 1.** Likely involvement of infection by *Toxoplasma gondii* in the development of schizophrenia.

question remains to be resolved, which is why most individuals with signs of infection by *T. gondii* are asymptomatic and only a few develop psychiatric disorders.

Schizophrenia is a complex disease with innumerable symptoms, and its presentation and severity vary among patients. According to the infectious hypothesis of this disease (**Figure 1**), differences among patients would be influenced by their genetic predisposition or vulnerability, their immune status, the timing of parasitization (congenital, neonatal, or adult), the time interval since their first contact, and/or the particular brain area(s) affected. Characteristics of the infection also play a role, including its source (oocysts or tissue cysts), possible interactions with other infectious agents, and the genotype; thus, genotypes II and III more frequently establish chronic infections and show a greater expression of tyrosine hydroxylase genes in comparison with genotype I, and they may be more strongly related to behavioral changes [205].

Finally, the biology of schizophrenia must be fully elucidated to support the appropriate design of disease‐modifying therapies or novel antipsychotic drugs. There appears to be sufficient evidence to suggest that schizophrenic patients with *T. gondii* infection could clini‐ cally benefit from a combined therapeutic approach based on the prescription of current or future antipsychotic drugs with antitoxoplasmic activity. However, published results have not been conclusive [206], and randomized controlled prospective trials are required in wider samples, stratifying schizophrenic patients into subgroups (e.g., by clinical phe‐ notype, pathophysiological mechanism, or response to treatment) and in relation to spe‐ cific types of *T. gondii* parasitization. Translational research must play a key role, with the involvement of psychiatric, neurologic, immunologic, biochemical, genetic, pharmacologi‐ cal, and microbiological investigators, among others, offering the possibility of using new and more effective methodologies. It appears highly likely that different causal agents are responsible for schizophrenia and that the pathogenic action of a particular microorganism such as *T. gondii* would only be relevant in certain patient subgroups, endorsing the need for personalized medicine.
