**3. Studies based on the detection of anti‐***Toxoplasma gondii* **antibodies**

For more than six decades, the relationship between schizophrenia and toxoplasmosis has been explored by studying a specific immune response [31]. Various meta‐analyses have demonstrated a significantly higher prevalence of anti‐*T. gondii* antibodies in schizophrenic patients than in controls, with odds ratios ranging between 2.7 [11, 32–34] and 1.8 [35].

In the natural time course of toxoplasmosis, IgM antibodies against *T. gondii* are the first to be detected in serum, a few days after infection. These are usually negativized between weeks 4 and 12 but can remain detectable for months or even years in a large number of patients. IgG antibodies are detected at around 2 weeks later than IgM antibodies, reaching a maximum level in the 2nd to 3rd month and persisting throughout life in residual titers. The presence of IgM antibodies in the absence of IgG indicates recent infection, while the presence of IgG indicates chronic infection, especially in the absence of IgM. The reactivation of a persistent infection can be accompanied by increased IgG and/or IgM values, although these antibodies can be undetectable in immunocompromised patients [36].

Most studies have centered on the humoral immune response, comparing anti‐*T. gondii* IgG and IgM antibodies between schizophrenic patients (in different clinical/therapeutic situa‐ tions) and controls. This method is widely employed because of the ease with which samples (usually serum, occasionally cerebrospinal fluid) can be gathered and the high degree of reproducibility, specificity, and sensitivity obtained. Many of these studies reported higher levels of antibodies (IgG and, in some studies, IgM) against *T. gondii* in patients with schizo‐ phrenia than in other populations, including patients with a different psychiatric disorder [32, 37–51]. However, findings have been inconsistent [52, 53], and account should be taken of the publication bias against studies without significant results [11].

Clinical manifestations differ between seropositive and seronegative schizophrenic patients, with a predominance in the former of positive symptoms (delirium, hallucinations, disorga‐ nized thinking), cognitive disorders (abstract thinking difficulties, disorientation, attention deficit), and agitation [50, 54]. Some researchers also observed that patients with schizophre‐ nia and anti‐*T. gondii* antibodies had a significantly higher risk of dying from natural causes [55] and were more likely to attempt suicide [56] in comparison with seronegative patients.

• There is a relatively high frequency of stillborns among both schizophrenic [23] and para‐

• Both diseases typically show a decreased prevalence in geographic areas with small popu‐

• Initial symptoms in both diseases commonly manifest between the second and third

• The prevalence of both diseases is higher among populations with lower socioeconomic

These and other published findings indicate that the two diseases have some similar features and may even be epidemiologically related. However, they are inadequate to establish etio‐ logical relationships, and a pathophysiological approach is required to explore causality.

For more than six decades, the relationship between schizophrenia and toxoplasmosis has been explored by studying a specific immune response [31]. Various meta‐analyses have demonstrated a significantly higher prevalence of anti‐*T. gondii* antibodies in schizophrenic patients than in controls, with odds ratios ranging between 2.7 [11, 32–34] and 1.8 [35].

In the natural time course of toxoplasmosis, IgM antibodies against *T. gondii* are the first to be detected in serum, a few days after infection. These are usually negativized between weeks 4 and 12 but can remain detectable for months or even years in a large number of patients. IgG antibodies are detected at around 2 weeks later than IgM antibodies, reaching a maximum level in the 2nd to 3rd month and persisting throughout life in residual titers. The presence of IgM antibodies in the absence of IgG indicates recent infection, while the presence of IgG indicates chronic infection, especially in the absence of IgM. The reactivation of a persistent infection can be accompanied by increased IgG and/or IgM values, although these antibodies

Most studies have centered on the humoral immune response, comparing anti‐*T. gondii* IgG and IgM antibodies between schizophrenic patients (in different clinical/therapeutic situa‐ tions) and controls. This method is widely employed because of the ease with which samples (usually serum, occasionally cerebrospinal fluid) can be gathered and the high degree of reproducibility, specificity, and sensitivity obtained. Many of these studies reported higher levels of antibodies (IgG and, in some studies, IgM) against *T. gondii* in patients with schizo‐ phrenia than in other populations, including patients with a different psychiatric disorder [32, 37–51]. However, findings have been inconsistent [52, 53], and account should be taken of the

Clinical manifestations differ between seropositive and seronegative schizophrenic patients, with a predominance in the former of positive symptoms (delirium, hallucinations, disorga‐ nized thinking), cognitive disorders (abstract thinking difficulties, disorientation, attention

**3. Studies based on the detection of anti‐***Toxoplasma gondii* **antibodies**

sitized [24] mothers.

62 Schizophrenia Treatment - The New Facets

lations of felines [25, 26].

decade of life [27, 28].

level and living in overcrowded conditions [29, 30].

can be undetectable in immunocompromised patients [36].

publication bias against studies without significant results [11].

The above studies suggest a strong association between these diseases, with a significantly higher frequency of chronic parasitization in schizophrenic patients than in other popula‐ tion groups. However, if schizophrenia is a consequence of chronic CNS infection, which usually takes place at an early age, the question arises as to why it typically appears between the second and third decades of life. According to Yolken et al. [51], a significant increase in IgG titers observed in patients with a first schizophrenia episode may be compatible with a reactivation of the infection (previously in latent phase) that becomes clinically manifest in the onset of the disease *via* an immune‐mediated mechanism. Some authors proposed that the immunoglobulins may cross the blood‐brain barrier in this situation and react with brain tissue antigens due to their molecular mimicry with *T. gondii* antigens. This is similar to obser‐ vations in such autoimmune diseases as systemic lupus erythematosus or in paraneoplastic syndromes [57]. Associations with the presence of anti‐*Toxoplasma* IgM are less well docu‐ mented [35], although Monroe et al. [58] reported in their meta‐analysis a significant 1.7‐fold greater likelihood of *T. gondii* IgM antibodies in patients with acute psychosis than in controls. It was concluded that *T. gondii* IgM antibodies may indicate either an acute/recent infection or a reinfection, possibly with a different genotype.

However, although a strong association has been described between schizophrenia and para‐ sitization, these studies do not provide evidence to confirm the hypothesis on the infectious etiology of schizophrenia, and a causal relationship has not been demonstrated. Contact with *T. gondii* may be favored by the anomalous behavior, disorganized lifestyle, and/or weaker socioeconomic situation of schizophrenics, with infection being the consequence rather than the cause of their disease, which may explain the positive serological results [50].
