We have presented the first controlled, age-adjusted, prospective, large study of TG infection in psychiatric patients with schizophrenia and major depression diagnosed according to ICD-10 and all recruited in the same geographic region and during the same period. We found that serofrequency (titer <1:16 vs titer ≥1:16) did not differ between groups but that serointensity (<1:16 vs 1:16–1:64 vs ≥1:128) did differ between patients and controls, with higher serointensity in the patients. The analyses of interrelationships within each group between the TG antibody titers and further immunologic or psychopathologic parameters revealed significant results for the schizophrenia group only. High antibody titers were associated with higher inflammatory responses and with first-episode status.
The unique meta-analysis by Torrey and coworkers31
of all published studies included only well-described and methodologically sound studies and calculated an odds ratio of average 2.73. There was no systematic effect of the size of the groups and the results. The number of studies with control groups matched by any means to the patient groups is low, ie, 4 of 23, of which 3 dealt with first-episode patients only. For these 4 studies, the odds ratios range between 2.19 and 5.45. We cannot explain these discrepancies between different studies. However, we suggest for consideration the following issue: matching of the comparison groups is important with respect to age and geographic region of residence (particularly urban vs rural) for the likelihood of acquiring the infection.32
We matched for both of these criteria, whereas none of the previously published studies did so. From our experience, controlling for age is essential. Slight differences in mean age, particularly disequilibrium between the microbiologically relevant age blocks, may shift the results. If we had compared the groups without adjusting for age, seropositives would have been significantly more frequent in the oldest group of patients with major depression. Thus, we think that studies that do not carefully adjust for age between groups must be considered with caution. Furthermore, studies that report “increased antibody levels” in patients must be carefully evaluated because increased antibody levels are not identical to increased frequency of seropositives.33,34
Our study is the first that also systematically collected information on the putative routes of infection. Patients and controls did not differ with respect to the frequency of these risk factors, but they did differ with respect to the interrelationship between these risk factors and seropositivity: the eating of raw meat in the patients and risky cat contact in the controls were associated with higher seropositivity. Thus, if this association points to the infectious route, our patients might have eaten infected raw meat more often, and the controls might have been hygienically less careful in their contacts with infected cats. On the basis of our data, we cannot further analyze this issue. However, if there is particular risk behavior in psychiatric patients, it would be useful to know this and to specifically intervene.
We found that serotiters were significantly higher in the 2 patient groups compared with the controls in all individuals older than 45 years. Moreover, the patients with schizophrenia demonstrated significant interrelationships between the titer category (serointensity) and the course of the disorder as well as with inflammatory variables and the use of immunomodulatory medications. Our results are consistent with previous studies that found increased serotiters in first-episode patients with schizophrenia.33,34
As mentioned before, increased serotiters are not necessarily in the range of the microbiologically high titers suggestive of recent infection and, therefore, might rather support the more intense antibody response of the host.35
Consequently, the higher antibody titers in the first-episode patients, regardless of age, might be based on the special condition of the patients. This is further supported by the additional interrelationship between high antibody titers and increased CRP levels and numbers of leukocytes as markers of inflammatory activity. There is a vast literature on immunologic peculiarities in individuals with schizophrenia.1,36–40
In the light of TG infection, these data are of special interest.1,36
As mentioned previously, one basic host defense strategy is through proinflammatory T-helper lymphocytes, ie, TH
It was described that individuals with schizophrenia with acute symptomatology display increased TH
1-associated cytokine responses, returning to control levels during successful antipsychotic treatment.41
Therefore, an infection such as TG might recurrently induce a TH
1 response that modulates the serotonin and dopamine neurotransmitter systems, leading to respective psychotic symptomatology. Antipsychotic treatment that reorganizes these neurotransmitter systems reduces the symptoms by modulating this common final pathway. Immunomodulating antipsychotics28,37,42
in addition might become involved in the host defense against this infection. We found that the use of immunomodulating antipsychotics was associated with lower TG titers. We suggest that the cytokine pattern of increased TH
1 response in patients with acute symptoms might be caused by the proinflammatory response to infections such as TG. To our knowledge, there is no published study that investigated TG infection and TH
1 immune variables simultaneously. Such a study will be necessary to determine whether TG infections in individuals with schizophrenia are associated with increased TH
1 activation; it might also provide an explanation for the diverse findings in schizophrenia on the overactivation of TH
1 or TH
2 cytokines (for review of the TH
2 hypothesis of schizophrenia see Schwarz39
We found high TG titers in first-episode patients and an association between high titers and increased CRP and leukocyte values, as well as an association between the use of immunomodulating antipsychotics and low titers. One reason could be the use of immunomodulating antipsychotics from the first episode onward. On the other hand, because the high titers were seen in both first-episode and chronic-course patients, continuously high titers might favor a chronic course. Furthermore, a strong proinflammatory immune response to properly control TG microcysts could be counterproductive. One can speculate whether modulating this intense immune response might improve the clinical course in the patients with high titers and chronic course, as well as prevent the high-titer, first-episode patients from developing a chronic course.
Even if our data cannot answer all the questions and speculations presented, they represent the first detailed data on several important variables, and they support continued research on these questions. If TG infection is really able to induce a proinflammatory immune response that leads to dysregulated serotonin and dopamine neurotransmitter systems, to clinically relevant psychiatric symptoms, and perhaps even to the precipitation of schizophrenia in vulnerable subjects,43
then a specific and effective treatment of this infection, coupled with a better understanding of how this vulnerability is defined, will be mandatory.