Treatment with anti-toxoplasmic activity (TATA) for toxoplasma positive patients with bipolar disorders or schizophrenia: A cross-sectional study
Introduction
Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorders (BD) are among the four most disabling mental, neurological and substance abuse (MNS) illnesses worldwide with a global social cost of respectively 23.7 and 16.8 millions disability-adjusted life years (DALYs) (Collins et al., 2011). This is partly explained by the fact that classic psychiatric treatments still remain unsatisfactory with no available biomarkers to predict their efficacy. Thus, identifying biomarkers that may help to precisely choose a particular antipsychotic and/or mood stabilizer may therefore improve effectiveness, tolerance, adherence and long-term outcomes in the frame of a personalized-based medicine approach (Torrey and Davis, 2012).
Among biomarkers, serological stigma of past infectious events gained increased attention in the last decades (see for review Arias et al., 2012, Brown and Patterson, 2011, Fond et al., 2013). The association between Toxoplasma gondii and respectively SZ (Alipour et al., 2011, Emelia et al., 2012, Hinze-Selch et al., 2007, Nascimento et al., 2012, Okusaga et al., 2011, Torrey et al., 2007, Torrey et al., 2012, Yolken et al., 2001, Yolken and Dickerson, 2009) and BD (Hamdani et al., 2013, Pearce et al., 2012, Tedla et al., 2011) is one of the most studied link between one pathogen and psychiatric disorders, with a 2.73 fold increase in overall odds of T. gondii seropositivity (Torrey et al., 2007).
Toxoplasmosis is the most common protozoa parasite infecting one third of the global human population (Kim and Weiss, 2008) and 43% of the French metropolitan population (Nogareda et al., 2014). Infection in humans generally occurs by ingesting tissue cysts from undercooked meat or raw meat, mainly pork and lamb, or by consuming food or drinks contaminated with sporulated oocysts from the environment (Nogareda et al., 2014). This intracellular parasite alters the expression of host cell genes (including brain cells) and persists in the form of cysts. These cysts can reactivate and release parasites by neo-spread throughout the host, depending on his/her immune status (Carruthers, 2002).
Usually asymptomatic among immuno-competent hosts, T. gondii is an obligate intracellular parasite. It can infect 30% of microglial cells and 10% of neurons and astrocytes in rats (da Silva and Langoni, 2009). In addition to the above-mentioned well-replicated association between T. gondii and SZ/BD, even in first episodes, other indirect arguments suggest a strong link between Toxoplasma infection and mental disorders. Higher levels of antibodies to T. gondii were found in the maternal sera of schizophrenic offsprings compared to maternal sera of healthy controls (Wang et al., 2006). T. gondii's neurotropism and its impact on dopamine pathway (Prandovszky et al., 2011, Wang et al., 2014) have been demonstrated. Dopamine disturbances may be associated with psychotic or manic episodes as well as with depressive episodes (Abi-Dargham, 2014, Dailly et al., 2004). A high anti-toxoplasma IgG levels have been also recently associated with higher number of suicide attempts (Alvarado-Esquivel et al., 2013, Okusaga and Postolache,). Evidence of toxoplasmic infection may therefore play a major role in pathogenesis but also on the therapeutic response to conventional psychiatric treatments.
One other major finding in this field was the discovery that several antipsychotic drugs, and mood stabilizers such as valproate, have anti-toxoplasmic activity (Treatment with Anti-Toxoplasmic Activity, TATA). It has been found that valproate and haloperidol may have respectively a higher in vitro anti-toxoplasmic activity compared to trimethoprim, a TATA of reference (Jones-Brando et al., 2003). This result was further replicated in animal models (Webster et al., 2006). Furthermore, a higher anti-toxoplasmic activity has been found for phenothiazines and other first-generation antipsychotics such as zuclopenthixol, cyamemazine and loxapine (Fond et al., 2014b, Goodwin et al., 2011). However, it is unclear whether the administration of TATA in toxopositive humans with psychiatric disorders was associated with better clinical outcomes compared to non-TATA treated toxopositive patients.
We conducted this retrospective study in a sample of stable bipolar and schizophrenic patients to determine if the administration of a TATA is associated with a better clinical outcome in a population of BD or SZ patients seropositive for Toxoplasma gondii infection.
Section snippets
Study population
One hundred and fifty two BD patients (type I and II), and 114 schizophrenic and schizo-affective patients (SZ) meeting DSM-IV criteria, were consecutively admitted in two university-affiliated psychiatric departments in France (Mondor Hospital, Créteil, University Paris-Est and Fernand Widal Hospital, Paris, University R Diderot). All were included in this study after approval by a French ethical committee and signed written informed consent for their participation.
Clinical variables
Patients were interviewed
Results
In our sample of 152 BD and 114 SZ (schizophrenia + schizo-affective) patients, 115 BD (75.6%), and 74 (64.9%) SZ were seropositive for T. gondii infection. The demographic and clinical characteristics of the sample are described in Table 1A (for BD) and Table 1B (SZ). In order to assess the potential effect of seropositivity to T. gondii on clinical symptoms, we ran a direct comparison between seropositive to seronegative patients.
As illustrated in Table 1A, we found that seropositive BD
Discussion
We explored retrospectively if the prescription of a psychotropic drug having anti-toxoplasmic activity (TATA+) in bipolar or schizophrenic/schizoaffective patients with positive antibodies against T. gondii. The main result of this study was that current TATA+ was associated with lower lifetime number of depressive episodes (p = 0.048), but not with manic or psychotic episodes. This result was not found in toxonegative BD patients, which suggests that toxoplasmic serological status may be a
Limits and future directions
There are several limitations to this work, mostly due to its ecological cross-sectional design. First, only current treatment was studied. The lifetime treatment may have also impacted our results. However it was not possible to assess accurately the impact of the lifetime treatments because of the specific design of our study. Treatments received were too numerous, with variable administration duration and observance. Future studies should consider this limit.
Second, there was a potential
Conclusion
In this cross-sectional retrospective study, we investigated TATA effects in toxopositive BD and SZ patients in a naturalistic manner. We found that TATA may be protective for bipolar depression relapse in toxopositive bipolar patients. Bipolar disorder is a major psychiatric disorder with very little or no known biomarker to guide choosing the efficient medication. A potential biomarker orientating treatment of choice in bipolar disorder deserves therefore consideration. Given that our data
Role of funding source
This work was supported by Agence Nationale pour la Recherche (ANR, Project V.I.P.), INSERM (Institut National de la Santé et de la Recherche Médicale), AP–HP (Assistance Publique des Hôpitaux de Paris), Fondation Fondamental (RTRS Santé Mentale) and by the Investissements d’Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02.
Contributors
Dr Guillaume Fond, Dr Laurent Boyer and Dr Hamdani wrote the manuscript.
All authors designed the study and wrote the protocol.
Dr Guillaume Fond and Dr Laurent Boyer managed the literature searches and analyses.
Dr Laurent Boyer managed the statistical analysis.
All authors contributed to and approved the final manuscript.
Conflict of interest
The authors report no conflict of interest.
Acknowledgments
We thank the collaborators of this analysis: Alice Michel, Jean-François Chabas, the nurses and secretaries from La conception Hospital, and Dr Alexandru Gaman, Fondation Fondamental, for editorial assistance. This work was supported by Agence Nationale pour la Recherche (ANR, Project V.I.P.), INSERM (Institut National de la Santé et de la Recherche Médicale), AP-HP (Assistance Publique des Hôpitaux de Paris), Fondation Fondamental (RTRS Santé Mentale) and by the Investissements d’Avenir
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2018, Schizophrenia ResearchCitation Excerpt :In other words, latent Toxoplasma infection has been found to be almost 3 times higher in this non-selected national sample of SZ subjects that is on average 8 years younger than the general population, while the rate of latent Toxoplasma infection increased throughout life. These results are consistent with those of a recent meta-analysis suggesting that the over-representation of Toxoplasma in SZ populations was found even before illness onset (Sutterland et al., 2015) and those of another French study carried out earlier in a different monocentric sample (Fond et al., 2015). Latent Toxoplasma infection has been associated with negative symptoms and excited symptoms, and specifically with delusion reference and alogia, independently of sociodemographic characteristics, treatments and comorbidities.
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Both authors equally directed the present work.