Treatment with anti-toxoplasmic activity (TATA) for toxoplasma positive patients with bipolar disorders or schizophrenia: A cross-sectional study

https://doi.org/10.1016/j.jpsychires.2015.02.011Get rights and content

Highlights

  • Toxoplasma gondii has been associated with respectively Schizophrenia (SZ) and Bipolar Disorder (BD).

  • BD toxopositive patients presented more lifetime depressive episodes when treated by drug having no anti-toxo activity.

  • It seems to be of importance to consider administering a drug with a clear anti-toxoplasmic activity (TATA+) for BD patients seropositive to T. gondii.

Abstract

Objective

The association between Toxoplasma gondii seropositivity and respectively Bipolar Disorder (BD) and Schizophrenia/Schizoaffective disorder (SZ) is one of the most studied link between one pathogen and psychiatric disorders. The aim of the present study was thus to retrospectively determine if the administration of an antipsychotic and/or a mood stabilizer having known in vitro Anti-Toxoplasmic Activity (TATA+) was associated with a better clinical outcome in a population of 152 BD or 114 SZ patients and seropositive for T. gondii infection compared to patients receiving a treatment without anti-toxoplasmic activity (TATA-).

Methods

This multicenter study was conducted in an academic public hospital during a 3-years period between 2009 and 2011. All consecutive inpatients and outpatients with SZ or BD diagnosis with a stable treatment for more than 4 weeks were recruited. socio-demographic and clinical characteristics measured with validated scales as well as a serological status for toxoplasmic infection were included. Treatments were classified according to their in vitro antitoxoplasmic activity. A multivariate model was used to determine the clinical characteristics that were significantly different between patients receiving a treatment with no antitoxoplasmic activity compared to others.

Results

BD patients with positive serum antibodies against T. gondii presented more lifetime depressive episodes (p = 0.048) after adjustment for age, sex and sociodemographic characteristics when treated by drug having no anti-toxo activity, compared to patients having received drugs with anti-toxo activity. A significant difference was not found in BD toxonegative patients and in SZ toxopositive or toxonegative patients.

Conclusions

It seems to be of importance to consider prescribing a drug with a clear anti-toxoplasmic activity (TATA+) for BD patients seropositive to T. gondii, in particular valproate that was found as the mood stabilizer with the highest antitoxoplasmic activity. Prospective randomized controlled trials are warranted to confirm this preliminary data.

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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