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Review

Is Toxoplasma gondii a Trigger of Bipolar Disorder?

by
Claudia Del Grande
1,
Luca Galli
2,
Elisa Schiavi
1,
Liliana Dell’Osso
1 and
Fabrizio Bruschi
2,*
1
Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Via Roma 67, 56127 Pisa, Italy
2
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
*
Author to whom correspondence should be addressed.
Pathogens 2017, 6(1), 3; https://doi.org/10.3390/pathogens6010003
Submission received: 3 October 2016 / Revised: 16 December 2016 / Accepted: 4 January 2017 / Published: 10 January 2017
(This article belongs to the Special Issue Toxoplasma gondii Infection)
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Abstract

:
Toxoplasma gondii, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between T. gondii and schizophrenia has been the most widely documented; however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected. T. gondii may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral Toxoplasma-induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between Toxoplasma gondii and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms.

Graphical Abstract

1. Introduction

Bipolar disorder (BD), a chronic and recurrent psychiatric illness, is one of the major causes of disability and mortality worldwide [1,2,3]. The etiology of BD is multifactorial, resulting from a complex interaction between genetic heritability and environmental risk factors [4,5]. Among these, infectious insults have been identified, and immune dysfunction seems to play a major role in the pathophysiology of this disorder, as widely documented by recent literature [6,7,8,9,10,11,12]. A chronic, mild inflammatory status in the periphery and in the brain was observed in BD patients (e.g., specific patterns of cytokines during manic/depressive episodes), and the dysregulation of inflammatory processes may also account for the medical comorbidities (atherosclerosis, hypertension, diabetes and obesity), as well as for auto-immune disorders (multiple sclerosis, thyrotoxicosis, ulcerative colitis, psoriasis and rheumatoid arthritis) that commonly occur in association with BD [11,12].
Although further evidence is needed to clarify the pathogenetic mechanisms underpinning BD, immunological abnormalities may help to explain the cyclic and recurrent course of the disease characterized by marked fluctuations in mood; moreover, they could allow one to identify novel promising neuroimmunological targets for the treatment of BD [13,14].
The implication of infectious agents, particularly Toxoplasma gondii (T. gondii), in the development of major psychosis has recently gained increasing attention [15,16,17,18,19,20,21]. In the last decade, the number of publications dealing with the relationship between toxoplasmosis and schizophrenia or BD has dramatically increased, as shown in Figure 1. However, the role of infectious agents remains controversial, and to date, no clear cause-effect etiopathogenetic relation can be established.
T. gondii is an intracellular protozoan parasite, which infects around one-third of humans worldwide, with prevalence rates that can reach up to 95% in the elderly population in some geographical areas [22,23,24]. In humans, T. gondii is commonly acquired by the oral ingestion of tissue cysts containing bradyzoites, through the consumption of undercooked meat infected with T. gondii; however, it can also be acquired via ingestion of the parasite’s oocysts, which can spread from the feces of infected cats [25,26] or through contaminated water [27]. This parasite has a particular tropism for muscle and brain tissue, where it remains localized in the form of cysts throughout life, establishing a chronic infection. The clinical presentation of infection may be heterogeneous, depending to a great extent on the immune status of the host, which is determined by both genetic and environmental factors [28]; it can range from an asymptomatic or negligible symptomatic form mostly observed in immune-competent individuals to severe forms presenting with encephalitis or multi-organ involvement, more frequently in immunocompromised hosts [22,26]. T. gondii has been shown to be a potent disrupter of fetal neurodevelopment, while congenital infection, occurring when a pregnant woman has a primary infection and transmits T. gondii to the fetus, has been associated with uveitis, chorioretinitis, encephalitis, epilepsy and psychomotor or mental retardation [29,30].
This review aims to describe the relationship that has emerged in recent years between toxoplasmosis and psychiatric disorders, focusing mainly on BD. The possible etiopathogenetic mechanisms underpinning this association were analyzed, emphasizing how the inflammatory damage induced in the brain tissue by the parasite might contribute to the emergence of clinical manifestations, as well as the progression of BD.

2. Relationship between Toxoplasma gondii and Bipolar Disorder

The first observations of an involvement of infectious agents, such as viruses, spirochetes and protozoa, in the pathogenesis of psychosis were described more than a century ago, as reviewed by Yolken and Torrey [15]. Infectious agents can cause psychosis both directly, by affecting neurons and brain structures, and indirectly, by the activation of a microbe-specific immune response and the subsequent release of neurotoxic factors [31,32].
A number of epidemiologic studies has recently highlighted the prominent role of T. gondii in the pathogenesis of several psychiatric disorders. Although latent toxoplasmosis was generally assumed to be relatively harmless in immune-competent individuals, there is now evidence that it may cause personality and behavioral changes in chronically-infected hosts, such as a reduction in reaction time and psychomotor performance, reduced intelligence quotient and aggression/impulsivity traits [33,34,35,36,37,38,39,40]. These observations are supported by prior animal models showing behavioral changes in T. gondii-infected mice, such as conversion from aversion to attraction to cat odor, motor coordination and sensory deficit and reduced exploratory activity [41,42,43,44]. It has been suggested that these behavioral changes may be caused by manipulation activity of the parasite aiming to increase the probability of its transmission from an intermediate to a definitive host [45].
T. gondii infection has also been associated with major psychosis [15,19,21,46,47] and with self-directed violence and suicidal behaviors [48,49,50,51,52]. In this context, the link between toxoplasmosis and schizophrenia has been the most widely investigated, with 42 studies showing higher rates of anti-T. gondii IgG antibodies in patients with schizophrenia as compared to psychiatrically healthy controls [16,53]. Nevertheless, an association between T. gondii exposure and the risk of BD has increasingly emerged in recent years [20,21,54,55,56].
A first study using a toxoplasmin intradermal test showed that high grade positivity was observed among patients with manic-depressive illness [57], and a more recent Ethiopian case-control study revealed a significantly higher seroprevalence of T. gondii infection in BD patients compared to healthy controls [58]. Some authors [36] also found that in a sample including 896 psychiatric inpatients with the primary diagnoses of schizophrenia, major depression, schizoaffective disorder or BD and 214 psychiatrically unaffected controls, the additional diagnosis of a personality disorder was significantly associated with T. gondii infection among all psychiatric inpatients. These data support that T. gondii infection can affect human behavior and personality traits.
In a cross-sectional survey conducted on a sample of 7440 individuals of 15–39 years old from the Third National Health and Nutrition Examination Survey, the association between T. gondii exposure and several well-defined mood disorders was examined [56]. Results of this study showed a significant relationship between Toxoplasma seropositivity and a subtype of BD type I in which both manic and depressive features were reported. Respondents with a prior T. gondii exposure were approximately 2.3-fold more likely to have a history of BD type I with manic and depressive symptoms than respondents who tested negative for T. gondii antibody. The authors hypothesized that the infection with the parasite may precipitate or accelerate depressive symptoms in patients with this subtype of BD. Conversely, no statistically-significant association was found between T. gondii seroprevalence and a history of major depression or dysthymia, according to observations from prior smaller studies [48,59,60]. It has been hypothesized that the positive association found between a subtype of BD type I and toxoplasmosis could be due to behavioral factors, probably more common among individuals with this mood disorder, exposing the patients to a greater risk of infection with the parasite. On the contrary, it is possible that major depressive disorders decrease the risk of behaviors related to T. gondii exposure [58]. Another case-control seroprevalence study investigated the potential association between T. gondii exposure and BD comparing the prevalence of anti-T. gondii IgG/IgM antibodies in a sample of 110 BD and 106 healthy controls all living in France, a country of high seroprevalence of toxoplasmosis [20]. Results of this study showed that both the seropositivity and the T. gondii antibody levels were significantly higher in BD patients as compared to controls; moreover, the seropositive participants had a 3.6-fold increased odds of having BD as compared to the seronegative group (p < 0.0001), with an odds ratio (OR) of 2.40 (p = 0.026) after adjustment for age, ethnic origin, foreign birth and current smoking. This OR is quite similar to that previously observed in samples of schizophrenic patients (OR = 2.70–2.73) [18,55]. Dickerson et al. [61] examined the levels of serum IgG and IgM antibodies to T. gondii and CMV antibodies in 57 patients hospitalized with a manic episode and in 743 individuals in other psychiatric groups belonging to bipolar or schizophrenic disorders compared with those in 314 non-psychiatric controls. Patients in the mania group were assessed up to three time points, and anti-T. gondii antibody levels were compared over time in this group. Results of this study showed that manic patients had a significantly elevated level of IgM antibodies to T. gondii at baseline as compared to the control group without a psychiatric diagnosis. Elevated anti-T. gondii IgM antibodies were not found in patients with the other psychiatric diagnoses, while the group of patients with a recent onset of psychosis alone had significantly elevated levels of IgG antibodies to T. gondii. Within the mania group, a significant difference between the prevalence of increased levels of T. gondii antibodies at the baseline and the follow-up time-point was detected. None of the groups had higher levels of IgG or IgM antibodies to CMV. Since elevated levels of IgM antibodies to T. gondii following reactivation or re-infection have been reported, Dickerson et al. [61] hypothesized that individuals with elevated IgM had undergone infection with or reaction to T. gondii around the time of their hospitalization for a manic episode, according to the fact the IgM antibody levels decreased over time. It is also possible that patients in the manic group display an aberrant production of antibody, perhaps related to aberrant class switching. Finally, a recent study conducted on a sample of 70 military women veterans analyzed for T. gondii IgG titer described biobehavioral relationships between chronic T. gondii infection, depression and dysphoric moods [62]. In contrast to the above studies, it is worth mentioning a recent study performed to evaluate the Toxoplasma seroprevalence of patients with BD I compared to healthy controls in Iran, a country with a very high prevalence of toxoplasmosis [63]: the authors showed no significant difference between BD I patients and healthy subjects in IgG antibodies (31.62% and 26.5%, respectively). In Table 1, we summarize the published sero-epidemiological studies investigating the association between T. gondii infection and BD.
We recently described the case of a 20-year-old Brazilian female affected by recurrent ocular toxoplasmic uveitis and BD with psychotic features. In this patient, a consistent relationship between ocular manifestations of T. gondii infection and the onset and recurrences of psychiatric symptoms was detected. Infection reactivation was directly documented through molecular analyses (nested-PCR), showing the presence of circulating DNA parasite at the time of occurrence of psychiatric symptoms and the high level of T. gondii-specific IgG [64].
Prenatal exposure to viruses or parasite with tropism for the central nervous system (CNS) is known to be a risk factor for later development of psychotic disorders [65,66]. Several studies showed that increased levels of maternal antibodies to T. gondii are associated with a higher risk of schizophrenia spectrum disorders in adult offspring [65,67]. Contrary to this, no significant association was found between prenatal exposure to T. gondii and the risk of BD in adult offspring, suggesting that congenital T. gondii infection could be a risk factor only for the development of schizophrenia and related psychosis, but not for BD [65,68,69]. Only one study, investigating whether certain Toxoplasma genotypes may be differentially associated with the risk of psychosis, found that the offspring of mothers with a serological pattern consistent with Toxoplasma genotype I infection were at significantly increased risk for the development of psychosis as compared with the matched unaffected control mothers, and the risk was statistically significant only for affective psychosis, including schizoaffective disorder-bipolar type, BD with psychotic features and major depressive disorder with psychosis. Conversely, no significant association between serological evidence of infection with other Toxoplasma genotype and offspring psychoses was detected [70]. The studies that investigated the relations between perinatal toxoplasmosis and BD are summarized in Table 2.
In addition, T. gondii has been linked to suicidal and aggressive behavior in patients with recurrent mood disorders and in younger patients with schizophrenia [48,50,71]. In a survey conducted in 20 European countries, a significant association between T. gondii seropositivity and national suicide rates was observed [72]. This would indicate that latent toxoplasmosis, along with other established suicide factors, might contribute to increasing the rates of suicide among BD patients. This hypothesis is corroborated by the observation that T. gondii-infected women have an increased risk of self-directed violence and suicide [49,51]. Furthermore, early reports found a significant association between seropositivity and T. gondii-specific IgG levels with non-fatal suicidal self-directed violence, which represents the most significant risk factor for completed suicide [48,52,73]. Given the strong relationship between suicidal and impulsive/aggressive behavior, Coccaro et al. [71] tested the hypothesis that IgG antibodies to T. gondii may be associated with higher aggression and impulsivity scores in a sample of 358 adult subjects with a DSM-5 diagnosis of intermittent explosive disorder (IED), non-IED psychiatric disorders (psychiatric controls) or psychiatrically healthy controls assessed with psychometric measures of aggression, impulsivity and related behaviors. Results of this study showed that T. gondii seropositivity status was associated with higher scores on the psychometric measures for aggression; the rate of T. gondii seropositivity in IED patients was significantly greater than that in healthy controls, although no significant difference was found between IED and non-IED patients in the seropositivity rate.
On the basis of available literature data, a T. gondii seropositivity status seems to be mostly associated with a greater prevalence of psychotic symptoms in schizophrenia patients, a greater number of depressive symptoms in BD patients and a chronic course of the psychiatric disease with higher suicidal and impulsive/aggressive behaviors [48,49,51,52,56,71,73,74]. However, the clinical characteristics and illness course of BD patients with a seropositivity to T. gondii in comparison with seronegative BD patients need to be more clearly defined.

3. The Role of T. gondii in the Etiopathogenesis of Psychiatric Disorders

Despite the great number of studies showing a relationship between T. gondii and the onset or recurrence of major psychosis, as well as human behavioral changes, it is difficult to clearly establish the role of T. gondii infection in the pathogenesis of psychiatric disorders. Direct and indirect etiopathogenetic mechanisms, including the permanent resident glia cell activation and the recruitment of peripheral immune cells, as well as effects on neurotransmission have been proposed.
Neuropathological studies have reported that glial cells, especially astrocytes, are selectively affected in both toxoplasmosis and schizophrenia, supporting their involvement in the emergence of T. gondii-related psychosis [75,76]. T. gondii probably migrates to the brain as early as seven days post-infection and crosses the blood-brain barrier through a “Trojan horse mechanism”. Alternatively, replication of T. gondii and lysis of infected endothelial cells could be required for the protozoan to cross the blood-brain barrier [77].
After reaching the CNS, the parasite can invade all nucleated cells and initiate the activation of resident microglia and astrocytes, the resident macrophages of the brain that will produce pro-inflammatory cytokines and free radicals, but also anti-inflammatory components; in murine models, it was found to infect 30% of microglial cells and 10% of neurons and astrocytes [78]. Initial signs of glia activation can be observed between seven and 10 days post-infection and are followed by the recruitment of peripheral T cells and mononuclear cells. The early activation of microglia and astrocytes correlates with the local production of chemokines and cytokines, which contributes to immune cell recruitment from the periphery. The effective control of parasite replication and disruption of the parasitophorous vacuole is dependent on cell extrinsic mechanisms, as well as cell intrinsic mechanisms, mediated by cytokine signals [79]. Within weeks or months, tachyzoites disappear, but bradyzoites remain in tissue cysts throughout the life of the host. Several in vitro studies found that the parasite can develop cysts in neurons and astrocytes [78], but a recent study showed that in the chronic phase of infection, cysts are detectable only in neurons [80].
The distribution of T. gondii cysts in the brain has been suggested to play an important role in the behavioral adaptive manipulation produced by the parasite in infected hosts [81]. In this regard, several studies suggest that T. gondii-containing cysts localize preferentially in the prefrontal cortex and amygdala, a structure involved in the regulation of fear behavior, although found throughout the brain [42,81,82]. Latent toxoplasmosis was also shown to induce dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion, which may deal with T. gondii-induced behavioral changes [83]. However, other studies reported widespread parasite cyst localization in infected rats rather than a specific localization to a certain brain region and showed a considerable inter-individual variation in tissue cyst density in different brain areas [84]. These data are corroborated by neurobiological studies showing that brain cysts are formed in the whole brain (cerebral hemispheres, hippocampus, amygdala, basal ganglia, cerebellum, cerebral cortex, brain stem and olfactory bulb) [47].
A T. gondii-induced alteration of the structure and function of corticolimbic circuits, which are involved in the modulation of impulsivity and aggression, could be responsible for behavioral changes observed in infected animals and humans [71,85]. Specifically, persistent T. gondii infection in mice has been associated with neuronal tissue lesions, impaired neuronal functions, ventricular dilation and neuroinflammation, suggesting that latent toxoplasmosis might contribute to neuroinflammation or neurodegeneration in genetically susceptible hosts [86].
Besides the proven neurotropism of T. gondii, the link between this parasite and psychiatric disorders could be also explained by its ability to influence neurotransmitter pathways. Indeed, T. gondii has been shown to increase dopamine (DA) levels, as well as to modulate serotonin, gamma-aminobutyric acid and glutamate signaling, all of which are implicated in aggressive behavior and in the pathogenesis of psychotic syndromes in human studies [16,87,88,89,90].
An increased metabolism of DA due to parasite infection has been observed especially in the limbic region, known to be altered in BD [91]. Gaskell et al. [92] have demonstrated that the parasite genome includes two genes encoding enzymes with tyrosine hydroxylase (TH) activity, and one of these genes is induced during the production of T. gondii bradyzoites. TH is the rate-limiting enzyme for DA synthesis in the brain, catalyzing the conversion of L-tyrosine to L-dihydroxyphenylalanine. In vitro studies showed that DA itself may play a role in the production/proliferation, chemoattraction, infection efficiency and stage conversion of T. gondii in the brain [93]. Prandovszky et al. [91], using both mammalian dopaminergic cells infected with T. gondii and brain sections of infected mice, showed a significant increase in DA metabolism in neural cells, with a direct correlation between the number of infected cells and the quantity of DA released. In this study, TH was also found in intracellular tissue cysts in brain tissue using antibodies specific for the parasite-encoded tyrosine hydroxylase. The T. gondii–induced release of DA has been proposed as a relevant neurochemical mechanism for parasite-induced psycho-behavioral abnormalities in Toxoplasma-infected rodents and possibly in humans [45,91,94].
Chronic T. gondii infection is also responsible for immunological alterations, such as a higher production of cytokines and other inflammatory mediators, in the brain of infected hosts [90]. In different stages of infection, the parasite induces the production of several cytokines, such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL-)1, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 IL-17, IL-23 and granulocyte macrophage colony-stimulating factor (GM-CSF), which are variably expressed by microglia cells, astrocytes and infiltrating CD4+ and CD8+ T cells [47]. These inflammatory modifications may have the downstream effect of modulating neurotransmission, leading to the occurrence of psychiatric symptoms and aggressive behavior [90,95,96]. Further, an association between increased peripheral levels of pro-inflammatory cytokines, such as IL-6 and TNF, and elevated cerebrospinal fluid levels of IL-6, in response to toxoplasmosis, has recently been associated with self-directed violence and suicide attempts [71,97,98].
A pro-inflammatory state involving both the innate and the adaptive immune response is well documented in depressive and manic episodes of BD, and a great amount of evidence indicates that inflammatory processes play a major role in the pathophysiology of this psychiatric disorder [9,11,99,100]. Human and animal studies have in fact demonstrated that mood symptoms can be induced by the activation of inflammatory reactions [101,102,103,104]. Moreover, many studies have documented specific patterns of increased levels of cytokines in different phases of BD: namely, the pro-inflammatory cytokines increased during mania seem to be IL-2, IL-6, IL-8 and INF-γ, whereas only IL-6 is increased during depressive episodes, with an imbalance between IL-6 levels and those of the anti-inflammatory cytokine IL-10 [105]. Elevated peripheral levels of TNF-α have been reported in BD patients during manic and depressive episodes [8], and cerebral spinal fluid (CSF) IL-1β levels were particularly increased in those patients with a history of BD with prominent psychotic symptoms [106]. More recently, the levels of soluble TNF receptor type 1 were found to be significantly lower in BD type II patients than in patients with BD type I, as well as in depressed BD patients compared to patients with manic/hypomanic and euthymic states [107]. Successful treatment with mood stabilizers leading to a euthymic state has been associated with a significant reduction of pro-inflammatory cytokines in BD subjects, with IL-6 levels returning to baseline after anti-manic and mood-stabilizing treatments [108,109,110]. Overall, these data suggest that manic phases and, to a lesser degree, depressive phases of BD are associated with a persistent and chronic low-grade pro-inflammatory state [9,11].
A recent study [55] observed a significant correlation between cognitive deterioration, IL-6 levels and T. gondii seropositivity in BD patients. According to this, growing data suggest that the “pro-inflammatory cytokines state” could be one of the mechanisms involved in cognitive deterioration in BD [111,112]. Long-term inflammation observed in T. gondii-infected BD patients may progressively impair cognitive functions through the disruption of neurogenesis processes, and IL-6 serum levels could be a useful and predictive immunological marker of cognitive decline in BD, as well as a valuable tool for designing personalized treatment.
T. gondii-induced cytokines, particularly IL-6, IL-1β and TNF-α, could indirectly affect neuronal function by the influence exerted on the hypothalamic-pituitary-adrenal axis (HPA), which is known to be linked to behavioral changes and to increased glucocorticoid levels [47]. These hormones act on the HPA axis with a negative feed-back mechanism reducing neuroplasticity and cellular resistance. This action may lead to an imbalance between glucocorticoids, mineralocorticoids and their high-density receptors, as well as to neuronal injury. In addition, the higher activity of the HPA axis induces the activation of macrophages, dendritic cells and T cells and the production of pro-inflammatory cytokines, with a positive feed-back mechanism. Glucocorticoids also increase the levels of tryptophan 2,3-dioxygenase (TDO) in the liver and the level of indoleamine 2,3-dioxygenases (IDO) in immune cells. IDO and TDO catalyze the opening of the tryptophan (TRP) indole ring, the first step for the synthesis of kynurenic acid. In the brain, kynurenine (a precursor of kynurenic acid) synthesis takes place mainly in astrocytes, which release newly-produced kynurenic acid into the extracellular environment, affecting the surrounding neurons. Immune response could interfere with the growth and survival of the parasite through the degradation of TRP to N-formylkynurenine [113].
The role of the kynurenine pathway is well defined in schizophrenic patients [114]; the first description of kynurenine upregulation in BD was published by Miller et al. [115], which observed increased levels of both kynurenine and kynurenic acid in the anterior cingulate in BD patients with a history of psychotic symptoms in post-mortem studies. A few years later, CSF studies confirmed an increase in kynurenic acid notably restricted to BD patients with a history of psychosis [116]. In line with data from the CSF and post-mortem studies, cultured human dermal fibroblasts obtained from patients with BD or schizophrenia are shown to release significantly more kynurenic acid than cells obtained from controls [117].
Finally, experimental studies in rats showed T. gondii infection to increase the expression of genes involved in the production of testosterone, a steroid that is known to reduce fear and enhance sexual attractiveness in males [71,118]. Additionally, there is evidence that Toxoplasma-infected men have a higher concentration of testosterone than Toxoplasma-free controls, while the opposite direction of testosterone shift has been detected in Toxoplasma-infected women. These findings could explain the observed gender specificity of behavioral shifts in Toxoplasma-infected subjects [119].

4. The Association between Autoimmune/Inflammatory Dysregulation, Infectious Agents and Risk of Bipolar Disorder

Autoimmune processes, as well as activated peripheral and central inflammatory responses, have been described in both schizophrenia and BD, supporting the view that dysregulation of the immune system represents an important vulnerability factor for psychosis [32,120,121,122].
Animal models of psychotic conditions have suggested that infections and other environmental stressors during gestation/early life can activate microglia cells, which have been increasingly implicated in neurodevelopmental processes, thereby disrupting brain development and setting the stage for vulnerability for later psychotic disorder [18,32,123]. A second environmental, infectious or stress-related trigger in later life could further activate microglia and mast cell release of pro-inflammatory cytokines, thus contributing to brain inflammation and psychosis [32,124]. Since T. gondii is known to be a potent disrupter of fetal neurodevelopment, the parasite-induced microglia activation and the subsequent induction of an inflammatory environment in the brain could be the mechanisms linking toxoplasmosis to the higher vulnerability to subsequent psychosis.
Several epidemiologic studies have demonstrated the high co-occurrence of autoimmune diseases, chronic inflammatory conditions and psychotic or mood disorders [121,125], leading some authors to hypothesize a common underlying immune abnormality for both autoimmunity and mental illness, at least in specific subgroups of psychotic patients [32]. According to this hypothesis, autoimmune diseases and psychotic disorders, mainly affective ones, exhibit common clinical characteristics, which is high familiarity, progression from prodromal subclinical to clinical disease and a cyclical exacerbation-remission pattern [32].
A nationwide, population-based, prospective cohort study [126] showed that any history of hospitalization for infection or autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 62% and 45%, respectively, and interestingly, the two risk factors interacted synergistically. In a genome-wide study comparing schizophrenia cases, BD cases, parents of cases and screened controls, Avramopoulos and collaborators [127] tested the hypothesis that environmental exposure to T. gondii, herpes simplex virus (HSV)-1, CMV, human herpes virus 6 and the food antigen gliadin may increase the risk for schizophrenia and BD and that the increased risk may be dependent on genetic variants. This study found that patients had higher seropositivity rates than controls for any of the serological analysis and higher C-reactive protein levels in both BD and schizophrenia, according to existing literature data [128,129]. Finally, another recent gene-environment interaction study investigated the possible effect of interactions between serologically documented exposure to T. gondii, CMV, HSV-1 or HSV-2 and polymorphisms of TLR2, TLR4 and NOD2 genes, which encode for pivotal pattern-recognition receptors, in a sample of 138 BD patients [130]. The genetic associations between TLR2, TLR4 and NOD2 polymorphisms with susceptibility to infections, on the one hand, and BD, on the other, have been previously reported in the literature [131,132,133,134,135,136]. Oliveira et al. [130], besides confirming the association between BD and T. gondii, first described a trend for an interaction between a TLR2 polymorphism and T. gondii seropositivity in conferring BD risk, suggesting that exposure to infection may modulate the immunogenetic background on BD.
Although preliminary, these findings highlight the close link between autoimmune/inflammatory processes, infections and the risk of psychosis and mood disorders, supporting the immunological hypothesis in the pathogenesis of at least specific subgroups of schizophrenic and BD patients.

5. Anti-Toxoplasmic Activity of Antipsychotics and Mood Stabilizers

It is noteworthy that some antipsychotic medications, commonly used for the treatment of BD and schizophrenia, have been demonstrated in vitro to possess antiprotozoal properties.
In a study investigating the levels of antibodies to infectious agents in the serum and CSF of individuals with recent onset schizophrenia in comparison with those of controls without psychiatric disease, untreated individuals with recent onset schizophrenia were found to have significantly increased levels of serum and CSF IgG antibodies to T. gondii as compared to controls. A significant reduction of T. gondii antibodies was found in those patients undergoing current drug treatment, suggesting that anti-psychotic medications may affect T. gondii replication [137]. However, conflicting results have been reported on the anti-toxoplasmic activity of psychotropic drugs. Jones-Brando and collaborators [138] investigated the relative ability of eight antipsychotics and four mood-stabilizing medications to inhibit cell invasion and/or replication of T. gondii tachyzoites in a cell culture system using human fibroblasts treated with test compounds and then exposed to Toxoplasma, in comparison with the antiprotozoal activity of trimethoprim, a folate antagonist commonly used for the treatment of toxoplasmosis. Among the tested medications, the antipsychotic haloperidol and the mood stabilizer valproic acid and its salt, sodium valproate, showed the most robust inhibitory activity, followed by 9-OH-risperidone, the principal metabolite of risperidone, and fluphenazine. It is of interest that this is the first study reporting an in vitro activity against T. gondii of a mood stabilizer, with therapeutic indices of valproic acid and sodium valproate equivalent to that of trimethoprim. Moreover, valproic acid was found to inhibit the parasite at a lower concentration than that found in the CSF and blood of individuals being treated with this mood stabilizer and displayed synergistic inhibitory activity with both haloperidol and trimethoprim. The other antipsychotics, such as chlorpromazine, had a modest therapeutic index, while carbamazepine was demonstrated to have only a small inhibitory effect, and anti-Toxoplasma activity was not found for lithium salts. In light of these findings, Webster et al. [139] hypothesized that the antipsychotic and mood-stabilizing activity of some medications may be achieved, or at least augmented, through their inhibition of T. gondii replication and invasion in infected individuals. In particular, these authors predicted that haloperidol and valproic acid would be at least as effective in preventing or alleviating T. gondii-induced cognitive and behavioral alterations as the standard anti-T. gondii chemotherapeutics pyrimethamine with dapsone. Results of this study showed that treatment of infected rats with, in order of decreasing efficacy, haloperidol, dapsone and valproic acid reduced the predatory risk behavioral traits observed in untreated rats. Since T. gondii tachyzoites require calcium in order to invade host cells, the anti-toxoplasmic activity of these drugs was supposed to be partly related to their calcium inhibitory properties [138,140,141]. More recently, Fond et al. [142] found that fluphenazine has a high inhibitory activity of parasite replication in vitro, in agreement with previous findings of Goodwin et al. [143], but also that zuclopenthixol, another first-generation antipsychotic, has a high activity against the parasite growth, therefore invalidating the previous hypothesis of a phenothiazine-specific class effect [143]. These authors also confirmed that haloperidol has no anti-toxoplasmic activity and performed a preliminary assay on several antipsychotics that have never been reported before, such as amisulpride, which showed no anti-toxoplasmic effect, and levomepromazine, loxapine and cyamemazine, which showed intermediate anti-toxoplasmic activity. Contrary to previous findings [138], in this study, valproate has no effect on parasite replication. Valproic acid was also found to be not effective in vivo in preventing acute toxoplasmosis in mice inoculated with T. gondii tachyzoites; additionally, no activity against tissue cysts was observed in chronically T. gondii-infected valproic acid-treated mice [144].
In a recent cross-sectional retrospective study, Fond et al. [145] evaluated the effect of the administration of a psychotropic drug having known in vitro anti-toxoplasmic activity (TATA+) on clinical outcome in a population of bipolar or schizophrenic/schizoaffective patients with a seropositivity to T. gondii, compared to patients receiving a treatment without anti-toxoplasmic activity (TATA−). Cyamemazine, fluphenazine, haloperidol, levomepromazine, loxapine, paliperidone, risperidone, thioridazine, zuclopenthixol and valproate were considered as TATA (“TATA+”), while amisulpride, aripiprazole, carbamazepine, clozapine, lamotrigine, lithium carbonate, olanzapine, quetiapine and tiapride were considered as having no or negligible anti-toxoplasmic activity (“TATA−”). The authors observed that a current TATA+ treatment was associated with lower lifetime number of depressive episodes (p = 0.048), but not with a lower number of manic or psychotic episodes. A significant difference was not found in BD toxo-negative patients, nor in schizophrenic toxo-positive or toxo-negative patients regarding lifetime and current mood or psychotic symptomatology. Results of this study suggest that toxoplasmic serological status may be a biomarker of interest for the prevention of bipolar depression through the administration of TATA+ drugs; moreover, they may partly explain discrepancies detected in the effectiveness of valproic acid, the mood stabilizer with the highest demonstrated anti-toxoplasmic activity in bipolar depression across studies [146]. Since depressive symptoms and episodes dominate the long-term course of BD and are associated with high levels of disability and an increased suicide risk [147], findings from the study of Fond et al. [145], if confirmed in further prospective randomized controlled trials, may have important implications for the management of Toxoplasma-seropositive BD patients.

6. Conclusions

In recent studies, infectious agents emerged as a group of well-defined environmental risk factors in psychiatric disorders, particularly schizophrenia and BD. The association between T. gondii seropositivity and schizophrenia/schizoaffective disorder is one of the most studied links between one pathogen and psychiatric disorder. However, growing emerging evidence has also documented an association between latent toxoplasmosis and the risk of BD and suicidal/aggressive behaviors. T. gondii infection, as previously suggested for schizophrenia [113], may contribute to the onset and the progressive course of the disease interacting with genetic hereditary predisposing factors, as well as affecting neurotransmitter systems and immune responses, which have recently been shown to be closely linked to the pathogenesis of BD and its medical comorbidities.
Despite the fact that evidence supporting a relationship between toxoplasmosis and BD has been presented in this review, this area remains controversial without cause-effect studies, and it is difficult, at present, to establish the direction of causality between T. gondii and BD; in fact, if the parasite could directly trigger a BD recurrence [9,138], the possibility that the modifications of the immune response, caused by a recrudescence of BD, can induce a reactivation of toxoplasmosis has to be also considered, as previously hypothesized for schizophrenia [15]. Certainly, further research is needed to investigate the role of T. gondii in larger samples of BD patients also including BD type II diagnosis and different stages of illness. Finally, it seems to be of importance to consider that the identification, prevention and treatment of infections like toxoplasmosis contributing to the etiopathogenesis of schizophrenia and BD could have a significant impact on the disease course. For this reason, every attempt to prevent toxoplasmosis should be encouraged, waiting for a reliable vaccine in humans.

Acknowledgments

The authors are grateful to Giulia Gray for editing the English.

Author Contributions

Fabrizio Bruschi designed and finalized the article. Claudia Del Grande wrote the main text. Luca Galli and Elisa Schiavi participated in writing the main text, and Luca Galli elaborated the PubMed results. Liliana Dell’Osso revised the final version.

Conflicts of Interest

The authors declare no conflict of interests.

References

  1. Judd, L.L.; Akiskal, H.S.; Schettler, P.J.; Endicott, J.; Leon, A.C.; Solomon, D.A.; Coryell, W.; Maser, J.D.; Keller, M.B. Psychosocial disability in the course of bipolar I and II disorders: A prospective, comparative, longitudinal study. Arch. Gen. Psychiatry 2005, 62, 1322–1330. [Google Scholar] [CrossRef] [PubMed]
  2. Collins, P.Y.; Patel, V.; Joestl, S.S.; March, D.; Insel, T.R.; Daar, A.S. Grand challenges in global mental health. Nature 2011, 475, 27–30. [Google Scholar] [CrossRef] [PubMed]
  3. Whiteford, H.A.; Degenhardt, L.; Rehm, J.; Baxter, A.J.; Ferrari, A.J.; Erskine, H.E.; Charlson, F.J.; Norman, R.E.; Flaxman, A.D.; Johns, N.; et al. Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease Study 2010. Lancet 2013, 382, 1575–1586. [Google Scholar] [CrossRef]
  4. Gershon, E.S.; Alliey-Rodriguez, N.; Liu, C. After GWAS: Searching for genetic risk for schizophrenia and bipolar disorder. Am. J. Psychiatry 2011, 168, 253–256. [Google Scholar] [CrossRef] [PubMed]
  5. Kerner, B. Genetics of bipolar disorder. Appl. Clin. Genet. 2014, 7, 33–42. [Google Scholar] [CrossRef] [PubMed]
  6. O’Brien, S.M.; Scully, P.; Scott, L.V.; Dinan, T.G. Cytokine profiles in bipolar affective disorder: Focus on acutely ill patients. J. Affect. Disord. 2006, 90, 263–267. [Google Scholar] [CrossRef] [PubMed]
  7. Dickerson, F.; Stallings, C.; Origoni, A.; Boronow, J.; Yolken, R. Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 2007, 31, 952–955. [Google Scholar] [CrossRef] [PubMed]
  8. Ortiz-Domínguez, A.; Hernández, M.E.; Berlanga, C.; Gutiérrez-Mora, D.; Moreno, J.; Heinze, G.; Pavón, L. Immune variations in bipolar disorder: Phasic differences. Bipolar. Disord. 2007, 9, 596–602. [Google Scholar] [CrossRef] [PubMed]
  9. Hamdani, N.; Doukhan, R.; Kurtlucan, O.; Tamouza, R.; Leboyer, M. Immunity, inflammation, and bipolar disorder: Diagnostic and therapeutic implications. Curr. Psychiatry Rep. 2013, 15, 387. [Google Scholar] [CrossRef] [PubMed]
  10. Canetta, S.E.; Bao, Y.; Co, M.D.; Ennis, F.A.; Cruz, J.; Terajima, M.; Shen, L.; Kellendonk, C.; Schaefer, C.A.; Brown, A.S. Serological documentation of maternal influenza exposure and bipolar disorder in adult offspring. Am. J. Psychiatry 2014, 171, 557–563. [Google Scholar] [CrossRef] [PubMed]
  11. Muneer, A. Bipolar Disorder: Role of Inflammation and the Development of Disease Biomarkers. Psychiatry Investig. 2016, 13, 18–33. [Google Scholar] [CrossRef] [PubMed]
  12. Rosenblat, J.D.; McIntyre, R.S. Bipolar Disorder and Inflammation. Psychiatr. Clin. N. Am. 2016, 39, 125–137. [Google Scholar] [CrossRef] [PubMed]
  13. Remlinger-Molenda, A.; Wojciak, P.; Michalak, M.; Karczewski, J.; Rybakowski, J.K. Selected cytokine profiles during remission in bipolar patients. Neuropsychobiology 2012, 66, 193–198. [Google Scholar] [CrossRef] [PubMed]
  14. Dickerson, F.; Stallings, C.; Origoni, A.; Vaughan, C.; Katsafanas, E.; Khushalani, S.; Yolken, R. A combined marker of inflammation in individuals with mania. PLoS ONE 2013, 8, e73520. [Google Scholar] [CrossRef] [PubMed]
  15. Yolken, R.H.; Torrey, E.F. Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol. Psychiatry 2008, 13, 470–479. [Google Scholar] [CrossRef] [PubMed]
  16. Yolken, R.H.; Dickerson, F.B.; Torrey, E.F. Toxoplasma and schizophrenia. Parasite Immunol. 2009, 31, 706–715. [Google Scholar] [CrossRef] [PubMed]
  17. Brown, A.S.; Derkits, E.J. Prenatal infection and schizophrenia: A review of epidemiologic and translational studies. Am. J. Psychiatry 2010, 167, 261–280. [Google Scholar] [CrossRef] [PubMed]
  18. Arias, I.; Sorlozano, A.; Villegas, E.; de Dios Luna, J.; McKenney, K.; Cervilla, J.; Gutierrez, B.; Gutierrez, J. Infectious agents associated with schizophrenia: A meta-analysis. Schizophr. Res. 2012, 136, 128–136. [Google Scholar] [CrossRef] [PubMed]
  19. Torrey, E.F.; Bartko, J.J.; Yolken, R.H. Toxoplasma gondii and other risk factors for schizophrenia: An update. Schizophr. Bull. 2012, 38, 642–647. [Google Scholar] [CrossRef] [PubMed]
  20. Hamdani, N.; Daban-Huard, C.; Lajnef, M.; Richard, J.R.; Delavest, M.; Godin, O.; Le Guen, E.; Vederine, F.E.; Lépine, J.P.; Jamain, S.; et al. Relationship between Toxoplasma gondii infection and bipolar disorder in a French sample. J. Affect. Disord. 2013, 148, 444–448. [Google Scholar] [CrossRef] [PubMed]
  21. Sutterland, A.L.; Fond, G.; Kuin, A.; Koeter, M.W.; Lutter, R.; van Gool, T.; Yolken, R.; Szoke, A.; Leboyer, M.; de Haan, L. Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: Systematic review and meta-analysis. Acta Psychiatr. Scand. 2015, 132, 161–179. [Google Scholar] [PubMed]
  22. Montoya, J.G.; Liesenfeld, O. Toxoplasmosis. Lancet 2004, 363, 1965–1976. [Google Scholar] [CrossRef]
  23. Dubey, J.P.; Jones, J.L. Toxoplasma gondii infection in humans and animals in the United States. Int. J. Parasitol. 2008, 38, 1257–1278. [Google Scholar] [CrossRef] [PubMed]
  24. Robert-Gangneux, F.; Dardé, M.L. Epidemiology of and diagnostic strategies for toxoplasmosis. Clin. Microbiol. Rev. 2012, 25, 264–296. [Google Scholar] [CrossRef] [PubMed]
  25. Jones, J.L.; Dargelas, V.; Roberts, J.; Press, C.; Remington, J.S.; Montoya, J.G. Risk factors for Toxoplasma gondii infection in the United States. Clin. Infect. Dis. 2009, 49, 878–884. [Google Scholar] [CrossRef] [PubMed]
  26. Weiss, L.M.; Dubey, J.P. Toxoplasmosis: A history of clinical observations. Int. J. Parasitol. 2009, 39, 895–901. [Google Scholar] [CrossRef] [PubMed]
  27. Bahia-Oliveira, L.M.; Jones, J.L.; Azevedo-Silva, J.; Alves, C.C.; Oréfice, F.; Addiss, D.G. Highly endemic, waterborne toxoplasmosis in north Rio de Janeiro state, Brazil. Emerg. Infect. Dis. 2003, 9, 55–62. [Google Scholar] [CrossRef] [PubMed]
  28. Bamne, M.; Wood, J.; Chowdari, K.; Watson, A.M.; Celik, C.; Mansour, H.; Klei, L.; Gur, R.C.; Bradford, L.D.; Calkins, M.E.; et al. Evaluation of HLA polymorphisms in relation to schizophrenia risk and infectious exposure. Schizophr. Bull. 2012, 38, 1149–1154. [Google Scholar] [CrossRef] [PubMed]
  29. Remington, J.S.; McLeod, R.; Thulliez, P.; Desmonts, G. Toxoplasmosis. In Infectious Diseases of the Fetus and Newborn Infant, 5th ed.; Remington, J.S., Klein, J., Eds.; WB Saunders: Philadelphia, PA, USA, 2001; pp. 205–346. [Google Scholar]
  30. Kaye, A. Toxoplasmosis: Diagnosis, treatment, and prevention in congenitally exposed infants. J. Pediatr. Health Care 2011, 25, 355–364. [Google Scholar] [CrossRef] [PubMed]
  31. Block, M.L.; Hong, J. Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism. Prog. Neurobiol. 2005, 76, 77–98. [Google Scholar] [CrossRef] [PubMed]
  32. Bergink, V.; Gibney, S.M.; Drexhage, H.A. Autoimmunity, inflammation, and psychosis: A search for peripheral markers. Biol. Psychiatry 2014, 75, 324–331. [Google Scholar] [CrossRef] [PubMed]
  33. Havlícek, J.; Gasová, Z.G.; Smith, A.P.; Zvára, K.; Flegr, J. Decrease of psychomotor performance in subjects with latent ‘asymptomatic’ toxoplasmosis. Parasitology 2001, 122, 515–520. [Google Scholar] [CrossRef] [PubMed]
  34. Flegr, J.; Zitková, S.; Kodym, P.; Frynta, D. Induction of changes in human behaviour by the parasitic protozoan Toxoplasma gondii. Parasitology 1996, 113, 49–54. [Google Scholar]
  35. Flegr, J.; Preiss, M.; Klose, J.; Havlícek, J.; Vitáková, M.; Kodym, P. Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol. Psychol. 2003, 63, 253–268. [Google Scholar] [CrossRef]
  36. Hinze-Selch, D.; Däubener, W.; Erdag, S.; Wilms, S. The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients. Folia Parasitol. 2010, 57, 129–135. [Google Scholar] [CrossRef] [PubMed]
  37. Flegr, J. Effects of Toxoplasma on human behavior. Schizophr. Bull. 2007, 33, 757–760. [Google Scholar] [CrossRef] [PubMed]
  38. Flegr, J. Influence of latent Toxoplasma infection on human personality, physiology and morphology: Pros and cons of the Toxoplasma-human model in studying the manipulation hypothesis. J. Exp. Biol. 2013, 216, 127–133. [Google Scholar] [CrossRef] [PubMed]
  39. Cook, T.B.; Brenner, L.A.; Cloninger, C.R.; Langenberg, P.; Igbide, A.; Giegling, I.; Hartmann, A.M.; Konte, B.; Friedl, M.; Brundin, L.; et al. “Latent” infection with Toxoplasma gondii: Association with trait aggression and impulsivity in healthy adults. J. Psychiatr. Res. 2015, 60, 87–94. [Google Scholar] [CrossRef] [PubMed]
  40. Novotná, M.; Hanusova, J.; Klose, J.; Preiss, M.; Havlicek, J.; Roubalová, K.; Flegr, J. Probable neuroimmunological link between Toxoplasma and cytomegalovirus infections and personality changes in the human host. BMC. Infect. Dis. 2005, 5, 54. [Google Scholar]
  41. Berdoy, M.; Webster, J.P.; Macdonald, D.W. Fatal attraction in rats infected with Toxoplasma gondii. Proc. Biol. Sci. 2000, 267, 1591–1594. [Google Scholar] [CrossRef] [PubMed]
  42. Vyas, A.; Kim, S.K.; Giacomini, N.; Boothroyd, J.C.; Sapolsky, R.M. Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc. Natl. Acad. Sci. USA 2007, 104, 6442–6447. [Google Scholar] [CrossRef] [PubMed]
  43. Gulinello, M.; Acquarone, M.; Kim, J.H.; Spray, D.C.; Barbosa, H.S.; Sellers, R.; Tanowitz, H.B.; Weiss, L.M. Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology. Microbes. Infect. 2010, 12, 528–537. [Google Scholar] [CrossRef] [PubMed]
  44. Gatkowska, J.; Wieczorek, M.; Dziadek, B.; Dzitko, K.; Dlugonska, H. Behavioral changes in mice caused by Toxoplasma gondii invasion of brain. Parasitol. Res. 2012, 111, 53–58. [Google Scholar] [CrossRef] [PubMed]
  45. Vyas, A. Mechanisms of Host Behavioral Change in Toxoplasma gondii Rodent Association. PLoS Pathog. 2015, 11, e1004935. [Google Scholar] [CrossRef] [PubMed]
  46. Amminger, G.P.; McGorry, P.D.; Berger, G.E.; Wade, D.; Yung, A.R.; Phillips, L.J.; Harrigan, S.M.; Francey, S.M.; Yolken, R.H. Antibodies to infectious agents in individuals at ultra-high risk for psychosis. Biol. Psychiatry 2007, 61, 1215–1217. [Google Scholar] [CrossRef] [PubMed]
  47. Fabiani, S.; Pinto, B.; Bonuccelli, U.; Bruschi, F. Neurobiological studies on the relationship between toxoplasmosis and neuropsychiatric diseases. J. Neurol. Sci. 2015, 351, 3–8. [Google Scholar] [CrossRef] [PubMed]
  48. Arling, T.A.; Yolken, R.H.; Lapidus, M.; Langenberg, P.; Dickerson, F.B.; Zimmerman, S.A.; Balis, T.; Cabassa, J.A.; Scrandis, D.A.; Tonelli, L.H.; et al. Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders. J. Nerv. Ment. Dis. 2009, 197, 905–908. [Google Scholar] [CrossRef] [PubMed]
  49. Ling, V.J.; Lester, D.; Mortensen, P.B.; Langenberg, P.W.; Postolache, T.T. Toxoplasma gondii seropositivity and suicide rates in women. J. Nerv. Ment. Dis. 2011, 199, 440–444. [Google Scholar] [CrossRef] [PubMed]
  50. Okusaga, O.; Langenberg, P.; Sleemi, A.; Vaswani, D.; Giegling, I.; Hartmann, A.M.; Konte, B.; Friedl, M.; Groer, M.W.; Yolken, R.H.; et al. Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia. Schizophr. Res. 2011, 133, 150–155. [Google Scholar] [CrossRef] [PubMed]
  51. Pedersen, M.G.; Mortensen, P.B.; Norgaard-Pedersen, B.; Postolache, T.T. Toxoplasma gondii infection and self-directed violence in mothers. Arch. Gen. Psychiatry 2012, 69, 1123–1130. [Google Scholar] [CrossRef] [PubMed]
  52. Alvarado-Esquivel, C.; Sánchez-Anguiano, L.F.; Arnaud-Gil, C.A.; López-Longoria, J.C.; Molina-Espinoza, L.F.; Estrada-Martínez, S.; Liesenfeld, O.; Hernández-Tinoco, J.; Sifuentes-Álvarez, A.; Salas-Martínez, C. Toxoplasma gondii infection and suicide attempts: A case-control study in psychiatric outpatients. J. Nerv. Ment. Dis. 2013, 201, 948–952. [Google Scholar] [CrossRef] [PubMed]
  53. Torrey, E.F.; Bartko, J.J.; Lun, Z.R.; Yolken, R.H. Antibodies to Toxoplasma gondii in patients with schizophrenia: A meta-analysis. Schizophr. Bull. 2007, 33, 729–736. [Google Scholar] [CrossRef] [PubMed]
  54. Dickerson, F.; Stallings, C.; Origoni, A.; Katsafanas, E.; Schweinfurth, L.; Savage, C.; Khushalani, S.; Yolken, R. Antibodies to Toxoplasma gondii and cognitive functioning in schizophrenia, bipolar disorder, and nonpsychiatric controls. J. Nerv. Ment. Dis. 2014, 202, 589–593. [Google Scholar] [CrossRef] [PubMed]
  55. Hamdani, N.; Daban-Huard, C.; Lajnef, M.; Gadel, R.; Le Corvoisier, P.; Delavest, M.; Carde, S.; Lépine, J.P.; Jamain, S.; Houenou, J.; et al. Cognitive deterioration among bipolar disorder patients infected by Toxoplasma gondii is correlated to interleukin 6 levels. J. Affect. Disord. 2015, 179, 161–166. [Google Scholar] [CrossRef] [PubMed]
  56. Pearce, B.D.; Kruszon-Moran, D.; Jones, J.L. The relationship between Toxoplasma gondii infection and mood disorders in the third National Health and Nutrition Survey. Biol. Psychiatry 2012, 72, 290–295. [Google Scholar] [CrossRef] [PubMed]
  57. Delgado García, G.; Rodríguez Perdomo, E. Reactivity of toxoplasmin intradermal test in neurotic and manic-depressive patients. Rev. Cubana Med. Trop. 1980, 32, 35–39. [Google Scholar] [PubMed]
  58. Tedla, Y.; Shibre, T.; Ali, O.; Tadele, G.; Woldeamanuel, Y.; Asrat, D.; Aseffa, A.; Mihret, W.; Abebe, M.; Alem, A. Serum antibodies to Toxoplasma gondii and Herpesvidae family viruses in individuals with schizophrenia and bipolar disorder: A case-control study. Ethiop. Med. J. 2011, 49, 211–220. [Google Scholar] [PubMed]
  59. Cetinkaya, Z.; Yazar, S.; Gecici, O.; Namli, M.N. Anti-Toxoplasma gondii antibodies in patients with schizophrenia--preliminary findings in a Turkish sample. Schizophr. Bull. 2007, 33, 789–791. [Google Scholar] [CrossRef] [PubMed]
  60. Hamidinejat, H.; Ghorbanpoor, M.; Hosseini, H.; Alavi, S.M.; Nabavi, L.; Jalali, M.H.; Borojeni, M.P.; Jafari, H.; Mohammadaligol, S. Toxoplasma gondii infection in first-episode and inpatient individuals with schizophrenia. Int. J. Infect. Dis. 2010, 14, e978–e981. [Google Scholar] [CrossRef] [PubMed]
  61. Dickerson, F.; Stallings, C.; Origoni, A.; Vaughan, C.; Katsafanas, E.; Khushalani, S.; Yolken, R. Antibodies to Toxoplasma gondii in individuals with mania. Bipolar. Disord. 2014, 16, 129–136. [Google Scholar] [CrossRef] [PubMed]
  62. Duffy, A.R.; Beckie, T.M.; Brenner, L.A.; Beckstead, J.W.; Seyfang, A.; Postolache, T.T.; Groer, M.W. Relationship between Toxoplasma gondii and Mood Disturbance in Women Veterans. Mil. Med. 2015, 180, 621–625. [Google Scholar] [CrossRef] [PubMed]
  63. Khademvatan, S.; Khajeddin, N.; Izadi, S.; Saki, J. Study of Toxoplasma gondii Infection in Patients with Bipolar Disorder. J. Med. Sci. 2013, 13, 215–220. [Google Scholar]
  64. Del Grande, C.; Contini, C.; Schiavi, E.; Rutigliano, G.; Maritati, M.; Seraceni, S.; Pinto, B.; Dell’Osso, L.; Bruschi, F. Bipolar Disorder With Psychotic Features and Ocular Toxoplasmosis. A Possible Pathogenetic Role of the Parasite? J. Nerv. Ment. Dis. 2016. [Google Scholar] [CrossRef] [PubMed]
  65. Mortensen, P.B.; Nørgaard-Pedersen, B.; Waltoft, B.L.; Sørensen, T.L.; Hougaard, D.; Yolken, R.H. Early infections of Toxoplasma gondii and the later development of schizophrenia. Schizophr. Bull. 2007, 33, 741–744. [Google Scholar] [CrossRef] [PubMed]
  66. Blomström, Å.; Karlsson, H.; Gardner, R.; Jörgensen, L.; Magnusson, C.; Dalman, C. Associations Between Maternal Infection During Pregnancy, Childhood Infections, and the Risk of Subsequent Psychotic Disorder--A Swedish Cohort Study of Nearly 2 Million Individuals. Schizophr. Bull. 2016, 42, 125–133. [Google Scholar] [CrossRef] [PubMed]
  67. Brown, A.S.; Schaefer, C.A.; Quesenberry, C.P.; Liu, L., Jr.; Babulas, V.P.; Susser, E.S. Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am. J. Psychiatry 2005, 162, 767–773. [Google Scholar] [CrossRef] [PubMed]
  68. Mortensen, P.B.; Pedersen, C.B.; McGrath, J.J.; Hougaard, D.M.; Nørgaard-Petersen, B.; Mors, O.; Børglum, A.D.; Yolken, R.H. Neonatal antibodies to infectious agents and risk of bipolar disorder: A population-based case-control study. Bipolar. Disord. 2011, 13, 624–629. [Google Scholar] [CrossRef] [PubMed]
  69. Freedman, D.; Bao, Y.; Shen, L.; Schaefer, C.A.; Brown, A.S. Maternal T. gondii, offspring bipolar disorder and neurocognition. Psychiatry Res. 2016, 243, 382–389. [Google Scholar] [CrossRef] [PubMed]
  70. Xiao, J.; Buka, S.L.; Cannon, T.D.; Suzuki, J.; Viscidi, R.P.; Torrey, E.F.; Yolken, R.H. Serological pattern consistent with infection with type I Toxoplasma gondii in mothers and risk of psychosis among adult offspring. Microbes Infect. 2009, 11, 1011–1018. [Google Scholar] [CrossRef] [PubMed]
  71. Coccaro, E.F.; Lee, R.; Groer, M.W.; Can, A.; Coussons-Read, M.; Postolache, T.T. Toxoplasma gondii infection: Relationship with aggression in psychiatric subjects. Clin. Psychiatry 2016, 77, 334–341. [Google Scholar] [CrossRef] [PubMed]
  72. Lester, D. Predicting European suicide rates with physiological indices. Psychol. Rep. 2010, 107, 713–714. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, Y.; Träskman-Bendz, L.; Janelidze, S.; Langenberg, P.; Saleh, A.; Constantine, N.; Okusaga, O.; Bay-Richter, C.; Brundin, L.; Postolache, T.T. Toxoplasma gondii immunoglobulin G antibodies and nonfatal suicidal self-directed violence. J. Clin. Psychiatry 2012, 73, 1069–1076. [Google Scholar] [CrossRef] [PubMed]
  74. Wang, H.L.; Wang, G.H.; Li, Q.Y.; Shu, C.; Jiang, M.S.; Guo, Y. Prevalence of Toxoplasma infection in first-episode schizophrenia and comparison between Toxoplasma-seropositive and Toxoplasma-seronegative schizophrenia. Acta Psychiatr. Scand. 2006, 114, 40–48. [Google Scholar] [CrossRef] [PubMed]
  75. Halonen, S.K.; Lyman, W.D.; Chiu, F.C. Growth and development of Toxoplasma gondii in human neurons and astrocytes. J. Neuropathol. Exp. Neurol. 1996, 55, 1150–1156. [Google Scholar] [CrossRef] [PubMed]
  76. Cotter, D.R.; Pariante, C.M.; Everall, I.P. Glial cell abnormalities in major psychiatric disorders: The evidence and implications. Brain Res. Bull. 2001, 55, 585–595. [Google Scholar] [CrossRef]
  77. Konradt, C.; Ueno, N.; Christian, D.A.; Delong, J.H.; Pritchard, G.H.; Herz, J.; Bzik, D.J.; Koshy, A.A.; McGavern, D.B.; Lodoen, M.B.; et al. Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system. Nat. Microbiol. 2016, 1, 16001. [Google Scholar] [CrossRef] [PubMed]
  78. Da Silva, R.C.; Langoni, H. Toxoplasma gondii: Host-parasite interaction and behavior manipulation. Parasitol. Res. 2009, 105, 893e8. [Google Scholar] [CrossRef] [PubMed]
  79. Courret, N.; Darche, S.; Sonigo, P.; Milon, G.; Buzoni-Gâtel, D.; Tardieux, I. CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain. Blood 2006, 107, 309–316. [Google Scholar] [CrossRef] [PubMed]
  80. Melzer, T.C.; Cranston, H.J.; Weiss, L.M.; Halonen, S.K. Host Cell Preference of Toxoplasma gondii Cysts in Murine Brain: A Confocal Study. J. Neuroparasitol. 2010, 1, N100505. [Google Scholar] [CrossRef] [PubMed]
  81. Berenreiterová, M.; Flegr, J.; Kuběna, A.A.; Němec, P. The distribution of Toxoplasma gondii cysts in the brain of a mouse with latent toxoplasmosis: Implications for the behavioral manipulation hypothesis. PLoS ONE 2011, 6, e28925. [Google Scholar] [CrossRef] [PubMed]
  82. McConkey, G.A.; Martin, H.L.; Bristow, G.C.; Webster, J.P. Toxoplasma gondii infection and behaviour—location, location, location? J. Exp. Biol. 2013, 216, 113–119. [Google Scholar] [CrossRef] [PubMed]
  83. Mitra, R.; Sapolsky, R.M.; Vyas, A. Toxoplasma gondii infection induces dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion. Dis. Model. Mech. 2013, 6, 516–520. [Google Scholar] [CrossRef] [PubMed]
  84. Dubey, J.P.; Ferreira, L.R.; Alsaad, M.; Verma, S.K.; Alves, D.A.; Holland, G.N.; McConkey, G.A. Experimental Toxoplasmosis in Rats Induced Orally with Eleven Strains of Toxoplasma gondii of Seven Genotypes: Tissue Tropism, Tissue Cyst Size, Neural Lesions, Tissue Cyst Rupture without Reactivation, and Ocular Lesions. PLoS ONE 2016, 11, e0156255. [Google Scholar] [CrossRef] [PubMed]
  85. Coccaro, E.F.; Sripada, C.S.; Yanowitch, R.N.; Phan, K.L. Corticolimbic function in impulsive aggressive behavior. Biol. Psychiatry 2011, 69, 1153–1159. [Google Scholar] [CrossRef] [PubMed]
  86. Hermes, G.; Ajioka, J.W.; Kelly, K.A.; Mui, E.; Roberts, F.; Kasza, K.; Mayr, T.; Kirisits, M.J.; Wollmann, R.; Ferguson, D.J.; et al. Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection. J. Neuroinflamm. 2008, 5, 48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Torrey, E.F.; Yolken, R.H. Toxoplasma gondii and schizophrenia. Emerg. Infect. Dis. 2003, 9, 1375–1380. [Google Scholar] [CrossRef] [PubMed]
  88. Coccaro, E.F.; Lee, R.; Kavoussi, R.J. Aggression, suicidality, and intermittent explosive disorder: Serotonergic correlates in personality disorder and healthy control subjects. Neuropsychopharmacology 2010, 35, 435–444. [Google Scholar] [CrossRef] [PubMed]
  89. Coccaro, E.F.; Lee, R.; Vezina, P. Cerebrospinal fluid glutamate concentration correlates with impulsive aggression in human subjects. J. Psychiatr. Res. 2013, 47, 1247–1253. [Google Scholar] [CrossRef] [PubMed]
  90. Flegr, J. How and why Toxoplasma makes us crazy. Trends Parasitol. 2013, 29, 156–163. [Google Scholar] [CrossRef] [PubMed]
  91. Prandovszky, E.; Gaskell, E.; Martin, H.; Dubey, J.P.; Webster, J.P.; McConkey, G.A. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism. PLoS ONE 2011, 6, e23866. [Google Scholar] [CrossRef] [PubMed]
  92. Gaskell, E.A.; Smith, J.E.; Pinney, J.W.; Westhead, D.R.; McConkey, G.A. A unique dual activity amino acid hydroxylase in Toxoplasma gondii. PLoS ONE 2009, 4, e4801. [Google Scholar] [CrossRef] [PubMed]
  93. Strobl, J.S.; Goodwin, D.G.; Rzigalinski, B.A.; Lindsay, D.S. Dopamine stimulates propagation of Toxoplasma gondii tachyzoites in human fibroblast and primary neonatal rat astrocyte cell cultures. J. Parasitol. 2012, 98, 1296–1299. [Google Scholar] [CrossRef] [PubMed]
  94. Stibbs, H.H. Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice. Ann. Trop. Med. Parasitol. 1985, 79, 153–157. [Google Scholar] [CrossRef] [PubMed]
  95. Fabiani, S.; Pinto, B.; Bruschi, F. Toxoplasmosis and neuropsychiatric disease: Can serological studies establish a clear relationship? Neurol. Sci. 2013, 34, 417–425. [Google Scholar] [CrossRef] [PubMed]
  96. Cox, D.; Chan, M.K.; Bahn, S. The potential of immune biomarkers to advance personalized medicine approaches for schizophrenia. J. Nerv. Ment. Dis. 2015, 203, 393–399. [Google Scholar] [CrossRef] [PubMed]
  97. Janelidze, S.; Mattei, D.; Westrin, Å.; Träskman-Bendz, L.; Brundin, L. Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain. Behav. Immun. 2011, 25, 335–339. [Google Scholar] [CrossRef] [PubMed]
  98. Lindqvist, D.; Janelidze, S.; Hagell, P.; Erhardt, S.; Samuelsson, M.; Minthon, L.; Hansson, O.; Björkqvist, M.; Träskman-Bendz, L.; Brundin, L. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol. Psychiatry 2009, 66, 287–292. [Google Scholar] [CrossRef] [PubMed]
  99. Munkholm, K.; Braüner, J.V.; Kessing, L.V.; Vinberg, M. Cytokines in bipolar disorder vs. healthy control subjects: A systematic review and meta-analysis. J. Psychiatr. Res. 2013, 47, 1119–1133. [Google Scholar] [CrossRef] [PubMed]
  100. Rosenblat, J.D.; Cha, D.S.; Mansur, R.B.; McIntyre, R.S. Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 53, 23–34. [Google Scholar] [CrossRef] [PubMed]
  101. Reichenberg, A.; Yirmiya, R.; Schuld, A.; Kraus, T.; Haack, M.; Morag, A.; Pollmächer, T. Cytokine-associated emotional and cognitive disturbances in humans. Arch. Gen. Psychiatry 2001, 58, 445–452. [Google Scholar] [CrossRef] [PubMed]
  102. Raison, C.L.; Capuron, L.; Miller, A.H. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends. Immunol. 2006, 27, 24–31. [Google Scholar] [CrossRef] [PubMed]
  103. Harrison, N.A.; Brydon, L.; Walker, C.; Gray, M.A.; Steptoe, A.; Critchley, H.D. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol. Psychiatry 2009, 66, 407–414. [Google Scholar] [CrossRef] [PubMed]
  104. Eisenberger, N.I.; Berkman, E.T.; Inagaki, T.K.; Rameson, L.T.; Mashal, N.M.; Irwin, M.R. Inflammation-induced anhedonia: Endotoxin reduces ventral striatum responses to reward. Biol. Psychiatry 2010, 68, 748–754. [Google Scholar] [CrossRef] [PubMed]
  105. Brietzke, E.; Stertz, L.; Fernandes, B.S.; Kauer-Sant’anna, M.; Mascarenhas, M.; Escosteguy Vargas, A.; Chies, J.A.; Kapczinski, F. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J. Affect. Disord. 2009, 116, 214–217. [Google Scholar] [CrossRef] [PubMed]
  106. Söderlund, J.; Olsson, S.K.; Samuelsson, M.; Walther-Jallow, L.; Johansson, C.; Erhardt, S.; Landén, M.; Engberg, G. Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder. J. Psychiatry Neurosci. 2011, 36, 114–118. [Google Scholar] [CrossRef] [PubMed]
  107. Bai, Y.M.; Su, T.P.; Tsai, S.J.; Wen-Fei, C.; Li, C.T.; Pei-Chi, T.; Mu-Hong, C. Comparison of inflammatory cytokine levels among type I/type II and manic/hypomanic/euthymic/depressive states of bipolar disorder. J. Affect. Disord. 2014, 166, 187–192. [Google Scholar] [CrossRef] [PubMed]
  108. Boufidou, F.; Nikolaou, C.; Alevizos, B.; Liappas, I.A.; Christodoulou, G.N. Cytokine production in bipolar affective disorder patients under lithium treatment. J. Affect. Disord. 2004, 82, 309–313. [Google Scholar] [CrossRef] [PubMed]
  109. Kim, Y.K.; Jung, H.G.; Myint, A.M.; Kim, H.; Park, S.H. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J. Affect. Disord. 2007, 104, 91–95. [Google Scholar] [CrossRef] [PubMed]
  110. Guloksuz, S.; Cetin, E.A.; Cetin, T.; Deniz, G.; Oral, E.T.; Nutt, D.J. Cytokine levels in euthymic bipolar patients. J. Affect. Disord. 2010, 126, 458–462. [Google Scholar] [CrossRef] [PubMed]
  111. Goldstein, B.I.; Kemp, D.E.; Soczynska, J.K.; McIntyre, R.S. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: A systematic review of the literature. J. Clin. Psychiatry 2009, 70, 1078–1790. [Google Scholar] [CrossRef] [PubMed]
  112. Kapczinski, F.; Kauer-Sant’Anna, M.; Andreazza, A.C.; Bond, D.J.; Lam, R.W.; Young, L.T.; Yatham, L.N. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int. J. Neuropsychopharmacol. 2009, 12, 447–458. [Google Scholar]
  113. Hinze-Selch, D.; Däubener, W.; Eggert, L.; Erdag, S.; Stoltenberg, R.; Wilms, S. A controlled prospective study of Toxoplasma gondii infection in individuals with schizophrenia: Beyond seroprevalence. Schizophr. Bull. 2007, 33, 782–788. [Google Scholar] [CrossRef] [PubMed]
  114. Myint, A.M.; Schwarz, M.J.; Verkerk, R.; Mueller, H.H.; Zach, J.; Scharpé, S.; Steinbusch, H.W.; Leonard, B.E.; Kim, Y.K. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain. Behav. Immun. 2011, 25, 1576–1581. [Google Scholar] [CrossRef] [PubMed]
  115. Miller, C.L.; Llenos, I.C.; Dulay, J.R.; Weis, S. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 2006, 16, 1073–1074. [Google Scholar] [CrossRef] [PubMed]
  116. Olsson, S.K.; Samuelsson, M.; Saetre, P.; Lindström, L.; Jönsson, E.G.; Nordin, C.; Engberg, G.; Erhardt, S.; Landén, M. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. J. Psychiatry Neurosci. 2010, 35, 195–199. [Google Scholar] [CrossRef] [PubMed]
  117. Johansson, A.S.; Owe-Larsson, B.; Asp, L.; Kocki, T.; Adler, M.; Hetta, J.; Gardner, R.; Lundkvist, G.B.; Urbanska, E.M.; Karlsson, H. Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: Cytokine challenge increases production of 3-hydroxykynurenine. J. Psychiatr. Res. 2013, 47, 1815–1823. [Google Scholar] [CrossRef] [PubMed]
  118. Lim, A.; Kumar, V.; Hari Dass, S.A.; Vyas, A. Toxoplasma gondii infection enhances testicular steroidogenesis in rats. Mol. Ecol. 2013, 22, 102–110. [Google Scholar] [CrossRef] [PubMed]
  119. Flegr, J.; Lindová, J.; Kodym, P. Sex-dependent toxoplasmosis-associated differences in testosterone concentration in humans. Parasitology 2008, 135, 427–431. [Google Scholar] [CrossRef] [PubMed]
  120. Carter, C.S.; Bullmore, E.T.; Harrison, P. Is there a flame in the brain in psychosis? Biol. Psychiatry 2014, 75, 258–259. [Google Scholar] [CrossRef] [PubMed]
  121. Benros, M.E.; Nielsen, P.R.; Nordentoft, M.; Eaton, W.W.; Dalton, S.O.; Mortensen, P.B. Autoimmune diseases and severe infections as risk factors for schizophrenia: A 30-year population-based register study. Am. J. Psychiatry 2011, 168, 1303–1310. [Google Scholar] [CrossRef] [PubMed]
  122. Benros, M.E.; Eaton, W.W.; Mortensen, P.B. The epidemiologic evidence linking autoimmune diseases and psychosis. Biol. Psychiatry 2014, 75, 300–306. [Google Scholar] [CrossRef] [PubMed]
  123. Monji, A.; Kato, T.A.; Mizoguchi, Y.; Horikawa, H.; Seki, Y.; Kasai, M.; Yamauchi, Y.; Yamada, S.; Kanba, S. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2013, 42, 115–121. [Google Scholar] [CrossRef] [PubMed]
  124. Meyer, U. Developmental neuroinflammation and schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2013, 42, 20–34. [Google Scholar] [CrossRef] [PubMed]
  125. Ludvigsson, J.F.; Reutfors, J.; Osby, U.; Ekbom, A.; Montgomery, S.M. Coeliac disease and risk of mood disorders--a general population-based cohort study. J. Affect. Disord. 2007, 99, 117–126. [Google Scholar] [CrossRef] [PubMed]
  126. Benros, M.E.; Waltoft, B.L.; Nordentoft, M.; Ostergaard, S.D.; Eaton, W.W.; Krogh, J.; Mortensen, P.B. Autoimmune diseases and severe infections as risk factors for mood disorders: A nationwide study. JAMA Psychiatry 2013, 70, 812–820. [Google Scholar] [CrossRef] [PubMed]
  127. Avramopoulos, D.; Pearce, B.D.; McGrath, J.; Wolyniec, P.; Wang, R.; Eckart, N.; Hatzimanolis, A.; Goes, F.S.; Nestadt, G.; Mulle, J.; et al. Infection and inflammation in schizophrenia and bipolar disorder: A genome wide study for interactions with genetic variation. PLoS ONE 2015, 10, e0116696. [Google Scholar] [CrossRef] [PubMed]
  128. De Berardis, D.; Conti, C.M.; Campanella, D.; Carano, A.; Scali, M.; Valchera, A.; Serroni, N.; Pizzorno, A.M.; D’Albenzio, A.; Fulcheri, M.; et al. Evaluation of C-reactive protein and total serum cholesterol in adult patients with bipolar disorder. Int. J. Immunopathol. Pharmacol. 2008, 21, 319–324. [Google Scholar] [PubMed]
  129. Singh, B.; Chaudhuri, T.K. Role of C-reactive protein in schizophrenia: An overview. Psychiatry Res. 2014, 216, 277–285. [Google Scholar] [CrossRef] [PubMed]
  130. Oliveira, J.; Kazma, R.; Le Floch, E.; Bennabi, M.; Hamdani, N.; Bengoufa, D.; Dahoun, M.; Manier, C.; Bellivier, F.; Krishnamoorthy, R.; et al. Toxoplasma gondii exposure may modulate the influence of TLR2 genetic variation on bipolar disorder: A gene-environment interaction study. Int. J. Bipolar. Disord. 2016, 4, 11. [Google Scholar] [CrossRef] [PubMed]
  131. Schröder, N.W.; Schumann, R.R. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect. Dis. 2005, 5, 156–164. [Google Scholar] [CrossRef]
  132. van Well, G.T.; Sanders, M.S.; Ouburg, S.; Kumar, V.; van Furth, A.M.; Morré, S.A. Single nucleotide polymorphisms in pathogen recognition receptor genes are associated with susceptibility to meningococcal meningitis in a pediatric cohort. PLoS ONE 2013, 8, e64252. [Google Scholar] [CrossRef] [PubMed]
  133. Oliveira, J.; Busson, M.; Etain, B.; Jamain, S.; Hamdani, N.; Boukouaci, W.; Amokrane, K.; Bennabi, M.; Le Guen, E.; Dargél, A.A.; et al. Polymorphism of Toll-like receptor 4 gene in bipolar disorder. J. Affect. Disord. 2014, 152–154, 395–402. [Google Scholar] [CrossRef] [PubMed]
  134. Oliveira, J.; Hamdani, N.; Busson, M.; Etain, B.; Bennabi, M.; Amokrane, K.; Boukouaci, W.; Fortier, C.; Marzais, F.; Bengoufa, D.; et al. Association between toll-like receptor 2 gene diversity and early-onset bipolar disorder. J. Affect. Disord. 2014, 165, 135–141. [Google Scholar] [CrossRef] [PubMed]
  135. Oliveira, J.; Hamdani, N.; Etain, B.; Bennabi, M.; Boukouaci, W.; Amokrane, K.; Fortier, C.; Marzais, F.; Bengoufa, D.; Bellivier, F.; et al. Genetic association between a ‘standing’ variant of NOD2 and bipolar disorder. Immunobiology 2014, 219, 766–771. [Google Scholar] [CrossRef] [PubMed]
  136. Oliveira, J.; Etain, B.; Lajnef, M.; Hamdani, N.; Bennabi, M.; Bengoufa, D.; Sundaresh, A.; Chaabane, A.B.; Bellivier, F.; Henry, C.; et al. Combined effect of TLR2 gene polymorphism and early life stress on the age at onset of bipolar disorders. PLoS ONE 2015, 10, e0119702. [Google Scholar] [CrossRef] [PubMed]
  137. Leweke, F.M.; Gerth, C.W.; Koethe, D.; Klosterkötter, J.; Ruslanova, I.; Krivogorsky, B.; Torrey, E.F.; Yolken, R.H. Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 2004, 254, 4–8. [Google Scholar] [CrossRef] [PubMed]
  138. Jones-Brando, L.; Torrey, E.F.; Yolken, R.H. Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr. Res. 2003, 62, 237–244. [Google Scholar] [CrossRef]
  139. Webster, J.P.; Lamberton, P.H.; Donnelly, C.A.; Torrey, E.F. Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii’s ability to alter host behaviour. Proc. Biol. Sci. 2006, 273, 1023–1030. [Google Scholar] [CrossRef] [PubMed]
  140. Pezzella, N.; Bouchot, A.; Bonhomme, A.; Pingret, L.; Klein, C.; Burlet, H.; Balossier, G.; Bonhomme, P.; Pinon, J.M. Involvement of calcium and calmodulin in Toxoplasma gondii tachyzoite invasion. Eur. J. Cell Biol. 1997, 74, 92–101. [Google Scholar] [PubMed]
  141. Johannessen, C.U. Mechanisms of action of valproate: A commentatory. Neurochem. Int. 2000, 37, 103–110. [Google Scholar] [CrossRef]
  142. Fond, G.; Macgregor, A.; Tamouza, R.; Hamdani, N.; Meary, A.; Leboyer, M.; Dubremetz, J.F. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur. Arch. Psychiatry Clin. Neurosci. 2014, 264, 179–183. [Google Scholar] [CrossRef] [PubMed]
  143. Goodwin, D.G.; Strobl, J.S.; Lindsay, D.S. Evaluation of five antischizophrenic agents against Toxoplasma gondii in human cell cultures. J. Parasitol. 2011, 97, 148–151. [Google Scholar] [CrossRef] [PubMed]
  144. Goodwin, D.G.; Strobl, J.; Mitchell, S.M.; Zajac, A.M.; Lindsay, D.S. Evaluation of the mood-stabilizing agent valproic acid as a preventative for toxoplasmosis in mice and activity against tissue cysts in mice. J. Parasitol. 2008, 94, 555–557. [Google Scholar] [CrossRef] [PubMed]
  145. Fond, G.; Boyer, L.; Gaman, A.; Laouamri, H.; Attiba, D.; Richard, J.R.; Delavest, M.; Houenou, J.; Le Corvoisier, P.; Charron, D.; et al. Treatment with anti-toxoplasmic activity (TATA) for Toxoplasma positive patients with bipolar disorders or schizophrenia: A cross-sectional study. J. Psychiatr. Res. 2015, 63, 58–64. [Google Scholar] [CrossRef] [PubMed]
  146. Selle, V.; Schalkwijk, S.; Vázquez, G.H.; Baldessarini, R.J. Treatments for acute bipolar depression: Meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry 2014, 47, 43–52. [Google Scholar] [CrossRef] [PubMed]
  147. Musetti, L.; Del Grande, C.; Marazziti, D.; Dell’Osso, L. Treatment of bipolar depression. CNS Spectr. 2013, 18, 177–187. [Google Scholar] [CrossRef] [PubMed]
Pathogens 06 00003 g001 550
Figure 1. Publications available in PubMed in the last 10 years focusing on the relationship between schizophrenia or bipolar disorder and toxoplasmosis. Search terms were “Toxoplasma gondii”, “toxoplasmosis”, “neuropsychiatric disorders”, “bipolar disorder”, “schizophrenia”, “mania”, “psychotic symptoms”. We only included papers assessing schizophrenia and bipolar disorder.
Figure 1. Publications available in PubMed in the last 10 years focusing on the relationship between schizophrenia or bipolar disorder and toxoplasmosis. Search terms were “Toxoplasma gondii”, “toxoplasmosis”, “neuropsychiatric disorders”, “bipolar disorder”, “schizophrenia”, “mania”, “psychotic symptoms”. We only included papers assessing schizophrenia and bipolar disorder.
Pathogens 06 00003 g001
Table
Table 1. Sero-epidemiological studies investigating the association between T. gondii infection and bipolar disorder.
Table 1. Sero-epidemiological studies investigating the association between T. gondii infection and bipolar disorder.
Authors (Year), CountryStudy DesignToxo DeterminationSample SizeDescription of AssociationLimitations
Delgado Garcia, Rodriguez Perdomo (1980) [57], CubaCase-control studyToxoplasmin intradermal test270 individuals (50 pts with manic-depressive psychosis, 120 neurotics, 100 HC)The highest percentage of reactors was found among pts with manic-depressive psychosis (66.0%); the intensity of reaction was also higher among these pts.Small sample size
Hinze-Selch et al. (2010) [36], GermanyCross-sectional studyIgG levels1110 (270 SCH, 465 MD, 67 schizoaffective disorder, 87 BD, 214 HC)Additional diagnosis of a personality disorder is significantly associated with T. gondii infection among all psychiatric inpatients.Small sample size of BD pts
Tedla et al. (2011) [58], EthiopiaCase-control studyIgG levels495 (214 SCH, 171 BD, 71 HC)Higher T. gondii seroprevalence in individuals with SCH (OR = 4.7) and BD (OR = 3).No IgM determination
Pearce et al. (2012) [56], USACross-sectional studyIgG levels7440 (individuals 15–39 years old from the Third National Health and Nutrition Examination Survey)Significant relationship between Toxoplasma seropositivity and lifetime history of a BD I subtype with manic and depressive episodes (adjusted OR = 2.4, p < 0.05). No statistically-significant association between T. gondii seroprevalence and a history of MD or dysthymia.Small number of respondents with both BD I and positive serology for T. gondii; no IgM determination
Hamdani et al. (2013) [20], FranceCase-control studyIgM/IgG levels216 (110 BD, 106 HC)BD pts had significantly higher seropositivity to T. gondii and higher anti-T. gondii IgG titers as compared to HC (76.9% vs. 48.2%, p = 0.00045; 3.06 ± 1.07 vs. 2.07 ± 1.9, p = 0.002). IgM antibodies detection was negative for the whole sample. Seropositive participants had a 3.6-fold odds risk of BD as compared to seronegative group (p < 0.0001) (adjusted OR = 2.40, p = 0.026).Small sample size
Dickerson et al. (2014) [61], USACross-sectional studyIgM/IgG levels assessed up to three time points1114 (57 individual with mania, 743 other psychiatric groups, 314 non-psychiatric controls)Significantly elevated levels of anti-T. gondii IgM in pts with mania as compared to non-psychiatric controls (OR = 2.33, p < 0.04 at hospital admission; OR = 2.32, p < 0.02 at study entry during the hospital stay). Significant difference between the prevalences of increased levels of anti-T. gondii IgM at the baseline and the follow-up time-point (t = 2.97, p < 0.003). Significantly elevated levels of IgG antibodies to T. gondii (OR = 2.42, p < 0.04) in the recent onset psychosis group alone.Time of T. gondii infection is unknown; clinical assessments only during the hospital stay; lack of measurement of symptom scores at hospital admission
Khademvatan et al. (2013) [63], IranCross-sectional studyIgM/IgG levels317 (117 BD I; 200 HC)No significant difference in prevalence of anti-T. gondii IgG antibodies between BD I pts and HC (31.62% vs. 26.5%, p = 0.3). No significant difference between IgM levels in the two groups.No BD II pts
Duffy et al. (2015) [62], USACross-sectional studyIgM/IgG levels70 (veteran women)Positive relationships between T. gondii and depressive symptoms, anger, confusion and overall mood disturbance.Small sample size
SCH: schizophrenia; MD: major depression; pts: patients; BD: bipolar disorder; HC: healthy controls.
Table
Table 2. Studies on the relations between perinatal infection with T. gondii and bipolar disorder.
Table 2. Studies on the relations between perinatal infection with T. gondii and bipolar disorder.
Authors (Year), CountryStudy DesignToxo DeterminationSample SizeDescription of AssociationLimitations
Xiao et al. (2009) [70], USACase-control studyIgG levels and serotyping837 (219 sera from pregnant women whose children developed SCH and affective psychotic illnesses in adult life and 618 matched unaffected control mothers)No association between maternal antibodies to T. gondii and risk of psychoses in the offspring. Only the offspring of mothers with a serological pattern consistent with Toxoplasma type I infection are at significantly increased risk for the development of psychosis (p = 0.03). The elevated risk for subsequent psychoses associated with maternal infection with the type I strain is statistically significant for patients with affective psychosis (p = 0.005), but not for those with schizophrenic and other non-affective psychosis.Moderate sensitivity of serotyping; unknown indicators of the timing of maternal infection
Mortensen et al. (2011) [68], DenmarkCase-control studyIgG levels (neonatal dried blood spots)154 (127 BD pts and 127 matched controls)No association between marker of T. gondii prenatal infection and risk of BD.Small study samples; absence of information about specific serotypes of Toxoplasma; unknown indicators of the timing of maternal infection
Freedman et al. (2016) [69], USACase-control studyIgG levels (maternal sera)255 (85 BD cases and 170 comparison subjects)Maternal T. gondii IgG is not associated with the risk of BD in offspring.Small sample size; absence of information about specific serotypes of Toxoplasma; unable to determine when the infection occurred in relation to the pregnancy or birth
SCH: schizophrenia; pts: patients; BD: bipolar disorder.

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Del Grande, C.; Galli, L.; Schiavi, E.; Dell’Osso, L.; Bruschi, F. Is Toxoplasma gondii a Trigger of Bipolar Disorder? Pathogens 2017, 6, 3. https://doi.org/10.3390/pathogens6010003

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Del Grande C, Galli L, Schiavi E, Dell’Osso L, Bruschi F. Is Toxoplasma gondii a Trigger of Bipolar Disorder? Pathogens. 2017; 6(1):3. https://doi.org/10.3390/pathogens6010003

Chicago/Turabian Style

Del Grande, Claudia, Luca Galli, Elisa Schiavi, Liliana Dell’Osso, and Fabrizio Bruschi. 2017. "Is Toxoplasma gondii a Trigger of Bipolar Disorder?" Pathogens 6, no. 1: 3. https://doi.org/10.3390/pathogens6010003

APA Style

Del Grande, C., Galli, L., Schiavi, E., Dell’Osso, L., & Bruschi, F. (2017). Is Toxoplasma gondii a Trigger of Bipolar Disorder? Pathogens, 6(1), 3. https://doi.org/10.3390/pathogens6010003

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