Schizophrenia and bipolar disorders: The Toxoplasma connection.

The infectious etiology of psychiatric illnesses has remained an unexplored area till recently. During the past two decades, numerous studies from multiple angles have tried to link chronic toxoplasmosis with schizophrenia and bipolar disorders, among others. Most of the evidence has come from serological studies in the patient population, but other facets have also been explored. This review examines the various areas from which a causal link has been deduced and includes: (a) serological studies, (b) effect of maternal toxoplasmosis on children, (c) neurotransmitter studies, (d) parasite localization in the brain, (e) role of cytokines, and (f) psychotherapy and its effect on Toxoplasma. However, multiple factors may play a role in the etiopathogenesis of psychiatric illnesses, and chronic Toxoplasma infection may be considered an important risk factor for the genesis and symptomatology of schizophrenia and bipolar disorders. Copyright:

INTRODUCTION

Schizophrenia and bipolar disorders share various common characteristics so that they can be viewed in a dimensional continuum view, as opposed to a categorical dichotomous vision.[1] Besides clinical features, it has been shown that they exhibit similar genetic and neurocognitive determinants as well.[2] The etiology of these disorders remains largely unclear and is believed to be multifactorial. These include genetic predisposition,[3] environmental factors,[4] and certain infectious agents, particularly Toxoplasma gondii.[56] T. gondii is an apicomplexan coccidian parasite which is primarily linked with teratogenicity due to the transplacental passage and a cause of encephalitis in immunocompromised patients, particularly in those with HIV infection.[7] The reservoir of this protozoan parasite is the members of the cat family, and they pass the oocysts in its feces. Humans may get the infection by consumption of water or food contaminated with oocysts or by eating undercooked meats (pork, lamb, poultry, etc.,) containing tissue cysts.[8]

HISTORICAL FINDINGS

In an early study performed in 1947 by Eichenwald, mental retardation was linked to congenital toxoplasmosis.[9] Studies conducted in Poland in the early 1950s found higher rate of Toxoplasma infection among psychiatric department patients compared to controls (52% vs. 25%, odds ratio [OR]: 3.19).[10] Kramer had summarized 114 cases of symptomatic adult toxoplasmosis published between 1940 and 1964 and mentioned that “psychiatric disturbances were very frequent,” occurring in 24 cases.[11] Piekarski et al., working with animals, first reported that T. gondii caused impaired learning and memory in mice and rats.[12]

EXISTING EVIDENCE IN FAVOR OF TOXOPLASMA LINK

In the past two decades, numerous studies have been conducted to find a direct link between chronic toxoplasmosis and schizophrenia/bipolar disorders, apart from various other neuropsychiatric illnesses. These can be grouped under the following heads:

Evidence from seroprevalence studies

Effect of maternal toxoplasmosis on children

Neurotransmitter studies

Parasite localization in the brain

Role of cytokines

Pharmacotherapy of psychiatric disease.

Seroprevalence studies

In one of the earliest studies from Cuba, 50 patients with manic-depressive psychosis, 120 neurotics, and 100 healthy individuals were studied by testing with toxoplasmin intradermal test. The highest percentage of reactors was found among patients with manic-depressive psychosis (66.0%), and the intensity of reaction was higher among patients with manic-depressive psychosis.[13] In another study, immunoglobulin G (IgG) detection was used to determine the prevalence and level of antibodies to T. gondii, cytomegalovirus (CMV), and herpes simplex virus (HSV)-1and HSV-2 in individuals with schizophrenia, bipolar disorder, and unaffected controls. The seroprevalence of T. gondii infection was higher in individuals with schizophrenia (adjusted OR = 4.7; 95% confidence interval [CI] [1.5, 15.1]) and bipolar disorder (adjusted OR = 3.0; 95% CI [1.1, 8.6]) than in unaffected controls. The level of IgG to CMV was also significantly higher in individuals with schizophrenia and bipolar disorder.[14] The association of Toxoplasma-specific IgG results with mood disorder outcomes in 7440 respondents from the third National Health and Nutrition Survey in the USA revealed a significant relationship between T. gondii seroprevalence and bipolar disorder Type I.[15] In a study from France, a country with high prevalence of toxoplasmosis, the prevalence of IgG/IgM class antibodies for T. gondii infection was compared between 110 bipolar disorder patients and 106 healthy controls. The seropositive group for IgG antibodies had a 2.7 fold odds of having the disease as compared to the seronegative group (OR = 2.17; 95% CI = 1.09–4.36; P = 0.028).[16] A recent systematic review and meta-analysis found that patients with bipolar disorder are more likely to be infected by T. gondii than controls (OR = 1.26).[17] Another meta-analysis included 11 studies and demonstrated overall increased odds of having bipolar disorder in those with IgG to T. gondii, with an OR of 1.52.[6] Thus, there seems to be robust evidence for an association between bipolar disorders and seropositivity for T. gondii infection.

The association between schizophrenia and T. gondii seems to be equally strong, as evidenced by numerous reports. The first meta-analysis of the reports concerning this aspect was published in 2007[18] and updated by the same authors in 2012.[5]

In the first study,[18] published and unpublished controlled studies that used serological methods for measuring T. gondii antibodies to assess in patients diagnosed with schizophrenia were selected for analysis. Forty-two studies carried out in 17 countries over five decades were identified; 23 of these (6 unpublished) met selection criteria. The combined OR was 2.73 (95% CI: 2.10–3.60). In the later study,[5] the previous study finding was replicated with 15 additional studies and found an OR 2.71 (95% CI: 1.93–3.80). In a recent case–control survey, IgG and IgM class antibodies against T. gondii were measured in 798 patients from a public psychiatric hospital in China and in 681 nonpsychiatric controls from the general population in the same region. A significantly elevated seropositive rates of anti-Toxoplasma IgG and IgM were found in patients with schizophrenia, as well as those with bipolar disorder.[19] In a large case–control study, register data on 81,912 individuals from the Danish Blood Donor Study were reviewed to identify individuals who have a psychiatric diagnosis (n = 2591). Plasma samples were analyzed for Toxoplasma IgG antibodies and were detected in 25.9% of the population and were also associated with schizophrenia (OR: 1.47; 95% CI: 1.03–2.09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (incident rate ratio: 2.78; 95% CI: 1.27–6.09). According to the authors, this large-scale serological study is the first one to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia.[20]

Effect of maternal toxoplasmosis on children

Existing case–control studies have found no significant correlation between maternal seropositivity and development of bipolar disorders in the offspring.[21] In contrast, there seems to be a robust association between maternal infection and development of schizophrenia among the offspring. Increased levels of maternal antibodies to T. gondii have been correlated with adult-onset schizophrenia in the offspring. In one of the earlier studies, a large birth cohort born between 1959 and 1967 was studied by serological assays for Toxoplasma IgG antibody by dye test on maternal serum specimens from pregnancies. The adjusted OR of schizophrenia/schizophrenia spectrum disorders for participants with high maternal Toxoplasma IgG antibody titers was 2.61 (95% CI = 1.00–6.82).[22] In a Danish study, the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns was assessed. The patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders. T. gondii IgG levels corresponding to the upper quartile among controls were significantly associated with schizophrenia risk (OR = 1.79; P = 0.045) which supports an association between T. gondii and early-onset schizophrenia.[23] In conclusion, recent studies have associated childhood infections with a later diagnosis of schizophrenia and indicate that the associations between early life infection and the later development of schizophrenia are not explained by factors shared between related individuals or by genetic liability for schizophrenia.[24]

Neurotransmitter studies

Various neurotransmitters play vital roles in the pathogenesis of psychiatric disorders and chief among them include dopamine, serotonin, gamma-aminobutyric acid, and glutamate.[25] Dopamine plays a key role since increased concentration of dopamine in the brain is responsible for the positive symptoms in both bipolar disorders and schizophrenia.[2627] Moreover, nearly all modern antipsychotics either decrease the dopamine concentration or downregulate the receptor activity on neural cells.[28] It has been shown that the genome of T. gondii contains two genes encoding tyrosine hydroxylase which metabolizes phenylalanine as well as tyrosine with substrate preference for tyrosine. Thus, the enzymes catabolize phenylalanine to tyrosine and tyrosine to L-3,4-dihydroxyphenylalanine.[29] A subsequent study then showed that these genes are expressed in the brain tissue of an infected host and possibly responsible for the overproduction of dopamine in tissue cysts of Toxoplasma.[26] A double knockout of both genes can elucidate the complete picture of the actual functions of this enzyme in the parasite. A downregulation of D1 type dopamine receptors and dopamine metabolizing enzyme monoamine oxidase A with Toxoplasma infection has also been noted.[30] Thus, it seems that the increased concentration of dopamine in the cysts and their surroundings, generated through multiple pathways, is responsible for the positive symptoms of schizophrenia in some patients with acute schizophrenia. This might also explain the association between chronic toxoplasmosis and schizophrenia. Apart from dopamine, glutamate signaling in the brain may also be altered with infection. In one recent study, increased extracellular glutamate with chronic infection and a two-fold reduction in expression of the glutamate transporter in glial cells has been noted.[31] During Toxoplasma infection, the reduced expression of glutamate transporter in glial cells adds to the increased level of glutamate in extracellular spaces, and these unregulated levels can cause neuroexcitotoxicity. Global disruption (which also includes frontal cortex) of the cytoskeletal component β-tubulin III and loss of dendritic spines may be a result of glutamate excitotoxicity. Network connectivity, as measured by electroencephalogram, is also significantly reduced in chronic infection and has also been demonstrated in bipolar disorder and schizophrenia.[31]

Parasite localization in the brain

Toxoplasma shows neurotropism, and the parasite migrates within the brain tissue (predominantly gray matter), localizing in astrocytes, microglia, and neurons,[25] and the dormant form or bradyzoite can persist in the host brain for many years and maybe till death.[32] The distribution of T. gondii cysts in the brain plays an important role in the behavioral changes in infected hosts. In this regard, several studies suggest that T. gondii-containing cysts localize preferentially in the prefrontal cortex and amygdala, structures involved in the regulation of fear behavior.[3334] On the other hand, widespread parasite cyst localization in infected rats has been reported, including the cerebral hemispheres, hippocampus, basal ganglia, cerebellum, cerebral cortex, and brain stem.[35] Alteration of the structure and function of corticolimbic circuits, which are involved in the modulation of impulsivity and aggression, have been observed which could be responsible for behavioral changes observed in infected animals and humans.[3637]

Role of cytokines

Chronic T. gondii infection is characterized by increased levels of host immune activity and neuroinflammation.[38] There is upregulation of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and IL-1 β.[39] It has been seen that there exist specific patterns of increased levels of cytokines in different phases of bipolar disorders: the pro-inflammatory cytokines including IL-2, IL-6, and IL-8 and interferon (IFN)-γ are increased during mania, whereas only IL-6 is increased during depressive episodes.[40] Elevated peripheral levels of TNF-α have been reported in bipolar disorder patients during manic and depressive episodes.[41] Successful treatment with mood stabilizers leading to a euthymic state has been associated with a significant reduction of pro-inflammatory cytokines in these participants, with IL-6 levels returning to baseline after treatments.[42] Overall, these data suggest that manic phases and, to a lesser degree, depressive phases of bipolar disorder are associated with a persistent and chronic low-grade pro-inflammatory state.[43]

IFN-γ also stimulates the release of indoleamine 2,3-dioxygenase which catabolizes tryptophan.[44] This decreases the levels of tryptophan and also generates the accumulation of some harmful metabolites, particularly kynurenic acid (KYNA). High concentrations of KYNA, detected in cerebrospinal fluid (CSF) of schizophrenic patients, are considered a potential cause of cognitive disorders in schizophrenia.[25] The principal source of KYNA is astrocytes, the cells preferably chosen by T. gondii for replication.[45] KYNA also acts as an antagonist for glutamate ionic receptors and is able to inhibit α7 nicotinic acetylcholine receptors, modulating dopaminergic and glutamatergic neurotransmission.[46] Thus, chronic T. gondii infection induces early activation of tryptophan metabolism and KYNA production in schizophrenic patients.

Pharmacotherapy of Toxoplasma and psychiatric disease

The in vitro antiprotozoal effects of phenothiazine-related compounds have been documented since the late 1800s.[47] In one of the first studies, Jones-Brando et al.[47] investigated the ability of eight antipsychotics and four mood-stabilizing drugs to inhibit cell invasion and/or replication of T. gondii using human fibroblasts treated with test compounds and then exposed to Toxoplasma. The effect of these drugs was also compared to trimethoprim which is used for the treatment of toxoplasmosis. Among the tested medications, the antipsychotic haloperidol and the mood stabilizer valproic acid and sodium valproate showed the maximum inhibitory activity, followed by risperidone and fluphenazine. The therapeutic indices of valproic acid and sodium valproate were found to be equivalent to that of trimethoprim and showed synergistic inhibitory activity with both haloperidol and trimethoprim. Anti-Toxoplasma activity was not found for lithium salts. In another study[48] investigating the levels of antibodies to infectious agents in the serum and CSF of individuals with recent-onset schizophrenia, it was found that untreated individuals with recent-onset schizophrenia had significantly increased levels of serum and CSF IgG antibodies to T. gondii as compared to controls. Moreover, a significant reduction of T. gondii antibodies was found in those patients undergoing current drug treatment, suggesting that antipsychotic medications may affect T. gondii replication. In a more recent cross-sectional retrospective study, Fond et al.[49] evaluated the effect of the administration of a psychotropic drug having known in vitro anti-toxoplasmic activity (treatment with anti-toxoplasmic activity [TATA]+ve) on clinical outcome in a population of bipolar or schizophrenic/schizoaffective patients who were T. gondii seropositive and compared it to patients receiving a treatment with drugs without anti-toxoplasmic activity (TATA −ve). Cyamemazine, fluphenazine, haloperidol, levomepromazine, loxapine, paliperidone, risperidone, thioridazine, zuclopenthixol, and valproate were considered as TATA +ve, whereas amisulpride, aripiprazole, carbamazepine, clozapine, lamotrigine, lithium carbonate, olanzapine, quetiapine, and tiapride were considered as having no or negligible anti-toxoplasmic activity or TATA −ve. The authors observed that a current TATA +ve 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 neither found in bipolar disorder and Toxoplasma-negative patients nor in schizophrenic Toxoplasma-positive or negative patients regarding lifetime and current mood or psychotic symptomatology. Thus, it can be said that in T. gondii seropositive patients, TATA +ve medications may be helpful in preventing bipolar depression. In light of the above observations, it seems possible that some therapeutic activities of these antipsychotic drugs could be mediated by inhibition of mental disorder-associated infections. The antimicrobial side effects of these drugs should be taken into consideration in the treatment of Toxoplasma-infected patients or in the process of searching for new antipsychotic and/or new antiparasitic drugs.[27]

CONCLUSION

A strong body of evidence has surfaced in the past two decades implicating chronic T. gondii infection as an important risk factor for certain psychiatric illnesses, particularly schizophrenia and bipolar disorders. However, the multifactorial genesis of these psychiatric illnesses should also be kept in mind while interpreting the above findings. A trend of decreasing seroprevalence has been observed in many European countries and the USA over the past few decades, probably attributed, at least in part, to the hygienic improvements in animal husbandry.[50] On the other hand, stable or increasing seroprevalences have been reported in other parts of the world,[51] and an overall global seroprevalence of 30% has been described.[52] This high burden superimposed with the fact that there is no effective treatment for latent toxoplasmosis poses a grave risk for the development of psychiatric illnesses in the vulnerable population. Timely diagnosis and treatment of acute toxoplasmosis may play an important role in the prevention of chronic toxoplasmosis and its consequences.

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Conflicts of interest

There are no conflicts of interest.