Toxoplasmosis and Schizophrenia: A Systematic Review and Meta‐Analysis of Prevalence and Associations and Future Directions

Contopoulos‐Ioannidis, Despina G.; Gianniki, Maria G; Truong, Angeline; Montoya, José G.

doi:10.1176/appi.prcp.20210041

Cited by 17 publications

(13 citation statements)

References 81 publications

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“…T. gondii -induced changes in behavioral responses to predator stress is not merely a rodent curiosity; approximately one-third of the human population carries a chronic T. gondii infection, and while most infected people are grossly asymptomatic, toxoplasmosis can have devastating effects on the fetal brain and is associated with greater risk for schizophrenia, OCD, ASD, suicide, and homicide in people with latent T. gondii infection (Contopoulos-Ioannidis et al 2022, Cook et al 2015, Nayeri et al 2022, Nayeri et al 2020, Torrey & Yolken 2003, Virus et al 2021). Thus, further study of NE and DA circuitry underlying T. gondii -induced behavioral changes in rodents and of catecholaminergic drugs as therapies for disorders with stress-responsive repetitive behaviors are warranted.…”

Section: Discussionmentioning

confidence: 99%

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

Liu

Lustberg

McCann

2023

Preprint

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Rodents infected with the parasite Toxoplasma gondii show reduced aversion to predator odor and diminished neophobia, and infection in humans is associated with increased risk of neuropsychiatric disorders. Norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and T. gondii suppresses dopamine β-hydroxylase (Dbh) expression thereby reducing NE and increasing DA, which may contribute to the disruption of innate host behaviors. We examined the consequences of Dbh knockout (Dbh -/-) on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls. Over the first 10 min of predator odor exposure, controls exhibited robust defensive burying behavior, whereas Dbh -/- mice showed high levels of grooming. Defensive burying was potently suppressed in controls by drugs that reduce NE transmission, while excessive grooming in Dbh -/- mice was blocked by DA receptor antagonism. In response to a cotton square scented with a novel neutral odor (lavender), most control mice shredded the material, built a nest, and fell asleep within 90 min. Dbh -/- mice failed to shred the lavender-scented nestlet, but still fell asleep. In contrast, controls sustained high levels of arousal throughout the predator odor test and did not build nests, while Dbh -/- mice were asleep by the 90-min time point, often in shredded bobcat urine-soaked nesting material. Compared with controls exposed to predator odor, Dbh -/- mice demonstrated decreased c-fos induction in the anterior cingulate cortex (ACC), lateral septum (LS), periaqueductal gray (PAG), and bed nucleus of the stria terminalis, but increased c-fos in the LC and medial amygdala. These data indicate that relative ratios of central NE and DA signaling coordinate the type and valence of responses to predator odor, and suggest that Dbh -/- mice may represent a useful monogenetic model of neurobiological changes conferred by T. gondii infection.

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Section: Discussionmentioning

confidence: 99%

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

Liu

Lustberg

McCann

2023

Preprint

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“…Testosterone has also a pivotal role on behavioral traits in males and females, such as aggressive behavior [22,[82][83][84]. On the other hand, latent toxoplasmosis is also involved in the etiopathogenesis of different behavioral alterations (e.g., psychoticism [43], aggressive behavior [85,86], and violent behavior [87]) and neuropsychiatric diseases, such as schizophrenia [88,89], depression [90,91] and anxiety disorders [90,92,93], obsessive compulsive disorder (OCD) [94], and autism spectrum disorder (ASD) [95][96][97][98]. Different mechanisms have been proposed to be involved in the etiopathogenesis of these disorders following T. gondii infection, including CNS Inflammation [99,100], neurotransmitter alterations (alterations in dopamine [101][102][103][104][105][106] and serotonin synthesis [91]) and testosterone alteration [22,107].…”

Section: Plos Onementioning

confidence: 99%

Toxoplasma gondii infection and testosterone alteration: A systematic review and meta-analyses

Abdoli,

Ghaffarifar,

Sharifi

et al. 2024

PLoS ONE

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Background Toxoplasma gondii (T. gondii) is a worldwide distributed protozoan parasite which has infected a wide range of warm-blooded animals and humans. The most common form of T. gondii infection is asymptomatic (latent); nevertheless, latent toxoplasmosis can induce various alterations of sex hormones, especially testosterone, in infected humans and animals. On the other hand, testosterone is involved in behavioral traits and reproductive functions in both sexes. Hence, the purpose of this systematic review is to summarize the available evidence regarding the association between T. gondii infection and testosterone alteration. Methods In the setting of a systematic review, an electronic search (any date to 10 January 2023) without language restrictions was performed using Science Direct, Web of Science, PubMed, Scopus, and Google Scholar. The PRISMA guidelines were followed. Following the initial search, a total of 12,306 titles and abstracts were screened initially; 12,281 were excluded due to the lack of eligibility criteria or duplication. Finally, 24 articles met the included criteria. A mean±standard deviation (SD) was calculated to assess the difference of testosterone between T. gondii positive and T. gondii negative humans. The possibility of publication bias was assessed using Egger’s regression. P-value < 0.05 was considered statistically significant. Results This systematic review identified 24 articles (18 studies in humans and six studies in animals). Most human studies (13 out of 19) reported an increased level of testosterone following latent toxoplasmosis in males, while three studies reported decreased levels and two studies reported an insignificant change. Eleven articles (seven datasets in males and seven datasets in females) were eligible to be included in the data synthesis. Based on the random-effects model, the pooled mean± SD of testosterone in T. gondii positive than T. gondii negative was increased by 0.73 and 0.55 units in males and females, respectively. The Egger’s regression did not detect a statistically significant publication bias in males and females (p = value = 0.95 and 0.71), respectively. Three studies in male animals (rats, mice, and spotted hyenas) and two studies in female animals (mice and spotted hyenas) reported a decline in testosterone in infected compared with non-infected animals. While, one study in female rats reported no significant changes of testosterone in infected than non-infected animals. Moreover, two studies in male rats reported an increased level of testosterone in infected than non-infected animals. Conclusions This study provides new insights about the association between T. gondii infection and testosterone alteration and identifies relevant data gaps that can inform and encourage further studies. The consequence of increased testosterone levels following T. gondii infection could partly be associated with increased sexual behavior and sexual transmission of the parasite. On the other hand, declining testosterone levels following T. gondii infection may be associated with male reproductive impairments, which were observed in T. gondii-infected humans and animals. Furthermore, these findings suggest the great need for more epidemiological and experimental investigations in depth to understand the relationship between T. gondii infection and testosterone alteration alongside with future consequences of testosterone alteration.

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“…1 Research thus far indicates a possible relationship between positive serology for toxoplasmosis or latent toxoplasmosis and the development of psychiatric disorders such as obsessivecompulsive disorder (OCD) and schizophrenia. [6][7][8][9] Patients with treatment-resistant OCD were found to have higher rates of IgG-positive toxoplasma serology, although this relationship was not supported in children. 7,10 Latent toxoplasmosis has also been shown to increase the risk of depression and suicidal behavior.…”

Section: Introductionmentioning

confidence: 98%

Positive Toxoplasma IgG Serology Is Associated with Increased Overall Mortality – A Propensity Score–Matched Analysis

Montalbano,

Kung,

Franco-Paredes

et al. 2024

The American Journal of Tropical Medicine and Hygiene

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Toxoplasma gondii is a prevalent parasitic disease with significant morbidity and mortality in immunocompromised populations. We lack long-term outcomes for latent infections. We aimed to elucidate the relationship between latent T. gondii infection and mortality risk. We queried TriNetX, a international multicenter network, to validate mortality risk differences among patients with positive or negative toxoplasma IgG through propensity score matching (PSM). We excluded patients with toxoplasmosis disease by International Classification of Diseases codes or polymerase chain reaction testing. We found 28,138 patients with available toxoplasma IgG serology. Seropositive patients were older and had a male preponderance. More seropositive patients identified as Hispanic, Latino, or Black persons. Patients who were positive for T. gondii IgG serology were slightly more likely to have underlying heart failure, a transplanted organ or tissue, malignant neoplasms of lymphoid or hematopoietic tissues, and diseases of the nervous system than seronegative controls. After PSM of patients with positive (N = 6,475) and negative (N = 6,475) toxoplasma IgG serologies, toxoplasmosis-positive patients were more likely to have long-term drug use but less likely to suffer from behavioral disorders. The overall PSM 1- and 5-year mortality was higher among patients with a positive toxoplasma IgG serology. The risk of schizophrenia was increased at 5 years. We found a prevalence of toxoplasma IgG positivity of 0.03% during the last 3 years. Latent T. gondii associates with a higher overall mortality risk. The study of social determinants of health and follow-up studies are necessary to corroborate the findings and find possible causal mechanisms.

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Toxoplasmosis and Schizophrenia: A Systematic Review and Meta‐Analysis of Prevalence and Associations and Future Directions

Cited by 17 publications

References 81 publications

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

Toxoplasma gondii infection and testosterone alteration: A systematic review and meta-analyses

Positive Toxoplasma IgG Serology Is Associated with Increased Overall Mortality – A Propensity Score–Matched Analysis

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