T. gondii infection might be "a contributing causal factor for schizophrenia"

T. gondii mentioned in the title of this post refers to Toxoplasma gondii, a parasite with something of a rather interesting profile and history (see here and see here). I've talked quite a bit on this blog about T. gondii and it's various 'associations', but of particular interest has been the suggestion of a 'connection' between T. gondii exposure and risk of psychiatric diagnoses like schizophrenia (see here).

The findings reported by Kristoffer Sølvsten Burgdorf and colleagues [1] (open-access available here) add further evidence to such a 'psychiatric' connection with their conclusion that: "exposure to T. gondii might be a contributing causal factor for developing schizophrenia." Researchers arrived at their conclusion following the examination of an intriguing initiative called the Danish Blood Donor Study (DBDS). Started in 2010, the DBDS includes records for over 100,000 patients and "contains DNA and EDTA plasma samples, consecutive for all donors returning for blood donation after enrolment." That's a lot of data. So: authors "identified all individuals in the DBDS cohort registered with psychiatric disorders, suicidal behavior, or traffic accidents (N=5,953)." Said participants were matched with 'suitable' controls (N=7,101) and stored samples were analysed for "immunoglobulin (IgG) class antibodies against T. gondii and CMV." CMV by the way, refers to cytomegalovirus. Contact with (congenital) CMV has also been talked about on this blog (see here). CMV (exposure) also shares a potential *link*  with "psychiatric disorders, cognitive deficits, suicidal behavior, and traffic accidents."

Results: "Of the 11,546 studied individuals, 2,990 and 7,020 individuals, respectively, tested positive for IgG class antibodies against T. gondii (25·9%) or CMV (60·8%)." Onward: "We found that individuals with a T. gondii infection had increased odds of being diagnosed with schizophrenia disorders compared to those without infection." Because researchers were also able to access other national databases containing details on outcomes like diagnosis of a psychiatric disorder and 'attempting suicide' and cross-reference them with their participants, they were also able to look at "temporality, with pathogen exposure preceding outcome" as a factor. And when they did, that T. gondii exposure - schizophrenia association was described as "even stronger." The other data on T. gondii or CMV exposure in relation to traffic accidents or suicide attempts was not as statistically strong, and indeed nothing showed significance when temporality was taken into consideration in relation to causation. On that basis, I'm gonna leave that part of the results without further comment.

This was a good study. It drew on data from a well-defined group (those Scandinavian databases 'do it' yet again) and was able to take into account the important issue of temporality. It wasn't a perfect study - "We cannot rule out that socio-economic factors could potentially account for part or all of the observed causal effect" - and said nothing about possible mechanism(s) of effect however. That being said, I'm willing to go along with the conclusions made and the need for a lot more investigation in this area linking T. gondii exposure and subsequent risk of mental illness. In particular whether new or existing treatment methods for T. gondii *might* hold the promise of much more...

And whilst on the topic of T.gondii and the specific input from cats on the spread of T. gondii (see here and see here), I'll state here and now that I am not a great believer in the idea of 'cat eradication' as mentioned by some researchers recently [2]. That being said, a toxoplasmosis vaccines for cats (see here) sounds like a really good idea...

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[1] Sølvsten Burgdorf K. et al. Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders. Brain Behav Immun. 2019 Jan 24. pii: S0889-1591(18)30699-8.

[2] de Wit LA. et al. Potential public health benefits from cat eradications on islands. PLoS Negl Trop Dis 13(2): e0007040

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The FACE-SZ initiative: inflammation and latent Toxoplasma infection in schizophrenia

The FACE-SZ initiative mentioned in the title of this post refers to the National FondaMental Expert Center (FACE-SZ) Cohort, a French collaboration designed to further knowledge about schizophrenia (SZ). The year 2018 has already been quite a year for peer-reviewed publications stemming from this initiative (see here), previously covering some really important topics.

Today I'm discussing two papers from the FACE-SZ scheme: the first from Guillaume Fond and colleagues [1] covered the issue of latent Toxoplasma infection and schizophrenia, and the second also from Fond and colleagues [2] observed that peripheral low-grade inflammation seemed to be something over-represented when it came to "ultra resistance to treatment in schizophrenia (UTRS)." The common ground between the papers is the immune system and how 'activation' of the immune system *might* have some important connections to the presentation of schizophrenia (see here).

Toxoplasma infection is a topic that has been mentioned in the context of schizophrenia before (see here). The causative agent of such infection - Toxoplasma gondii - is most definitely one of Nature's survivors; even to the point of potentially 'making' mortal enemies 'attracted' to waste products of the other (see here). There's still some debate about the hows-and-whys of T.gondii and Toxoplasma infection in relation to schizophrenia, but the collected data is not easily ignored when it comes to an over-representation of infection in the context of schizophrenia and its symptoms (see here and see here).

The first Fond paper [1] reports data from a cohort of some 250 people diagnosed with schizophrenia and "included between 2015 and 2017 in the national FondaMental Expert Center (FACE-SZ) Cohort." Alongside looking for the presence of Toxoplasma infection - "Latent Toxoplasma infection was defined by T. gondii IgG ratio ≥0.8, equivalent to ≥10 international units" - researchers also looked for signs of peripheral inflammation as per their measurement of everyone's favourite pentraxin: highly sensitive C reactive protein (CRP). I should also mention that CRP also has quite a peer-reviewed publication history when it comes to schizophrenia (see here) albeit not always in agreement (see here).

They reported that almost three-quarters of their cohort (184/250) showed signs of latent Toxoplasma infection, equating to Toxoplasma being "almost 3 times more frequent in SZ population compared to general population in France." Not only that but such infection seemed to correlate with some important clinical measurements of schizophrenia, and "Treatments with Anti-Toxoplasmic Activity (TATA)" also correlated with lower depressive symptoms.

The second Fond paper [2] focused on 'chronic low-grade peripheral inflammation' as again, high sensitivity CRP (hs-CRP) was the analyte of choice. The focus this time around was on a sub-group classified as showing "ultra resistance to treatment in schizophrenia (UTRS)" and to see if the such inflammation was *associated* with such cases. Including a starting participant number of over 600 people all diagnosed with schizophrenia, researchers reported that about 10% fell into that UTRS grouping. Among this 10%, they reported something of important relationship between UTRS and levels of CRP as a marker of inflammation. Such a relationship also held when taking into account other, potentially influential variables: "adjustment for age, sex, current daily tobacco smoking, metabolic syndrome and antidepressant consumption." The authors opine that further studies should be directed to look at whether 'treating' such low-grade inflammation *might* have an important effect on some of the presented symptoms of schizophrenia.

Taken together, I'm hoping that readers can see the value of the FACE-SZ initiative, and what it could mean for research looking at the possible aetiology and pathology of at least some cases of schizophrenia. Yes, I appreciate that genetics and environment are going to be important to schizophrenia (as they seem to be for just about every behavioural/psychiatric label) but with that immune system 'connection' there could be lots of research opportunities including some potentially novel treatments to be examined. Once again, the immune system seems to be doing an awful lot more than just playing protector against various pathogens...

To close, and noting the mention of T.gondii in today's post, the news doesn't seem to be all that great when it comes to cat ownership...

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[1] Fond G. et al. Latent toxoplasma infection in real-world schizophrenia: Results from the national FACE-SZ cohort. Schizophr Res. 2018 May 27. pii: S0920-9964(18)30265-2.

[2] Fond G. et al. Chronic low-grade peripheral inflammation is associated with ultra resistant schizophrenia. Results from the FACE-SZ cohort. Eur Arch Psychiatry Clin Neurosci. 2018 May 28

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Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms

It's been a while since I last talked about Toxoplasma gondii on this blog (see here). All the initial research excitement from a few years back on how T. gondii exposure might correlate with various psychiatric symptoms/conditions seems to have been toned down in recent times. Still, I continue to be fascinated with the idea that at least for some, exposure to T. gondii might be more than just a somatic thing...

The findings reported by Lindgren and colleagues [1] illustrate how my interest in the gondii remains justified as per their conclusion: "Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms." Based on data from Finland - "Health 2000, a large cross-sectional health survey of the Finnish general population aged 30 and above" - the authorship team included on the Lindgren paper contain some names familiar to the T. gondii research scene: namely Faith Dickerson and Robert Yolken.

So, the presence of lifetime psychotic-like symptoms via "section G of the Composite International Diagnostic Interview, Munich version (M-CIDI)" were analysed alongside seropositivity to Toxoplasma "defined as a cutoff of 50IU/ml of IgG antibodies" in nearly 6000 participants. Various other potentially interfering variables - "age, gender, education, region of residence, cat ownership, and C-reactive protein measuring inflammation" - were also thrown into the statistical mix. Cat ownership by the way, refers to the [disputed] research hypothesis that some cats might be unwitting hosts for the gondii with potential onward implications for owners (see here).

Results: "T. gondii seropositivity was significantly associated with clinically relevant psychotic-like symptoms... and with the number of psychotic-like symptoms." That being said, presenting with an immune profile suggestive of some contact with T. gondii did not show any significant connection with diagnosed conditions with a psychotic element to them such as schizophrenia. The authors however, felt confident enough to say that psychotic symptoms might not be totally unrelated to T. gondii exposure.

Accepting that there may be various reasons why someone might present with clinically-relevant psychotic-like symptoms [2] I find good reason to continue with the research agenda looking at T. gondii exposure and human behaviour on the basis of results such as those from Lindgren. The spectrum of labels - behavioural/psychiatric - potentially *associated* with T. gondii exposure is not to be sniffed at [3]. Even if only a proportion of cases are found to be *associated* with gondii exposure, there are treatments readily available (see here) to manage the infection. Whether such intervention(s) might also provide some relief of psychiatric symptoms alongside, is something too that needs more investigation...

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[1] Lindgren M. et al. The association between toxoplasma and the psychosis continuum in a general population setting. Schizophr Res. 2017 Jul 12. pii: S0920-9964(17)30391-2.

[2] Cosgrave J. et al. The interaction between subclinical psychotic experiences, insomnia and objective measures of sleep. Schizophr Res. 2017 Jul 12. pii: S0920-9964(17)30397-3.

[3] de Barros JL. et al. Is there any association between Toxoplasma gondii infection and bipolar disorder? A systematic review and meta-analysis. J Affect Disord. 2017 Feb;209:59-65.

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ALSPAC says no to cat ownership - psychosis risk hypothesis but...

"While pregnant women should continue to avoid handling soiled cat litter, given possible T. gondii exposure, our study strongly indicates that cat ownership in pregnancy or early childhood does not confer an increased risk of later adolescent PEs [psychotic experiences]."

So said the findings reported by Francesca Solmi and colleagues [1] (open-access) who brought a smile to any reader of the title of their paper: "Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort." For those who might not be aware of the hypothesis, cat ownership has been previously linked to 'adverse' psychological outcomes (see here) tied into some peer-reviewed evidence on one possible environmental factor linked to psychosis and conditions manifesting psychosis: Toxoplasma gondii.

ALSPAC - Avon Longitudinal Study of Parents and Children - brought it's quite significant scientific prowess to bear on the question of whether "cat ownership in pregnancy and childhood (ages 4 and 10 years) was associated with psychotic experiences (PEs) in early (age 13, N = 6705) and late (age 18, N = 4676) adolescence, rated from semi-structured interviews." Having a cat in the house was not the only question asked by Solmi et al as the presence of other pets were also investigated: "dogs, rabbits, rodents, birds (all waves), and tortoises and fish (from 21 months)." PEs were assessed at approximate ages of 13 and 18 years old via responses to the "psychotic-like symptoms interview (PLIKSi), a semi-structured interviewer-rated screening assessment for PEs." Various other variables were also factored into the examination of any effect or not.

Results: well, as per the opening sentence to this post, cat ownership did not seem to be related to later PEs. The potential caveat being that in some of their analyses there did seem to be a possible association - "Owning a cat at age 4 years was associated with higher odds of having PEs at age 13 years in univariable models" - but the significance of this association disappeared when adjustments for other potentially confounding variables were made. Obviously this kind of study can't control for every single potentially confounding variable but they did at least try.

Why the disparity between these results and the previous ones suggestive of a possible connection between childhood cat ownership and later adverse psychological health? Well, an important point is made by Solmi and colleagues: "Our study was based on PEs in early and late adolescence, unlike other studies which were based on a clinical diagnosis of schizophrenia." In other words. psychotic experiences might be part and parcel of schizophrenia but not necessarily all that schizophrenia encompasses and not necessarily just enough to merit a diagnosis of schizophrenia. They do also go on to highlight how the previous report on the association may also not have included the range of potentially confounding variables that were included and controlled for in the current study as another possibility for the differences reported. Having said that [2]...

Does the T. gondii - schizophrenia hypothesis fall as a result of the Solmi results? Probably not. Solmi et al hint that even though cat ownership probably isn't related to PEs, they do not totally debunk the idea that there may be a connection. They did not for example, look for the presence of contact with T. gondii in this particular study (others have) as per serological examination of participants. I say this bearing in mind that not every moggy is necessarily infected with T. gondii or anything else. Sweeping generalisations on all cats are not required.

Music to close, and containing the lyric 'Caringosity killed the Kerouac cat', a chirpy little number from a band with quite a contentious name...

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[1] Solmi F. et al. Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychol Med. 2017 Feb 22:1-9.

[2] Fuller Torrey E. et al. The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res. 2000 Nov 30;46(1):17-23.

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Solmi F, Hayes JF, Lewis G, & Kirkbride JB (2017). Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychological medicine, 1-9 PMID: 28222824

T. gondii and OCD?

It's been a while since I've talked about Toxoplasma gondii on this blog; the parasite that more than most, has been linked with all-manner of different psychiatric labels (see here for example). Although still the topic of some discussion, I'm swayed towards the possibility that there may be some important *associations* to be seen when it comes to this survivor and human behaviour(s) outside of just making rats attracted to cat urine (see here) to improve reproduction chances.

Indeed, in that context I offer up the findings reported by Flegr & Horáček [1] who presented results pertinent to "earlier reports of the association between toxoplasmosis and OCD [obsessive compulsive disorder]." OK, the first thing to note about this study is that: "Examined subjects provided the information about their toxoplasmosis and OCD statuses themselves, which could result in underrating the strength of observed associations." Most people probably wouldn't falsely admit to being toxoplasmosis positive but I can imagine that a few people might not want to share such sensitive information for various reasons.

Researchers examined data from over 7400 volunteers (participants), asking about their toxoplasmosis status and also whether they had been diagnosed with OCD, a condition characterised by obsessive thoughts and compulsive behaviours, or one or more of a variety of other neuropsychiatric labels. The symptoms of OCD were also characterised on the basis of the use of the Obsessive-Compulsive Inventory-Revised (OCI-R) (self-completed).

They observed the incidence of OCD to be present in approximately 2% of their cohort. They also observed that where toxoplasmosis was reported, these participants were quite a bit more likely to also report being diagnosed with OCD. A similar relationship also held when it came to the presence of a learning (intellectual) disability too. When researchers also took into account those self-report scores on the OCI-R, they noted that in those with toxoplasmosis "even the OCD-free subjects, scored higher on the OCI-R." Ergo, something of a relationship between T. gondii and OCD (diagnosed or symptoms) may exist.

Accepting the methodological failings of the Flegr / Horáček study, their data do indeed seem to tally with other independent study [2] in this area, albeit still quite limited in quality and amount. Such research also potentially ties into other investigations on other behavioural/psychiatric labels where the gondii has been implicated (see here for example) that might overlap with cases of OCD. There are however still questions to answer, not least which came first, psychiatric presentation or infection with the gondii? Could a behavioural or psychiatric diagnosis increase the risk that someone is more likely to become infected by the gondii? I suppose given what OCD encompasses - "fear of contamination by disease, infection or an unpleasant substance" - one could argue that OCD is not exactly a great template for coming into contact with T. gondii and becoming infected. But before I, or anyone else, jumps to conclusions, more investigation(s) are implied on the nature of the relationship and onward any pertinent biological mechanisms...

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[1] Flegr J. & Horáček J. Toxoplasma-infected subjects report an Obsessive-Compulsive Disorder diagnosis more often and score higher in Obsessive-Compulsive Inventory. Eur Psychiatry. 2016 Dec 16;40:82-87.

[2] Miman O. et al. Is there any role of Toxoplasma gondii in the etiology of obsessive-compulsive disorder? Psychiatry Res. 2010 May 15;177(1-2):263-5

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Flegr J, & Horáček J (2016). Toxoplasma-infected subjects report an Obsessive-Compulsive Disorder diagnosis more often and score higher in Obsessive-Compulsive Inventory. European psychiatry : the journal of the Association of European Psychiatrists, 40, 82-87 PMID: 27992837

The neuropathology linking T. gondii infection and schizophrenia?

A quote to begin: "findings suggest that T gondii [Toxoplasma gondii] infection causes substantial and widespread immune activation indicative of neural damage and reactive tissue repair in the animal model that partly overlaps with changes observed in the brains of schizophrenia patients."

So said the very interesting paper by Jakub Tomasik and colleagues [1] who set about comparing results from a mouse model of "chronic T gondii infection" looking for serum and brain signatures with those in postmortem "brain samples from 35 schizophrenia patients and 33 healthy controls." Researchers found that mice infected with T. gondii were pretty 'immune-stimulated' as a result; also manifesting with "neural damage and reactive tissue repair". Some of these immune consequences also seemingly 'overlapped' with what was observed in the very precious brain samples from those previously diagnosed with schizophrenia, particularly when it came to "C-reactive protein (CRP), interleukin-1 beta (IL-1β), interferon gamma (IFNγ), plasminogen activator inhibitor 1 (PAI-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), and vascular cell adhesion molecule 1 (VCAM-1)." The authors conclude that any shared pathophysiology might be "a key step towards understanding their specific contributions to pathogenesis."

I'd like to think that the Tomasik paper is an important next step in the whole idea that T. gondii infection might show some important links with at least some schizophrenia (see here). Still a point of discussion in some quarters [2] insofar as the hows and whys of any association (see here), there is nevertheless, some quite reliable research appearing in the peer-reviewed domain to suggest that there may a link, correlation if you will, between this parasitic protozoan and the appearance of some schizophrenia or schizophrenia-linked symptoms. Putting some scientific flesh on the bones of 'mechanisms' through which infection might link to schizophrenia is important.

That being said, I do think we have to be slightly cautious when it comes to changes in immune function in relation to schizophrenia being solely pinned down to T. gondii infection. Given for example, the growing significance of something like CRP to schizophrenia in general (see here), I think you would be hard-pressed to say this is all down to T. gondii infection. Indeed, the maternal immune activation hypothesis may well play a role here (see here) as might the wider implications of something like inflammation when it comes to the wider arena of psychiatry (see here).

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[1] Tomasik J. et al. Shared Immune and Repair Markers During Experimental Toxoplasma Chronic Brain Infection and Schizophrenia. Schizophr Bull. 2015 Sep 20. pii: sbv134.

[2] Wolf PJ. & Hamilton FE. Flawed analyses undermine proposed relationship between childhood cat ownership and schizophrenia. Schizophr Res. 2015 Aug 14. pii: S0920-9964(15)00427-2.

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Tomasik J, Schultz TL, Kluge W, Yolken RH, Bahn S, & Carruthers VB (2015). Shared Immune and Repair Markers During Experimental Toxoplasma Chronic Brain Infection and Schizophrenia. Schizophrenia bulletin PMID: 26392628

T. gondii infection and autism?

I was interested to read the paper by Joseph Prandota and colleagues [1] who observed that: "latent chronic T. gondii [Toxoplasma gondii] infection have an important impact on triggering and development of ASD [autism spectrum disorders], at least in a subset of autistic children, and this requires some modification(s) of its diagnostic procedures and treatment regimens." Big words, I'm sure you'll agree.

From the start I'll indicate that I'm interested in T. gondii on this blog. This parasitic protozoan is one of nature's survivors (and thrivers) with effects that may go far beyond your ordinary parasite. Aside from potentially making rats attracted to cats (or cat urine), I've been particularly interested in the collected research looking at a possible association between T. gondii and the presentation of schizophrenia (see here for example). The idea that infection with T. gondii under the right circumstances may be associated with a condition as complicated as schizophrenia is not without its critics, but in a world of increasing pluralisation of such labels (see here) I'd be minded to keep T. gondii on the research agenda (see here) for now.

The Prandota findings, based on a small-ish group of children diagnosed with ASD living in Egypt, take things one step further when it comes to T. gondii and it's potentially wide-ranging effects. Working with the aim to "estimate the seroprevalence of chronic toxoplasmosis among autistic children" researchers set about assaying for "anti-T. gondii IgG antibody seroposivity" alongside a couple of other parameters including "serum levels of IFN-g and nitric oxide (NO) in T. gondii-positive and T. gondii-free patients." I might add that a positive anti-T. gondii IgG result indicates previous exposure to T. gondii. It does not necessarily mean current or on-going infection which can only be reliably ascertained via other tests (see here).

Results: "11 (29.3%) out of the 46 autistic children... were positive for serum anti-T. gondii IgG antibodies as compared with 2 patients (4%) with toxoplasmosis found among 50 control children." Age was one of the parameters that seemed to play a role in infection history which kinda stands to reason (the older you are, the more likely that you have an exposure). Further: "Autistic children with toxoplasmosis had markedly increased both serum IFN-g and NO concentrations... as compared with the values obtained in patients without toxoplasmosis."

I don't want to over-analyse the Prandota results at this stage in terms of what elevations of IFN-γ and NO might mean to T. gondii infection in autism, so I won't. The authors go into some detail about immune function, tryptophan metabolism and even glutathione gets a mention in relation to these issues, but I'd prefer to stick to the T. gondii estimates for now.

As far as I can see, this is one of the first times that T. gondii infection has been discussed with autism in mind. That over a quarter of cases in the Prandota sample were found to have been in immunological contact with the protozoan is interesting and suggests that further independent investigations should be initiated in this area. I would, for example, be interested to know whether such findings are transferable to other geographical sites? Does cat ownership show any link to findings as per some discussions in schizophrenia (see here)? Are there any links with other 'autism-related' issues as suggested by Abdoli & Dalimi [2]? And, with some of my own research interests in mind (see here) could such findings further extend the observations of Emily Severance and colleagues [3] talking about T. gondii infection and "sensitivity to gluten" beyond schizophrenia (see here)? Well, it's not as if anti-gliadin antibodies (IgG) are strangers to [some] autism (see here).

As for treating any on-going toxoplasmosis, well in the US at least, this might just have got a little bit more expensive...

Questions (and answers) remain.

Music: Artful Dodger - Movin' Too Fast.

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[1] Prandota J. et al. Increased Seroprevalence of Chronic Toxoplasmosis in Autistic Children: Special Reference to the Pathophysiology of IFN-γ and NO Overproduction. International Journal of Neurology Research. 2015; 3: 102-122.

[2] Abdoli A. & Dalimi A. Are There any Relationships between Latent Toxoplasma gondii Infection, Testosterone Elevation, and Risk of Autism Spectrum Disorder? Front Behav Neurosci. 2014 Sep 24;8:339.

[3] Severance EG. et al. Anti-gluten immune response following Toxoplasma gondii infection in mice. PLoS One. 2012;7(11):e50991.

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Joseph Prandota, Noha Abdel Fattah Elleboudy, Khadiga Ahmed Ismail, Osama Kamal Zaki, & Hanan Hussein Shehata (2015). Increased Seroprevalence of Chronic Toxoplasmosis in Autistic Children: Special Reference to the Pathophysiology of IFN-γ and NO Overproduction International Journal of Neurology Research, 1 (3), 102-122 : 10.17554/j.issn.2313-5611.2015.01.30

Toxoplasma seropositivity and pediatric cognitive functions

A brief post for you today as I keep a promise made in a previous entry to cover the paper by Angelico Mendy and colleagues [1] who concluded that: "Toxoplasma seropositivity may be associated with reading and memory impairments in school-aged children."

Based on the analysis of over 1700 children/young adults aged 12-16 years old "who participated to the Third National Health and Nutrition Examination Survey" researchers examined the possibility of a relationship between various psychometric test scores - "including math, reading, visuospatial reasoning and verbal memory" - and Toxoplasma seropositivity (that is, showing immunological evidence of either past or current infection by Toxoplasma gondii). Finding that approximately 7% of participants were seropositive for contact with the protozoan, researchers also highlighted a possible correlation between infection history and issues with both reading ability and memory capacity. This 'relationship' also appeared to be mediated by serum vitamin E levels in that: "Toxoplasma-associated memory impairment was worse in children with lower serum vitamin E concentrations." A good write-up of the study can be found here.

As regular readers might know (and are probably pretty bored of hearing about) I'm really rather interested in T. gondii and in particular the growing tide of peer-reviewed research hinting at a possible link between this organism and [some] schizophrenia. Accepting there is still quite a bit more to do looking at the possibility of link between the gondii and schizophrenia - including answering important questions about whether childhood cat ownership might be a risk factor - I'd like to think that the Mendy results might have a further role to play. I'm specifically thinking about the idea that cognitive decline (if I can call it that) might be part and parcel of schizophrenia and even something that pre-dates the onset of symptoms [2]. I draw back from making too many speculations in this area bearing in mind correlation is not the same as causation and the requirement for replicative investigations but would be rather interested to see if Mendy et al will be producing any follow-up data of their participants with a view to say, the prevalence of schizophrenia as a function of T. gondii seropositivity and/or psychometric scores?

Music: My Bloody Valentine - You Made Me Realise.

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[1] Mendy A. et al. Toxoplasma gondii seropositivity and cognitive functions in school-aged children. Parasitology. 2015 May 20:1-7.

[2] Keefe RS. The longitudinal course of cognitive impairment in schizophrenia: an examination of data from premorbid through posttreatment phases of illness. J Clin Psychiatry. 2014;75 Suppl 2:8-13.

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Mendy A, Vieira ER, Albatineh AN, & Gasana J (2015). Toxoplasma gondii seropositivity and cognitive functions in school-aged children. Parasitology, 1-7 PMID: 25990628

Clinical course of schizophrenia and Toxoplasma gondii infection

Regular readers of this blog probably know that I'm quite interested in the idea that the parasitic organism known as Toxoplasma gondii might have some rather interesting 'connections' to the presentation of [some] schizophrenia (see here). That the cat that might be sat in front of you as you read this post might have the ability to 'share' such a marvellous organism such as T. gondii as per the 'feline zoonosis theory of schizophrenia' (see here) is another aspect that has been also been discussed.

The paper by Tuncay Çelik and colleagues [1] (open-access available here) further adds to the growing peer-reviewed literature on this topic with their findings indicating that: "Toxoplasma-infected subjects had 15× higher probability of having continuous course of disease [schizophrenia] than Toxoplasma-free subject." I might add that before anyone gets the wrong idea about the labelling of schizophrenia as a 'disease', those are the authors words not mine.

A few pointers on the Çelik study might be useful:

• A total of 94 participants diagnosed with schizophrenia (median age: 40 years) were included for study. Various details were garnered about participants including "illness status, clinical course, awareness of the illness, electroconvulsive therapy, compliance with medication and illness type" and used as 'indicators of prognosis' to "compare with the anti-Toxoplasma gondii serological status."
• Blood samples were provided to screen for anti-Toxoplasma gondii IgG antibodies - a measure of recent or past exposure to T. gondii - and participants were grouped according to seropositivity or not. 
• Results: approaching half of participants were positive for anti-Toxoplasma gondii IgG antibodies (46%). Based on reports of illness status - chronic, partial remission or remission to a great extent - the "T. gondii seropositivity rate among ‘chronic’ patients was found to be 72% whereas it was 22% in partial remission group and no case was positive in remission to a great extent group." This implies that those with an on-going presentation of schizophrenia (i.e. not remitting) were quite a bit more likely to be positive for immunological evidence of recent or past exposure to T. gondii.
• Taking into account the clinical course of schizophrenia - ranging from a single episode of symptoms to continuous presentation - authors reported that "T. gondii infection was significantly more prevalent among the ‘continuous’ group than the others." I'm not an expert on the lifelong presentation of schizophrenia or rather symptoms associated with schizophrenia so will have to take the authors word for it on this occasion. 
• On the basis of these and other results, the authors conclude that: "a negative correlation between the clinical picture of schizophrenia and the presence of anti-T. gondii IgG antibodies in patients with latent toxoplasmosis" is present. Further that: "T. gondii infections may be associated with worse prognosis among patients with schizophrenia."

Stepping back and realising that this was a 'snapshot' study where only one testing occasion was used for T.gondii exposure and schizophrenia symptom presentation on top of the "small size of the study group", these are interesting results. We are told that "none of the patients showed clinical evidence of immunodeficiency" which may yet be an important point when it comes to ascertaining the hows and whys of T.gondii infection and a condition as complicated as schizophrenia.

The idea that the clinical course of schizophrenia - some schizophrenia - may be to some degree 'affected' by the presence of antibodies to T. gondii is an intriguing one. Not only does it offer further evidence for the involvement of the immune system in cases (see here) but also the tantalising prospect that clearance of the pathogen might affect the symptom profile. We know, for example, that certain antipsychotics drugs used in the management of schizophrenia and psychosis may also possess certain 'anti-parasitic' actions [2] and could already be working by this mode of action. Whether this also means that more traditional anti-parasitic measures might also have a clinical place under certain circumstances is a question that remains unanswered (bearing in mind my caveat about not providing medical or clinical advice on this blog). It's not as if other 'medicines' haven't been looked at with schizophrenia in mind before (see here).

Oh, and I'll perhaps come to the paper by Mendy and colleagues [3] suggesting that: "Toxoplasma seropositivity may be associated with reading and memory impairments in school-aged children" at some point in the future and what it could mean for at least some schizophrenia with cognitive functions in mind...

Music: Longfellow - Kiss-Hug-Make Up.

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[1] Çelik T. et al. Association between latent toxoplasmosis and clinical course of schizophrenia - continuous course of the disease is characteristic for Toxoplasma gondii-infected patients. Folia Parasitol (Praha). 2015 Jan 1;62. pii: 2015.015.

[2] Fond G. et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014 Mar;264(2):179-83.

[3] Mendy A. et al. Toxoplasma gondii seropositivity and cognitive functions in school-aged children. Parasitology. 2015 May 20:1-7.

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Celik T, Kartalci S, Aytas O, Akarsu GA, Gozukara H, & Unal S (2015). Association between latent toxoplasmosis and clinical course of schizophrenia - continuous course of the disease is characteristic for Toxoplasma gondii-infected patients. Folia parasitologica, 62 PMID: 25960559

Childhood cat ownership and risk of later life schizophrenia?

'I' before the 'E' except after 'C'.

"Is childhood cat ownership a risk factor for schizophrenia later in life?"

That was the rather peculiar question posed and partially answered in the paper by Fuller Torrey and colleagues [1]. They concluded that "cat ownership in childhood is significantly more common in families in which the child later becomes seriously mentally ill."

For those new to this topic, it might sound rather strange that cat ownership in childhood might elevate the risk of mental illness. But just before you smirk and click away, please read on a little further.

Previous research had hinted that cat ownership during childhood might be one of a number of factors linked to the presentation of psychosis [2] based on findings from some of the authorship group as part of their feline zoonosis theory of schizophrenia [3]. Zoonotic diseases, by the way, are diseases that can be transmitted from animals to people. The idea intersecting with a growing evidence base specifically suggesting that Toxoplasma gondii, a protozoan that finds a home in some cats and is shed in cat poo(p), might be linked to quite a few cases of schizophrenia (see here) following the potential crossing of the gondii from cats to humans.

I've covered the possibility of a link between T. gondii and cases of schizophrenia quite a few times on this blog (see here and see here for example). I have to say that the evidence is getting pretty strong for the possibility of a link between T. gondii exposure and risk of [some] schizophrenia with the requirement for quite a bit more investigation into the possible mechanisms involved. The idea that T. gondii, once it has found a home in someone, might be able so extremely affect a person's behaviour is also not as outlandish as it may first sound. 'Rats attracted to cats' was a post a few years back (see here) demonstrating the potential of T. gondii to affect animal behaviour and drive rats to become sexually attracted to cat urine followed by an almost certain death to the rat but continued survival for the parasite. Human are slightly more complicated creatures than rats but the idea of T. gondii leading to/causative of other behaviours has been entertained in the research literature [4].

Before anyone gets any ideas that I'm somehow 'anti-cat' based on this and other posts, I'm not. Whilst myself allergic to cats, I'm as sold on the cuteness of the Lego movie 'believe' poster as the next person. What however this line of scientific investigation does suggest is that one should always be a little bit cautious about the potential risks specifically associated with cat ownership. How, as well as being relevant to pregnant women, young family members should know about the potential issues of T. gondii when it comes to keeping a cat and in particular, keeping clear of places they poo(p). Some common sense guidance has been recently published with this in mind (see here).

Music: Arctic Monkeys - Mardy Bum (spoken in my best Sheffield accent).

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[1]  Fuller Torrey E. et al. Is childhood cat ownership a risk factor for schizophrenia later in life? Schizophrenia Research. 2015. 18 April.

[2] Fuller Torrey E. et al. The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res. 2000 Nov 30;46(1):17-23.

[3] Fuller Torrey E. & Yolken RH. Could schizophrenia be a viral zoonosis transmitted from house cats? Schizophr Bull. 1995;21(2):167-71.

[4] Ling VJ. et al. Toxoplasma gondii Seropositivity and Suicide rates in Women. The Journal of nervous and mental disease. 2011;199(7):440-444.

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Fuller Torrey, E., Simmons, W., & Yolken, R. (2015). Is childhood cat ownership a risk factor for schizophrenia later in life? Schizophrenia Research DOI: 10.1016/j.schres.2015.03.036

Toxoplasma gondii and schizophrenia (again and again)

The findings reported by Ainsah Omar and colleagues [1] (open-access available here) adding further weight to the notion of a "strong association between the active Tg [Toxoplasma gondii] infection and schizophrenia" are set out for your reading consumption today.

Continuing a research topic that has already enjoyed quite a bit of air time on this blog (see here and see here) whereby the parasite T. gondii known to cause the condition toxoplasmosis might also be implicated in at least some cases of schizophrenia, Omar et al report some pretty stark differences in rates of seropositivity between cases of schizophrenia (n=101) and asymptomatic controls (n=55).

"The serofrequency of Tg IgG antibodies (51.5%, 52/101) and DNA (32.67%, 33/101) among patients with schizophrenia was significantly higher than IgG (18.2%, 10/55) and DNA (3.64%, 2/55) of the controls." IgG antibodies refers to immune status with regards to a particular agent with the focus on past or recent exposure to said pathogen. In this respect, the results suggest that over half of participants with schizophrenia had met with T. gondii at some point compared with nearly 20% of controls. Insofar as active infection measured by IgM antibodies to T. gondii, the authors reported no significant difference in rates between the groups. DNA, as in measurement for the presence of T. gondii DNA as evidence of infection, also showed some interesting differences between the groups in favour of the schizophrenia group.

"In our study, the OR [odds ratios] of having schizophrenia among those with positive Tg DNA (OR=12.9) was much higher than those with positive Tg IgG antibody (OR=4.8)." This sentence in particular hints at some of the novelty behind the results from Omar et al with their focus on both antibody response to T. gondii infection and their more direct method of looking for T. gondii DNA.

"Although there was significant difference in the seropositivity of Tg IgG and Tg DNA between the 2 groups, however, there was no significant difference between the serointensity of Tg IgG antibody and DNA between schizophrenia patients and controls. These could possibly be due to the effects of antipsychotic medications which caused the reduction in the level of Tg IgG antibody and DNA by inhibiting the replication of Tg." I've talked before on this blog about how a wide variety of the medicines we use in modern times may have so many more 'effects' than those listed on the package insert. Certain antipsychotic drugs are known to possess "anti-toxoplasmic activity" [2] and one might entertain the fact that when used for some with schizophrenia there is the potential for some effect mediated via this pathway. I would like to see a lot more medicines tested for their anti-parasitic effects [3] that's for sure.

Of course one has to be a little cautious not to make too many generalisations from the findings from Omar and other research groups [4] (several other research groups [5]) about the idea that T. gondii might be linked to cases of schizophrenia. But as part of a wider research strategy [6] and accepting the moves towards the possible pluralisation of schizophrenia (see here), I believe there is quite a bit more to see in this area...

Music: The Cure - Pictures Of You.

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[1] Omar A. et al. Seropositivity and Serointensity of Toxoplasma gondii Antibodies and DNA among Patients with Schizophrenia. Korean J Parasitol. 2015 Feb;53(1):29-34.

[2] Fond G. et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014 Mar;264(2):179-83.

[3] Fond G. 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 Feb 24. pii: S0022-3956(15)00043-6.

[4] Cevizci S. et al. Seroprevalence of anti-Toxoplasma gondii and anti-Borrelia species antibodies in patients with schizophrenia: a case-control study from western Turkey. World J Biol Psychiatry. 2015 Mar 16:1-7.

[5] Khademvatan S. et al. Toxoplasma gondii Exposure and the Risk of Schizophrenia. Jundishapur J Microbiol. 2014 Nov;7(11):e12776.

[6] Severance EG. et al. Gastroenterology Issues in Schizophrenia: Why the Gut Matters. Current Psychiatry Reports. 2015; 17: 27.

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Omar A, Bakar OC, Adam NF, Osman H, Osman A, Suleiman AH, Manaf MR, & Selamat MI (2015). Seropositivity and Serointensity of Toxoplasma gondii Antibodies and DNA among Patients with Schizophrenia. The Korean journal of parasitology, 53 (1), 29-34 PMID: 25748706

Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis

A very brief post today to bring to your attention once again the paper by Joel Monroe and colleagues [1] which concluded that there was: "An increased seroprevalence of T. gondii [Toxoplasma gondii] IgM in patients with acute psychosis". I had touched upon this study in a previous post not-so-long-ago covering T. gondii infection and schizophrenia (see here) which also covered some of the various background research history on this topic.

Looks like his optometrist has a sense of humor.

What's more to say? Well, not much more aside from another choice quote from Monroe et al about how their meta-analysis: "complements and extends previous findings, suggesting that infections may be relevant to the etiopathophysiology of relapse in some patients with schizophrenia" as a function of those IgM antibodies. Indeed, the very interesting connection between infection, immune response to infection and psychiatric symptoms seems to be going further and faster than I'd ever envisaged [2].

Next stop: mechanisms of effect, and how about the paper from Parlog and colleagues [3] for starters, followed by a little more discussion about how we might reduce exposure to the bloody gondii [4]...

Spandau Ballet: Gold.

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[1] Monroe JM. et al. Meta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis. Schizophr Bull. 2014 Nov 9. pii: sbu159.

[2] Krause DL. et al. Infectious Agents are Associated with Psychiatric Diseases. Ment Illn. 2012 Jul 11;4(1):e10.

[3] Parlog A. et al. Toxoplasma gondii induced neuronal alterations. Parasite Immunol. 2014 Nov 6. doi: 10.1111/pim.12157.

[4] Opsteegh M. et al. Intervention Strategies to Reduce Human Toxoplasma gondii Disease Burden. Clin Infect Dis. 2014 Sep 15. pii: ciu721.

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Monroe JM, Buckley PF, & Miller BJ (2014). Meta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis. Schizophrenia bulletin PMID: 25385789

One fifth of schizophrenia cases linked to Toxoplasma gondii?

"The PAF [population attributable fraction] for schizophrenia in those exposed to T. gondii is tentatively 21.4%". That was the headline conclusion made by Prof. Gary Smith [1] in his modelling analysis estimating what percentage of cases of schizophrenia might involve the protozoan Toxoplasma gondii. Some of the accompanying media about this potentially very important finding can be found here and here.

You don't need to study scaring, you just do it.

Although no expert on the PAF - defined as [2]: "the proportional reduction in average disease risk over a specified time interval that would be achieved by eliminating the exposure(s) of interest from the population while distributions of other risk factors in the population remain unchanged" - the author seems to have undertaken some nifty statistical analysis to calculate how many cases of schizophrenia might not occur if T. gondii infection wasn't present.

For those who might not be up to speed with this area, there is quite a bit of evidence to suggest that T. gondii infection (or history of infection) may well tie into the presentation of schizophrenia [3]. The evidence is not altogether straight-forward in this area [4] including some potential involvement for food (see a previous post), but there is certainly something more to see in this area of investigation and perhaps further in psychiatry. As I write this post, yet another study has found evidence of a possible link with schizophrenia in mind [5] and a meta-analysis [6]  has reported: "An increased seroprevalence of T. gondii IgM in patients with acute psychosis". I'll be coming back to that last paper in a subsequent post.

Prof. Smith has quite sensibly called for quite a bit more inspection of the possible connection between T. gondii infection and schizophrenia over and above just "ridiculing the idea of a connection". In the press release about his study he notes: "In other words, we ask, if you could stop infections with this parasite, how many cases could you prevent?” Smith said. “Over a lifetime, we found that you could prevent one-fifth of all cases. That, to me, is significant."

Knowing what we are starting to know about schizophrenia, it's direct and indirect impact on a person and the all-important possibility of plurality issues, I would have to agree that some priority be given to this line of thought albeit in conjunction with other factors undoubtedly moderating any relationship.

And since we're on the topic of organisms potentially affecting human behaviour, I'll draw your attention to a recent paper by Robert Yolken and colleagues [7] (a veteran of the T. gondii - schizophrenia research correlation) on Chlorovirus ATCV-1 and cognitive functions...

Music to close: Marina and the Diamonds with Primadonna.

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[1] Smith G. Estimating the population attributable fraction for schizophrenia when Toxoplasma gondii is assumed absent in human populations. Preventive Veterinary Medicine. 2014. October 23.

[2] Rockhill B. et al. Use and misuse of population attributable fractions. Am J Public Health. 1998 January; 88(1): 15–19.

[3] Torrey EF. et al. Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull. 2012 May;38(3):642-7.

[4] Li Y. et al. Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel. Schizophr Res. 2013 Dec;151(1-3):36-42.

[5] Khademvatan S. et al. Toxoplasma gondii Exposure and the Risk of Schizophrenia. Jundishapur Journal of Microbiology. 2014 November; 7(11): e12776.

[6] Monroe JM. et al. Meta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis. Schizophr Bull. 2014 Nov 9. pii: sbu159.

[7] Yolken RH. et al. Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice. Proc Natl Acad Sci U S A. 2014 Oct 27. pii: 201418895.

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Smith, G. (2014). Estimating the population attributable fraction for schizophrenia when Toxoplasma gondii is assumed absent in human populations Preventive Veterinary Medicine DOI: 10.1016/j.prevetmed.2014.10.009

The gondii and generalised anxiety disorder

Toxoplasma gondii (T. gondii) has been absent from discussions on this blog for a while now. I'm going to remedy that today with this post talking about the paper from Markovitz and colleagues [1] who concluded: "T. gondii infection may play a role in the development of GAD [generalized anxiety disorder]".

"You have saved our lives. We are eternally grateful"

Based on participants taking part in the Detroit Neighborhood Health Study exposure to T. gondii "defined by seropositivity and IgG antibody levels" was measured in approaching 500 people. Psychiatric diagnoses including depression, PTSD (posttraumatic stress disorder) and GAD were ascertained and data analysed to see if there was anything correlation-wise between T. gondii exposure and the various conditions.

The results suggested that T. gondii exposure was "associated with a 2 times greater odds of GAD" when taking into account various potential confounding variables. Those with some of the highest antibody levels to T. gondii were over three times at greater risk of GAD, potentially suggesting a dose-response relationship. Ergo, "T. gondii infection is strongly and significantly associated with GAD" but with more research to do.

Although no expert on GAD, I was a little puzzled by the Markovitz results. My previous musings on T. gondii and how it manages to alter rodent behaviour would seem to imply that this protozoan has an opposite effect on animal anxiety (i.e. reducing or modifying anxiety and predation-related fear [2]). Of course mice/rats are mice/rats and not humans but one might have expected something of an opposite effect [3].

That being said, this is not the first time that anxiety (human anxiety) has been mentioned alongside T. gondii as per the paper by Groër and colleagues [4] (open-access). In that case authors concluded that: "Higher T gondii immunoglobulin G titers in infected women were related to anxiety and depression during pregnancy". Some clarification is perhaps needed in this area...

To close, music I've probably linked to before but it's so good I'm gonna do it again: REM and It's the End of the World...

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[1] Markovitz A. et al. Toxoplasma gondii and anxiety disorders in a community-based sample. Brain Behav Immun. 2014 Aug 11. pii: S0889-1591(14)00418-8.

[2] Kaushik M. et al. The role of parasites and pathogens in influencing generalised anxiety and predation-related fear in the mammalian central nervous system. Horm Behav. 2012 Aug;62(3):191-201.

[3] Gonzalez LE. et al. Toxoplasma gondii infection lower anxiety as measured in the plus-maze and social interaction tests in rats A behavioral analysis. Behav Brain Res. 2007 Feb 12;177(1):70-9.

[4] Groër MW. et al. Prenatal depression and anxiety in Toxoplasma gondii-positive women. Am J Obstet Gynecol. 2011 May;204(5):433.e1-7.

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Markovitz A, Simanek AM, Yolken R, Galea S, Koenen KC, Chen S, & Aiello AE (2014). Toxoplasma gondii and anxiety disorders in a community-based sample. Brain, behavior, and immunity PMID: 25124709