The kynurenine pathway and some autism

"Our data indicated that there were alterations to the KP [kynurenine pathway] in ASD [autism spectrum disorder]. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted."

Those were some of the rather interesting results reported by Chai Lim and colleagues [1] suggesting that when it comes to tryptophan metabolism in relation to autism, the continued sole focus on serotonin and melatonin (see here) might not be the best overall research strategy.

Detailing results based on the examination of an: "Immunological profile and the KP metabolic signature" for a small group of Omani children diagnosed with autism (n=15) and their "age-matched healthy siblings" (n=12), researchers reported their findings. That specific detail about "increased production of the downstream metabolite, quinolinic acid" may indeed be an important one given connections with things like activated microglia for example [2] and the rise and rise of the 'constant gardener' with autism in mind (see here).

Obviously further studies are required to confirm the Lim findings in light of converse findings [3] (albeit reported in cerebrospinal fluid). Mention that their results might "help rationalize the efficacy of sulforaphane treatment in ASD" (yes, broccoli sprouts and autism) is another aspect in need of further investigation in these days of plural autisms (see here) and a focus on 'best' and 'non' responders to the various intervention strategies put forward with autism in mind (see here). One might also need to further expand the links between autism and schizophrenia on the basis of any kynurenine-glutamatergic link (see here).

I might finally add that as quite a fan of the need for more research into the aromatic amino acids (tryptophan, tyrosine and phenylalanine) when it comes to a label like autism (see here), I'm also of the opinion that what goes on in our deepest, darkest recesses might also be a place to look when it comes to this research. Those trillions of wee beasties that call our gut home - the gut microbiota - may seemingly have quite an effect on some of the processes involved in something like tryptophan metabolism (see here) an onwards the (bio)chemistry of how the kynurenine pathway might tie into at least some autism. Investigation of the mechanism pertinent to such processes and whether 'changing' the gut microbiota environment might impact on them, seem to be important areas of further work. Oh and speaking of tryptophan metabolites, I'll be coming to the findings reported by Dieme and colleagues [4] quite soon...

Music: Oliver Cheatham - Get Down Saturday Night (although I was slightly underwhelmed by the film Ex Machina).

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[1] Lim CK. et al. Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. Autism Res. 2015 Oct 24.

[2] Heyes MP. et al. Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochemical Journal. 1996;320(Pt 2):595-597.

[3] Zimmerman AW. et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol. 2005 Sep;33(3):195-201.

[4] Dieme B. et al. Metabolomics study of urine in autism spectrum disorders using a multiplatform analytical methodology. J Proteome Res. 2015 Nov 5.

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Lim CK, Essa MM, de Paula Martins R, Lovejoy DB, Bilgin AA, Waly MI, Al-Farsi YM, Al-Sharbati M, Al-Shaffae MA, & Guillemin GJ (2015). Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. Autism research : official journal of the International Society for Autism Research PMID: 26497015

Immunosuppression as a therapeutic pathway of clozapine?

"Our data suggest that the superior therapeutic effect of clozapine may be a result of its presently shown immunosuppressive action."

So said the findings reported by Markus Larsson and colleagues [1] (open-access available here) who set about investigating "the effects of chronic treatment with antipsychotic drugs on brain levels of cytokines and KYNA [kynurenic acid]" in a rat model. The rationale for the study came in part from the idea that schizophrenia (or least some schizophrenia) may show more than a passing connection to a state of inflammation (see here) as well as a link to the kynurenine pathway (see here). Whether or not antipsychotic medication might show some 'effect' on these processes is still a little up in the air.

Then: "Rats were treated daily by intraperitoneally administered haloperidol (1.5 mg/kg, n = 6), olanzapine (2 mg/kg, n = 6), and clozapine (20 mg/kg, n = 6) or saline (n = 6) for 30 days." Kynurenic acid (KYNA) in brain tissue and levels of various cytokines (chemical messengers of the immune system) in cerebrospinal fluid (CSF) were assayed for among the various groups in comparison to a control group of animals receiving saline.

"Clozapine, but not haloperidol or olanzapine-treated rats displayed significantly lower cerebrospinal fluid (CSF) levels of interleukin-8 compared to controls." This is an interesting finding that needs to be treated with some caution given that aside from IL-8 all other cytokines were reported as being below the limits of detection of the analytical methods employed. Interleukin-8 (IL-8) is normally considered to be a pro-inflammatory cytokine specifically associated with acute inflammation [2]. With schizophrenia in mind, IL-8 has been tied into the whole maternal immune activation (MIA) theory of schizophrenia as per data such as those reported by Alan Brown and colleagues [3]. Brown et al reported on: "a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring." More directly, IL-8 levels in relation to 'some' schizophrenia [4] have been reported in the research literature.

That rats treated with clozapine showed a lower level of IL-8 than following use of the other antipsychotics has been translated by the authors as possible evidence that clozapine may have an immunosuppressive action. Granted we don't have 'before and after' data in the Larsson study so we have to be a little careful about generalisation but I do find this to be a tantalising prospect. Whilst it might not be new news to some readers that clozapine might be doing quite a bit more than we expected when it comes to its use in a condition like schizophrenia, the idea that immune function might be 'affected' by administration [5] is a new one for me. A quick survey of some of the other literature on the immuno-modulatory aspects to clozapine indeed reveals that there is something to see here. Chen and colleagues [6] for example, talked about the anti-inflammatory possibilities attached to something like clozapine.

Within the various discussions about how several psychiatric labels might have an important 'inflammatory' component behind them (see here) it's not outside of the realms of possibility that the other pharmacological actions of the drug might also be complemented by such immunological alterations too. This might be a bit of a double-edged sword insofar as working out a more targeted 'use' for the drug whilst at the same time realising how complex the immune system truly is and why we should be cautious about tinkering too much with it.

Music: Passenger - I'll Be Your Man.

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[1] Larsson MK. et al. Chronic Antipsychotic Treatment in the Rat - Effects on Brain Interleukin-8 and Kynurenic Acid. Int J Tryptophan Res. 2015 Sep 20;8:49-52.

[2] Harada A. et al. Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol. 1994 Nov;56(5):559-64.

[3] Brown AS. et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004 May;161(5):889-95.

[4] Zhang XY. et al. Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res. 2002 Oct 1;57(2-3):247-58.

[5] Røge R. et al. Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? Schizophr Res. 2012 Sep;140(1-3):204-13.

[6] Chen ML. et al. Regulation of macrophage immune responses by antipsychotic drugs. Immunopharmacol Immunotoxicol. 2013 Oct;35(5):573-80.

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Larsson MK, Schwieler L, Goiny M, Erhardt S, & Engberg G (2015). Chronic Antipsychotic Treatment in the Rat - Effects on Brain Interleukin-8 and Kynurenic Acid. International journal of tryptophan research : IJTR, 8, 49-52 PMID: 26448689

A rat model of early immune stimulation

It took me a few a reads of the paper by Anna Kubesova and colleagues [1] (open-access) to understand just how potentially important their findings might be to various conditions including schizophrenia and autism.

Reporting results of a study where "early immune stimulation induced by postnatal systemic administration of LPS [lipopolysaccharide]" was performed in rats, researchers examined various potential effects on "the levels of monoamines (dopamine, serotonin) and their metabolites, and the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid (GABA) in the brain" and "activation of the kynurenine pathway of tryptophan metabolism." Brain morphology, and in particular, hippocampal volume was also the topic of some investigation.

Before coming to the results, a few additional points are worthwhile mentioning. Rats were the participants of choice in this study. I say again, rats were the participants of choice. The use of the word 'postnatal' to denote how LPS - one of the artificial immune activation weapons of choice - was administered after birth was also of initial interest to me, given that prenatal immune activation (that is immune stimulation administered to pregnant mother mice/rats/monkeys and then analysis of the effects on offspring after birth conducted) has been where the majority of the research has been done in this area (see here). The authors do comment on this however: "The early postnatal period in rats corresponds approximately with the third trimester of human brain development" although the difference between injecting LPS into offspring rats vs. pregnant rats is still present. LPS was also administered via intraperitoneal injection, that is the into the peritoneum, the tissue that lines the abdominal wall.

OK, so what did they find? Well, quite a bit, for example:

• Analysis of neurotransmitters and metabolites in brain and plasma of LPS treated and control rats were carried out by "liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC–ESI-MS/MS)" based on methods reported in a previous study [2]. Curiously however, authors chose to present a HPLC trace (Figure 1) showing the separation of the analytes over and above the more superior mass spec results. I would have preferred to have seen those any day.
• The authors reported: "significantly increased levels of DOPAC [3,4-dihydroxyphenylacetic acid], HVA [homovanilic acid] and 5-HIAA [5-hydroxyindolacetic acid] and decreased levels of 5-HT [serotonin] and 3-MT [3-methoxytyramine] in each measured brain area in LPS treated animals compared with the control group."
• Further: "There were significantly increased levels of GLU [glutamate] in each measured brain area, decreased levels of GABA in the hippocampus and a decreasing trend of GABA in the prefrontal cortex in LPS treated animals compared with the control group."
• And also: "We detected significantly increased levels of TRP [tryptophan], KYN [kynurenine], 3-OH-KYN [3-hydroxykynurenine] and QUIN [quinolinic acid] in each measured brain area and plasma in LPS treated animals compared with the control group."
• Differences in brain morphology are also reported as per the finding: "early postnatal LPS administration led to a volume reduction of the hippocampus."

And with all that, again bearing in mind that this was a study of rats, the authors conclude that: "Our results suggest a pathogenetic link between early immune stimulation and neuropsychiatric disorders such and schizophrenia, mood disorders, anxiety disorders, autism, Parkinson’s disease and Alzheimer’s disease."

These are interesting results that require both replication and follow-up. Of all the findings presented as potentially being connected to early immune stimulation, I was particularly interested in those related to kynurenine and some previous work talking about a kynurenic acid hypothesis of schizophrenia (see here). Kubesova and colleagues do talk about their results not necessarily fitting in with the idea that elevated kynurenic acid (KYNA) might be linked to at least some cases of schizophrenia [3] as per the fact that they: "did not find any change of KYNA levels in the brain or plasma compared to the controls." Activation of this pathway and a link with those dastardly pro-inflammatory cytokines (see here) (which were surprisingly not measured in the current study) might however offer some important clues on how immune activation links into some of the metabolites of little 'ole tryptophan and where future work might go from there.

The findings of elevated levels of tryptophan in both plasma and brain of LPS treated animals and reduced levels of tyrosine hydroxylase positive cells in certain parts of the brain was also something which got me thinking. Tyrosine hydroxylase as one of the triad of aromatic amino acid hydroxylases (metabolising tryptophan, tyrosine and phenylalanine) is a valued user of something called tetrahydrobiopterin (BH4), a substrate which has been mentioned a few times on the blog with autism (see here), schizophrenia (see here) and more classically, phenylketonuria (PKU) (see here) in mind. Aside from the potential effect of immune activation on levels of tyrosine hydroxylase bearing in mind how this family of enzymes might not necessarily be too exclusive in what they metabolise [4], I'm wondering whether BH4 might be something else to look at in future work given it's already known-about link to immune activation [5] alongside say, levels of tryptophan hydroxylase too? Indeed, the fact also that higher levels of tryptophan were noted in LPS treated animals but lower levels of 5-HT (serotonin) in "each measured brain area" could be construed as offering further support for closer inspection of tryptophan enzyme chemistry in this immune related model.

I know animal studies such as this one have to be cautiously interpreted in terms of how well they extend to complex labels such as autism or schizophrenia, with their very wide degree of heterogeneity and important mix of comorbidities. This still doesn't stop me however from being really quite interested in where the Kubesova findings might eventually lead us. I might also link you to the paper from Luan and colleagues [6] and another area crying out for further study with maternal immune activation in mind...

Music: Nick Cave & The Bad Seeds with Red Right Hand.

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[1] Kubesolva A. et al. Biochemical, Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology. PLoS ONE. 2015; 10(1): e0115439.

[2] Najmanová V. et al. LC-ESI-MS-MS Method for Monitoring Dopamine, Serotonin and Their Metabolites in Brain Tissue. Chromatographia. 2011; 73: 143-149.

[3] Erhardt S. et al. The kynurenic acid hypothesis of schizophrenia. Physiol Behav. 2007 Sep 10;92(1-2):203-9.

[4] Roberts KM. & Fitzpatrick PF. Mechanisms of Tryptophan and Tyrosine Hydroxylase. IUBMB Life. 2013.; 65: 350–357.

[5] Neurauter G. et al. Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab. 2008 Sep;9(7):622-7.

[6] Luan R. et al. Maternal Lipopolysaccharide Exposure Promotes Immunological Functional Changes in Adult Offspring CD4+ T Cells. Am J Reprod Immunol. 2015 Jan 30.

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Kubesova A, Tejkalova H, Syslova K, Kacer P, Vondrousova J, Tyls F, Fujakova M, Palenicek T, & Horacek J (2015). Biochemical, Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology. PloS one, 10 (1) PMID: 25602957

Cytokines activating the kynurenine pathway in schizophrenia?

I'm a bit of a fan of tryptophan biochemistry on this blog. This quite remarkable aromatic amino acid and it's off-shoot metabolites, which appear to have no end of biological uses, have taken quite a bit of my blogging time down the years. Most recently was the suggestion that a metabolite slotting in between serotonin (5-HT) and melatonin might require quite a bit more investigation when it comes to at least some cases of autism (see here).

See ya later, President Fartfeathers.

The findings reported by Lilly Schwieler and colleagues [1] (open-access here) add to the scientific interest and their assertion that: "IL-6 [interleukin-6] induces the KYN [kynurenine] pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA [kynurenic acid] in patients with schizophrenia." IL-6 by the way, is a cytokine (chemical messenger of the immune system) which is normally taken to be a pro-inflammatory cytokine (see here). Kynurenine and it's metabolic relations, are yet another set of compounds derived from tryptophan. The kynurenic hypothesis of schizophrenia (see here) hints at some of the research history this compound (and metabolites) has with the condition.

The Schwieler paper is open-access but a few pointers might be in order:

• Looking at a "well-characterized cohort of olanzapine-treated patients with chronic schizophrenia" researchers set about looking at cerebrospinal fluid (CSF) levels of various cytokines compared to a small participant group of asymptomatic controls "free from current signs of psychiatric morbidity or difficulties in social adjustment at the time of sampling".
• Previously measured levels of "tryptophan metabolites of the KYN pathway" were also included in the study bundle. Researchers also looked at a possible 'interplay' between IL-6 and kynurenic acid in human astrocyte cultures. This involved stimulation of said cultures with IL-6 and measuring KYNA using triple quadrupole mass spectrometry.
• Results: "The CSF IL-6 concentration was elevated in patients with chronic schizophrenia compared with controls." No real surprises there considering what has been reported previously in this area of schizophrenia research [2] and the growing idea of inflammation and psychiatry being linked. 
• CSF levels of kynurenine and kynurenic acid were also elevated in the schizophrenia group compared to controls, but no significant differences were noted in the starting material (tryptophan) between the groups. Authors also confirmed that IL-6 did indeed significantly raise levels of kynurenic acid (KYNA) in astrocyte cultures.
• They conclude that "The increased production of KYNA in fetal human astrocytes following exposure of IL-6 shows that this cytokine is able to induce the activity of the KYN pathway." This process may also pertain to schizophrenia.

Aside from the limitations already pointed out by the authors in terms of some analytical issues and the spot sampling methodology employed, I might also point out that whilst participants with schizophrenia were all taking olanzapine (and other meds in some cases), the asymptomatic controls were "free from medication for at least 1 month". Granted olanzapine is not generally thought to directly impact on levels of IL-6 for example [3] but one can't discount that other, more indirect effects might come into play. Indeed, I'm going to be talking about olanzapine, gut bacteria and weight gain (see here) early in the New Year.

I'd like to introduce the paper by Johansson and colleagues [4] at this point, and their observations related to kynurenic acid and related metabolites in "cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals." Looking at cells specifically from participants (with all their biological heterogeneity), they similarly concluded that there was an "increase in ratio between neurotoxic 3-HK [3-hydroxykynurenine] and neuroinhibitory/neuroprotective KYNA following exposure to cytokines" in the bipolar and schizophrenia groups compared to controls. The 3-HK finding might be of even greater interest to schizophrenia given the suggestion of a link with redox modulation [5] and the idea that oxidative stress might be a factor to the condition [6].

What's more to say on this topic? Well, not much more aside from the fact that there may be a complicated relationship between immune function - immune signalling - and amino acid biochemistry which may very well impinge on presented behaviour. Such links also offer some interesting prospects for potential intervention too...

And to some music: Lower Than Atlantis - Here We Go.

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[1] Schwieler L. et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2014 Dec 2;39(6):140126.

[2] Kunz M. et al. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr. 2011 Sep;33(3):268-74.

[3] Hori H. et al. Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients. Int Clin Psychopharmacol. 2007 Jan;22(1):21-7.

[4] Johansson AS. et al. 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 Nov;47(11):1815-23.

[5] Colín-González AL. et al. The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum. Brain Res. 2014 Nov 17;1589:1-14.

[6] Flatow J. et al. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013 Sep 15;74(6):400-9.

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Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, Finn A, Bhat M, Samuelsson M, Lundberg K, Dahl ML, Sellgren C, Schuppe-Koistinen I, Svensson C, Erhardt S, & Engberg G (2014). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. Journal of psychiatry & neuroscience : JPN, 39 (6) PMID: 25455350

The kynurenic acid hypothesis of schizophrenia

I'm back to tryptophan again in this post. No matter how hard I try, I just can't seem to get away from this interesting aromatic amino acid and its seemingly far-reaching effects on many aspects of human health.

Kynurenic acid @ Wikipedia

Today I'm exploring an interesting hypothesis looking at how a metabolite of tryptophan, kynuernic acid, might hold some connection to cases of schizophrenia in the so-called kynurenic acid hypothesis of schizophrenia*.

OK, probably best to start with a few caveats. Me = not an expert on schizophrenia, is probably the biggest caveat and so apologies in advance for any errors or important omissions you might find in this post. Schizophrenia, from a conceptual point of view, probably shares some similarity with quite a few other behaviourally defined conditions like autism, insofar as being defined as a spectrum condition. This, together with the risk/effect of certain comorbidity, almost certainly implies that finding 'specifics' in terms of universal theories of causation or effect, are probably going to be difficult at best. Many roads might lead to Rome.

Schizophrenia unlike autism however, does not seem to be a developmental condition present from early infancy (despite the history linking the two conditions). This is not to say however that there may not be a strong genetic component to schizophrenia if you like 'waiting in the wings' to express itself as maturation and environment play their hands. Instead schizophrenia has been associated with different stages of symptom presentation: a prodromal period, an acute phase and a relapse phase (see here) with some marked inter-individual variation on the timing of these phases. One therefore has to be quite careful when ascribing markers or generic theories to schizophrenia based on all these factors.

Back to the kynurenic acid theory, and the finding of elevated kynurenic acid (kynurenate) in post-mortem brain samples from people with schizophrenia** represents one of the first discoveries of some possible connection. The connection between elevated levels of kynurenate in certain brain areas is matched by a suggestion of reduced glutamate receptor function. Reports of elevations of kynurenic acid in cerebrospinal fluid in cases of schizophrenia followed*** and not just once (here and here). 

Then things start to get a little more speculative as questions start being asked as to why elevated kynurenic acid is there in the first place. The enzymes (and their cofactors) along the pathway to the formation of kynurenic acid have come under scrutiny as for example, per this preliminary report from Holtze and colleagues**** (full-text) on SNPs in the kynurenine 3-monooxygenase (KMO) enzyme. That and reduced levels of mRNA and lower enzyme activity have been found*****. Another enzyme suggested to show some involvement in this tangled hypothesis is that of indoleamine 2,3-dioxygenase (IDO). The suggestion is that the immune system may be able to affect the functioning of IDO in cases of schizophrenia (here) and hence increase production of kynurenic acid with some interesting knock-on effects based on the antagonistic effects on things like N-methyl-D-aspartate (NMDA) and its receptor.

Fair enough. But are the findings actually related to schizophrenia or purely epiphenomenal? There have been a few clues suggesting specific effects from elevated kynurenic acid as per this paper****** on various cognitive functions related to schizophrenia. Indeed extrapolating from rodent studies seems to have been quite a popular thing to do with kynurenic acid in mind as per other papers (here, here and here). There are some interesting themes to this work focused on things like the timing of kynurenic acid exposure; so, adolescence seems to be quite a sensitive period. I assume this makes such work all the more 'attractive' given the timing of symptom onset (see here) in many cases of schizophrenia.

On balance, the collected evidence does seem to be at least pointing the way to kynurenic acid elevations as being related to cases of schizophrenia. But it doesn't just stop there. I've already mentioned a possible role for immune function in accounting for kynurenic acid levels in schizophrenia. Various infectious agents have been suggested to show some 'connection' to activation of the kynurenine pathway including influenza A (here) and an old friend, Toxoplasma gondii (here). Of course one has to be quite careful not to put all your inflammatory eggs in one basket when it comes to immune function and inflammation.

Accepting all this collected data, the question then turns to what can be done about kynurenic acid and any excessive production and what implications that might have for the presentation of schizophrenia. I think I've probably said it before but I will repeat myself: when we talk about medication to treat/manage this condition or that condition or any condition, interventions don't just generally affect one system and one system alone, they most likely with affect lots of different systems and exert quite a few effects. Antipsychotics for example, have been suggested to be quite good antiparasitics also (see here) bearing in mind the T.gondii link suggested with cases of schizophrenia. So it is with kynurenic acid in mind, as Myint and colleagues******* demonstrated in their study looking at the effects of antipsychotics on the kynurenine pathway among other things.

Perhaps even more surprising is the suggestion that medications which target some of the processes involved with inflammation such as the COX-2 inhibitors might also show some potential with kynurenic acid and schizophrenia in mind (here) together with a growing evidence base on the use of non-steroidal anti-inflammtory drugs (NSAIDs) for cases of schizophrenia (here). At this point I will stress that I am not providing or intending to provide medical advice nor endorsement about these strategies.

I've focused on schizophrenia and kynurenic acid in this post but recognise that this might not be an exclusive relationship bearing in mind all the issues previously cited on diagnosis and symptom presentation. Indeed I was particularly drawn to this paper******** by McFarlane and colleagues looking at the Dangermouse that is the BTBR mouse (see this post), and how hidden away in all the findings of this mouse model, issues with KMO might just have some function in cases of autism. Perhaps an area ripe for further investigation and in particular, when overlap exists in the dual presentation of autism and schizophrenia?

This post has been quite a brief overview of the potential role of kynurenic acid in cases of schizophrenia and as such I've only scratched the surface of the potential meaning of this work and tie-ups with other areas and other theories. What I hope I've demonstrated is that once again, looking at amino acid chemistry might hold some valuable clues about behaviourally-defined conditions, and in particular how the aromatic amino acids seem to be potentially big players in such conditions.

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* Erhardt S. et al. The kynurenic acid hypothesis of schizophrenia. Physiology & Behaviour. 2007; 92: 203-209.

** Schwarz R. et al. Increased cortical kynurenate content in schizophrenia. Biological Psychiatry. 2001; 50: 521-530.

*** Erhardt S. et al. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neuroscience Letters. 2001; 313: 96-98.

**** Holtze M. et al. Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. Journal of Psychiatry & Neuroscience. 2012: 37: 53-57.

***** Wonodi I. et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Archives of General Psychiatry. 2011; 68: 665-674.

****** Akagbosu CO. et al. Exposure to kynurenic acid during adolescence produces memory deficits in adulthood. Schizophrena Bulletin. December 2010.

******* Myint AM. et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain, Behavior & Immunity. 2011; 25: 1576-1581.

******** McFarlane HG. et al. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes, Brain & Behavior. 2008; 7: 152-163.

The trial of Toxoplasma gondii

Although self-directed harm and attempted suicide are probably not most people's favourite topic of conversation, it is a fact of life that they happen, and happen more regularly than many of us might think. The reasons for such behaviours are complex and to a large degree, unique to an individual's circumstances; acknowledging that external forces such as the economic downturn that we are all currently presented with, can play a role (see this post on Greece). It is indeed a sobering thought that even things like the work conditions of a father can conceivably impact on offspring risk of attempted and completed suicide* (full-text); such is the potential effect of the environment around us.

Not being an expert on the psychology of self-harm and suicide, I can't readily provide information on the intricate details of how a person arrives at such a situation. Up until a few years ago, I just assumed that the person themselves represents the starting point, and onwards how they cope (or not) with the situations they are presented with bearing in mind the various issues/conditions which can affect mental health. The suggestion that a person might not have as much control over such behaviours or ideations as we might think, seemed a little bit far-fetched; that is until I read a little more about organisms such as Toxoplasma gondii.

Toxoplasma gondii or T.gondii is one of nature's survivors. I don't want to go through all the details of its survival tricks or what it might conceivably do because they have to some extent already been covered in previous blog posts on rats being attracted to cats and mention of the possible link with cases of schizophrenia. Suffice to say that this is a parasite who knows how to keep its head above the water.

Indeed, having previously discussed some interesting data produced by Pedersen and colleagues** in this post on risk of schizophrenia spectrum disorders and T.gondii infection, I was equally interested in the latest paper from this research group*** (full-text) looking at self-directed violence and T.gondii infection. Sensational headlines like 'Are ‘Cat Ladies’ More Likely to Attempt Suicide?' are to be put to one side for now.

I'm not the first to cover this paper. I don't really want to regurgitate all the ins and outs of the latest study by Marianne Pedersen and colleagues (see Dr Emily Deans' post for a good dissection of the study), which by all accounts seemed to mimic their previous protocol: looking at more than 45,000 women giving birth in Denmark between 1992 and 1995, measuring IgG antibody levels to T.gondii and, on this occasion, seeing how this linked (or not) to the reports of suicide, attempted suicide and self-directed violence via hospital and death registers. Suffice to say that was a mammoth project both in terms of numbers and the work gone into the various studies.

There are several interesting parts to this study and its results which I do however want to mention. From a methodological point of view, the study highlights a potential 'predictive value' from IgG antibody levels to T.gondii and risk of self-directed violence and attempted suicide. Based on their statistics, the link between IgG antibodies and actual suicide showed the strongest relationship with a relative risk of 2.05 (95% CI, 0.78-5.20). Bear in mind however that out of the total 45,000+ women studied, only 18 women committed suicide, and 8 of them were seropositive for antibodies, so less than half.

The authors discuss the possible mechanism to account for the association found. I was interested in a couple of the ideas outlined:

• Once again those letters and that number, IL-6, crop up as possibly being related to the findings. I wasn't aware that apparently there may be a relationship between IL-6 levels and suicide attempts**** and hence how inflammatory cytokines may show some critical relationship to the presence of T.gondii. I suppose it is what the immune system is designed to do.
• Keeping with the inflammation theme, some discussion on a role for the enzyme indoleamine 2,3-dioxygenase (IDO) is also provided, taking us back to another previous dinner party guest, tryptophan. It doesn't stop at tryptophan however as kynurenic acid moves into the fray and its link to glutamatergic neurotransmission. I have a post scheduled fairly soon looking at the kynurenic acid hypothesis of schizophrenia***** just to give you a flavour of where this line of thought might lead.

This is an interesting area of work which although requiring a lot more investigation adds another layer to the idea that we might think we are in control of our destiny but perhaps not as much as we would like to be even outside of the various social nudging. As per my previous discussions on T.gondii there is also the issue of what we might be able to do if infection is picked up early enough, and importantly whether such intervention might actually in this case save lives. Again I link to this study by Goodwin and colleagues****** and their suggestion, to quote: "some agents used to treat schizophrenia have the ability to inhibit T. gondii proliferation in cell culture". Makes me wonder how many other medications and other products******* might have similar effects?

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* Aleck O. et al. The impact of fathers' physical and psychosocial work conditions on attempted and completed suicide among their children. BMC Public Health. 2006; 6: 77.

** Pedersen MG. et al. Toxoplasma infection and later development of schizophrenia in mothers. The American Journal of Psychiatry. 2011; 168: 814-821.

*** Pedersen MG, Mortensen PB, Norgaard-Pedersen B, & Postolache TT (2012). Toxoplasma gondii Infection and Self-directed Violence in Mothers. Archives of General Psychiatry, 1-8 PMID: 22752117

**** Lindqvist D. et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biological Psychiatry. 2009; 66: 287-292.

***** Erhardt S. et al. The kynurenic acid hypothesis of schizophrenia. Physiology & Behaviour. 2007; 92: 203-209.

****** Goodwin DG. et al. Evaluation of five antischizophrenic agents against Toxoplasma gondii in human cell cultures. The Journal of Parisitology. 2011; 97: 148-151.

******* Kavitha N. et al. In vitro Anti-Toxoplasma gondii activity of root extract/fractions of Eurycoma longifolia Jack. BMC Complementary & Alternative Medicine. 2012; 12: 91.