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.