Phenylalanine and schizophrenia: new directions for intervention?

As regular readers might already have noticed, amino acids are a bit of a obsession of mine on this blog. Out of all of them - and there are quite a few - I'm particularly interested in the aromatic amino acids and the their various connections to health and wellbeing. I've talked at length about some of the proposed connections made between amino acids such as tryptophan, tyrosine and phenylalanine to all manner of conditions but specifically with the autism spectrum in mind (see here).

The conversion. Matthews (2007) J Nutr. 137: 15495-15555.

Phenylalanine (or Phe) has been a particular favourite on this blog, not least because of its connection to that most classical 'diet can affect mental health' condition known as Phenylketonuria (PKU). As per other research chatter however, the connection between phenylalanine and PKU might just be the tip of the iceberg (see here). Indeed, today that iceberg just got a little bigger as I discuss the paper by Olaoluwa Okusaga and colleagues* (open-access) and their observations of elevated blood levels of phenylalanine in cases of schizophrenia. Such findings might indeed have some important management consequences as you'll see shortly when it comes to the use of something called BH4.

The Okusaga paper is open-access but a few of the important details:

• Well, one can't say that this was an under-powered study from a participant number point of view, as blood samples from 950 adult participants with a confirmed diagnosis of schizophrenia via the SCID were compared with 1000 asymptomatic controls for levels of phenylalanine and tyrosine.
• Analysis of samples was via HPLC with fluorescence detection, which whilst OK as a separative-detection method is not exactly the gold-standard that is mass spectrometry (MS) or nuclear magnetic resonance (NMR). 
• From the measures of phenylalanine and tyrosine, an estimate of the activity of phenylalanine hydroxylase (PAH) was also calculated and expressed as a phenylalanine: tyrosine ratio**. PAH represents an important step in the conversion of phenylalanine to tyrosine, which then proceeds down a metabolic pathway to eventually end up as dopamine. It's worth pointing out that dopamine has some important research history when it comes to the presentation of schizophrenia or at least, that's the suggestion (see here).
• Results: well bearing in mind some issues with the matching of the two sample groups in terms of age and BMI (a higher BMI in the schizophrenia group bearing in mind that these were not medication-naive participants), the schizophrenia group "had significantly higher Phe (geometric mean difference 1.26 µmol/L; CI 1.18 to 1.36, p<0.0001) and Phe:Tyr ratio (geometric mean difference 1.41; CI 1.33 to 1.48, p<0.0001) compared to healthy controls and this finding persisted after controlling for gender, age, education, and BMI differences between the 2 groups". As a group however, there was no significant differences for the schizophrenia and control groups when it came to measures of tyrosine although "lower levels of Tyr are more common among schizophrenia patients".
• The authors conclude that alongside further, more controlled study with regards to sample collection (including looking at measures of inflammation), there may also be some merit in looking at the potential effects of "Phe-lowering interventions in schizophrenia".

As I mentioned before, Phe-lowering interventions very much includes the use of BH4, but could also mean the rather more invasive use of a low phenylalanine diet (and then tyrosine supplements?) more commonly indicated for cases of PKU. I should point out that this does not mean I am in any way endorsing such a dietary change or pharmacological action at this time as a function of my caveat on this blog about not giving medical or clinical advice. That being said, the research gauntlet has been thrown down by the results of the Okusaga study so I'll be keeping my eyes open for future work in this area. 

There is other evidence suggestive of issues with the availability of BH4 in cases of schizophrenia as per the results from Richardson and colleagues*** which also extended to related schizoaffective disorder too****. Given that BH4 provides an important support service to a variety of enzymes relevant to the metabolism of aromatic amino acids (think tryptophan hydroxylase, TPH, for example), lower levels are probably not all that desirable. This might be particularly important to ensuring phenylalanine does not build up to too higher levels and the effects that can have*****.

Aside from the phenylalanine-lowering interventions call made from the Okusaga study, a few other questions are floating round my mind. So, at what point do phenylalanine levels become elevated in some cases of schizophrenia? I'd assume that as per the quite comprehensive use of the Guthrie test these days, we aren't talking about participants reaching the cut-off points for PKU in early infancy, so when does this issue present itself in cases of schizophrenia and why? I'm also interested in the cognitive effects of [chronic] elevated phenylalanine levels and how this might also map onto similar elevations noted in cases of schizophrenia too. Noting the increasing interest in cognition and schizophrenia (see this paper****** for example) and the growing  importance of cognitive impairment to cases, could the elevated phenylalanine results merely reflect this one facet of schizophrenia?

So you can see that there is a lot more to do in this area. Given also that schizophrenia, like autism, is probably better represented on a spectrum model, the question is also whether hyperphenylalaninemia in relation to cases of schizophrenia might represent one particular part of that schizophrenia spectrum? At least one other study suggests possibly******* (open-access) with quite a novel alternative method for detecting phenylalanine used. A lot more to do in this area methinks.

Music to close. Driftwood by Travis.

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* Okusaga O. et al. Elevated Levels of Plasma Phenylalanine in Schizophrenia: A Guanosine Triphosphate Cyclohydrolase-1 Metabolic Pathway Abnormality? PLoS ONE 2014. 9(1): e85945.

** Matthews DE. An Overview of Phenylalanine and Tyrosine Kinetics in Humans. J. Nutr. 2007; 137: 15495-15555.

*** Richardson MA. et al. Evidence for a tetrahydrobiopterin deficit in schizophrenia. Neuropsychobiology. 2005;52(4):190-201.

**** Richardson MA. et al. Analysis of plasma biopterin levels in psychiatric disorders suggests a common BH4 deficit in schizophrenia and schizoaffective disorder. Neurochem Res. 2007 Jan;32(1):107-13.

***** Pascucci T. et al. Behavioral and neurochemical characterization of new mouse model of hyperphenylalaninemia. PLoS One. 2013 Dec 20;8(12):e84697.

****** Keefe RS. & Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012;(213):11-37.

******* Teraishi T. et al. 13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients. Translational Psychiatry 2012; 2: e119.

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Olaoluwa Okusaga, Olesja Muravitskaja, Dietmar Fuchs, Ayesha Ashraf, Sarah Hinman, Ina Giegling, Annette M. Hartmann, Bettina Konte, Marion Friedl, Jason Schiffman, Elliot Hong, Gloria Reeves, & et al (2014). Elevated Levels of Plasma Phenylalanine in Schizophrenia: A Guanosine Triphosphate Cyclohydrolase-1 Metabolic Pathway Abnormality? PLoS ONE, 9 DOI: 10.1371/journal.pone.0085945