Folate receptor autoantibodies and (some) schizophrenia

I am the league's director, Silas Ramsbottom.

Upon reading the paper published by Ramaekers and colleagues [1] talking about the use of folinic acid in cases of schizophrenia as a function of the presence of "Auto-antibodies against folate receptor alpha (FRα)", I raised a little smile. Not only because the authors suggested that there may be quite a lot more to see in this area on top of some already interesting discussions about the folate cycle and schizophrenia, but also because of the 'overlap' with some autism findings which have been previously discussed on this blog (see here). Indeed, if readers would like quite a nice summary of this area of investigation - folate receptor autoantibodies - I'm minded to direct them to the paper by Richard Frye and colleagues [2] (open-access) which initially presented the idea of cerebral folate receptor autoantibodies occurring in autism to the world and was the source material for that previous blog post.

Quoting from the Ramaekers study text: "Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls". This was a study of those described as having "schizophrenia unresponsive to conventional treatment" and alongside the presence of those autoantibodies, researchers also assessed what some of the metabolic knock-on effects might have been in terms of analysis of spinal fluid levels of "MTHF [5,10-Methylenetetrahydrofolate] and the metabolites of pterins, dopamine and serotonin". It appears that FR autoantibodies may indeed affect levels of said compounds alongside "intermediates linked to metabolic processes affecting homocysteine levels... [and] synthesis of tetrahydrobiopterin". Homocysteine and tetrahydrobiopterin (BH4) in schizophrenia y'say?

"Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement." Without wishing to provide any medical or clinical advice on the utility of folinic acid for schizophrenia or anything else, these are interesting findings. This is not the first time that folinic acid has been discussed in the research literature with schizophrenia in mind as per the case report by Wang and colleagues [3]. In that single case, authors described the presence of the MTHFR mutation - "665C>T homozygous mutations in the MTHFR gene" - as the reason for secondary cerebral folate deficiency. Other authors have discussed more pertinent cases [4]. Obviously one would like to see more formal clinical trials on the use of folinic acid as potentially being appropriate for at least some of the [plural] schizophrenias. The important thing to take from the Ramaekers and other studies is that a panel of tests might be able to spot who might be best responders to this kind of intervention...

Music to close, and Peter Griffin sings the opening tune to Indiana Jones and The Last Crusade? Why not.

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[1] Ramaekers VT. et al. Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Mol Genet Metab. 2014 Oct 12. pii: S1096-7192(14)00311-4.

[2] Frye RE. et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry 2013;18(3):369-381. doi:10.1038/mp.2011.175.

[3] Wang Q. et al. Methylenetetrahydrofolate reductase deficiency-induced schizophrenia in a school-age boy. Zhongguo Dang Dai Er Ke Za Zhi. 2014 Jan;16(1):62-6.

[4] Ho A. et al. Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report. J Child Neurol. 2010 Jul;25(7):898-900.

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Ramaekers VT, Thöny B, Sequeira JM, Ansseau M, Philippe P, Boemer F, Bours V, & Quadros EV (2014). Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Molecular genetics and metabolism PMID: 25456743