Ramaekers VT et al. Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Mol Genet Metab. 2014 Dec;113(4):307-14.
This study suggests an exciting avenue for treatment and scientific inquiry in schizophrenia.
Previous reports have associated schizophrenia with perturbed folate metabolism, and cerebral folate deficiency due to serum antibodies against folate receptor alpha (which transfers methyltetrahydrofolate to the brain at the choroid plexus) has been reported in a patient with catatonic schizophrenia whose auditory hallucinations disappeared with folinic acid treatment. In this study, Ramaekers et al. first identified a 17-year-old girl diagnosed with refractory paranoid schizophrenia and multiple suicide attempts who was found to have low CSF MTHF levels associated with blocking antibodies against folate receptor alpha (FRa); folinic acid treatment resulted in a full recovery. They then recruited seventeen more patients with refractory schizophrenia, and screened them for blocking FRa antibodies and for evidence of cerebral folate deficiency. Surprisingly, they found that that 15/18 patients (83.3%) had positive FRa antibody titres, as opposed to 3.3% of controls, though levels fluctuated dramatically. Seven of these patients consented to a trial of folinic acid treatment and showed significant clinical improvement. The study also found a positive linear correlation between CSF MTHF and biopterin levels.
Further study is, of course, needed to confirm that cerebral folate deficiency due to FRa antibodies is a significant contributing factor to schizophrenia. In the current study, the number of patients was very small, and the trial of treatment with folinic acid was uncontrolled and non-blinded. Also, the inclusion of the initial patient, whose dramatic response prompted the study, into the study data, may have introduced a bias. Nevertheless, even if larger studies show the findings not to be easily generalisable, the fact that some patients do respond dramatically to treatment suggests that it may be worthwhile to screen for FRa antibodies and/or folinic acid responsiveness in patients with refractory schizophrenia.
This article makes for very enjoyable reading, as it includes a clear and concise review of the more recent NMDA glutamate receptor hypofunction hypothesis of schizophrenia, as well as of cerebral folate metabolism. The authors also propose an elegant hypothesis to connect the alternating positive and negative symptoms of schizophrenia with fluctuating titres of FRa antibodies.