Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies

Mol Genet Metab. 2014 Dec;113(4):307-14. doi: 10.1016/j.ymgme.2014.10.002. Epub 2014 Oct 12.


Background: Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide.

Methods: Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated.

Results: Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ(2)=21.6; p<0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean±SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement.

Conclusion: Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.

Keywords: Autoimmunity; Cerebral folate deficiency; Folate receptor; Schizophrenia; Treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies / blood*
  • Biopterin / cerebrospinal fluid
  • Child
  • Female
  • Folate Receptor 1 / immunology*
  • Folic Acid / analogs & derivatives
  • Folic Acid / blood
  • Folic Acid / cerebrospinal fluid
  • Homocysteine
  • Humans
  • Leucovorin / administration & dosage*
  • Male
  • Middle Aged
  • Schizophrenia / drug therapy*
  • Schizophrenia / immunology*
  • Young Adult


  • Autoantibodies
  • Folate Receptor 1
  • Homocysteine
  • Biopterin
  • 5,11-methenyltetrahydrohomofolate
  • Folic Acid
  • Leucovorin