How important are B12 and Folic Acid in treating Schizophrenia?

Schizophrenia has been, for over half a century, associated with poor B12 and poor folic acid status.

B12 and Folic Acid are so important in Schizophrenia because their deficiency predispose schizophrenics to greater difficulty manufacturing neurotransmitters on demand.

These neurotransmitters are needed on demand in brain areas in control of the sensory receipt of information which gets distorted and causes hallucinations and illusions. The outcome of sensory misinformation is further complicated in schizophrenics as other brain areas controlling executive functions (thought processing, planning) are compromised and when bombarded with sensory misinformation the result is psychotic delusional bizzare thought outputs.

B12 and Folic Acid deficiency aspects are best assessed by functional lab measurements of blood homocysteine. High homocysteine levels are detrimental in schizophrenia. The biochemical pathways that get weakened with B12 and folic acid deficiency are the methylation pathways. Methyl donation is a process that allows easier neurotransmitter production on demand. Neurotransmitter production is initiated via methylation processes at the DNA promoter region of brain cells. Adequate methylation is important to all psychiatric conditions including schizophrenia, mood disorder (anxiety, depression, bipolar), behavior disorders (ADD), and neurological disesase.

Our Review on Schizophrenia and our Orthomolecular Treatment Response articles are fully referenced and go into great detail on the assessment and treatment of undermethylation syndromes.

The following abstracts on methylation compromise provide further proof on the need for adequate methylation in schizophrenia. These abstracts look at:

  • The correlation between homocysteine, B12, and folic acid lab findings in schizophrenic pathology
  • Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms in schizophrenia pathology
  • B12 and folic acid recommendations by conventional evidence-based researchers as is applicable in the treatment of schizophrenia

1) Haidemenos A, Kontis D, Gazi A, Kallai E, Allin M, Lucia B. Plasma homocysteine, folate and B12 in chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Aug 15;31(6):1289-96. Epub 2007 Jun 2. 8th Psychiatric Department, Psychiatric Hospital of Attica, 374 Kavalas ave, 12462 Athens, Greece.

Elevated plasma levels of the amino acid homocysteine have been associated with schizophrenia, particularly in young male patients. Among other factors, low folate and vitamin B12 levels have been implicated in the increase in homocysteine. In order to investigate this association, we determined plasma homocysteine, folate and B12 levels in 97 (67 males and 30 females) inpatients with chronic schizophrenia and 103 (46 males and 57 females) controls. Patients and controls did not differ in folate or B12 levels, after adjusting for age. Patients with schizophrenia had higher plasma homocysteine than controls (mean=15.42 micromol/l in cases versus 11.54 micromol/l in controls: F(1,195)=17.978; p<0.001). This difference persisted after controlling for folate and B12 concentrations. Both male and female patients had increased plasma homocysteine compared to controls [(males: mean=16.61 micromol/l in cases versus mean=13.72 in controls: F(1,110)=5.54; p=0.020) (females: mean=12.78 micromol/l in cases versus mean=9.79 micromol/l in controls: F(1,84)=13.54; p<0.001)]. When dividing our sample into two age groups (age < and > or =50 years), both young and older females and younger males with schizophrenia had increased plasma homocysteine compared to controls. We therefore suggest that homocysteinemia is a general risk factor for schizophrenia. We further suggest that it is not limited to young male patients and is not necessarily associated with low folate or B12 levels.

2)Freeman JM, Finkelstein JD, Mudd SH. Folate-responsive homocystinuria and “schizophrenia”. A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity. N Engl J Med. 1975 Mar 6;292(10):491-6.

Homocystinuria and homocystinemia without hypermthioninemia, but with reccurent episodes of folate responseive schizophrenic-like behavior, was documented in a mildly retarded adolescent girl who lacked the habitus associated with cystathionine synthase deficiency. Enzymes involved in homocysteine-methionine metabolism were demonstrated to be normal. A defect in the ability to reducte N-5-10–methylenetetrahydrofolate to 5-methyltetrahydrofolate was demonstrated.Methylenetetrahydrofolate reductase was 18 per cent of control values. Methyltetrahydrofolate is used for the methylation of homocysteine to methionine, and a deficiency of this compound could explain the homocystinemia and homocystinuria.

3) Regland B, Johansson BV, Gottfries CG. Homocysteinemia and schizophrenia as a case of methylation deficiency. J Neural Transm Gen Sect. 1994;98(2):143-52. Department of Clinical Neuroscience, Mölndal Hospital, University of Göteborg, Sweden.

A 27-year-old woman is described whose disorder meets the DSM-III-R criteria for a diagnosis of schizophrenia and who was found to have a significantly increased serum level of homocysteine. Repeatedly, she improved on frequent cobalamin injections and deteriorated in periods without treatment. The effects of prolonged weekly treatment appeared to diminish as time went on, suggesting that the abnormality was not wholly cobalamin-dependent. It was found that methylenetetrahydrofolate reductase (MR) activity in cultured skin fibroblasts was reduced to a magnitude that is found among people with heterozygous deficiency. A defect in MR activity indicates a deficiency in methyltetrahydrofolate (MTHF), with a consequent reduction of the remethylation of homocysteine to methionine. Thus, reduced methylation may explain the increased levels of homocysteine and the transient effects of cobalamin treatment in the patient. Theoretically, MTHF should be the optimal treatment for her. The case reported highlights the importance of assessing the serum homocysteine level in order to detect methylation deficiency in patients with schizophrenia.

4) Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review.Am J Epidemiol. 2007 Jan 1;165(1):1-13. Department of Health Sciences, Alcuin College, University of York, York, United Kingdom.

The authors performed a meta-analysis of studies examining the association between polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, including MTHFR C677T and A1298C, and common psychiatric disorders, including unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia. The primary comparison was between homozygote variants and the wild type for MTHFR C677T and A1298C. For unipolar depression and the MTHFR C677T polymorphism, the fixed-effects odds ratio for homozygote variants (TT) versus the wild type (CC) was 1.36 (95% confidence interval (CI): 1.11, 1.67), with no residual between-study heterogeneity (I(2) = 0%)–based on 1,280 cases and 10,429 controls. For schizophrenia and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.44 (95% CI: 1.21, 1.70), with low heterogeneity (I(2) = 42%)–based on 2,762 cases and 3,363 controls. For bipolar disorder and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.82 (95% CI: 1.22, 2.70), with low heterogeneity (I(2) = 42%)-based on 550 cases and 1,098 controls. These results were robust to various sensitively analyses. This meta-analysis demonstrates an association between the MTHFR C677T variant and depression, schizophrenia, and bipolar disorder, raising the possibility of the use of folate in treatment and prevention.