For Bibliography and Research Abstracts regarding Folate or Methylfolate and Schizophrenia

Many individuals with schizophrenia have deficits in metabolism related to methylation, a metabolic process involving carbon donation.   This issues stem from multiple interrelated risk factors involving Cobalamine (B12), Folic Acid (Folate) and Pyridoxine (B6) and the enzymes that interact with these vitamins.

Specifically, low folate levels, high homocysteine levels, and poor folate activation genetics are common in schizophrenia, and these issues appear to confer significant increased risk for development and maintenance of the disorder.  While these deficits occur for a variety of reasons, research has shown that supplementation can correct some aspects of this problem and directly improve symptoms in many individuals.

 It is entirely possible that serious metabolic risk factors in schizophrenia can be reduced by high strength Methylfolate supplementation.

Methylfolate, also known as 5-MTHF or 5-Methylthetrahydrofolate, is the active form of folic acid.  It is specifically recommended because poorly performing genes (alleles) for the enzyme that activates folate have been shown to be common in schizophrenia (e.g., the C677T allele).  Providing inactive folate is not necessarily helpful in this situation.

As with many nutritional supplements, the length of time required to see positive changes with methylfolate (i.e., 2-6 months) is likely to be longer than with medications (i.e., 2-6 weeks).  It is also possible that high doses, as used in some studies (15 mg/day), are necessary to see benefits.

Methylation – an essential metabolic process

Methylation or Methyl Donation refers to common and essential metabolic processes where a single carbon is passed from vitamin cofactors to DNA, fats, proteins, or to molecules being built or destroyed.

Methylation Resistance refers to situations where carbon donation through vitamin assisted enzyme pathways is impaired.

Methylation capacity is renewed through the Methylation Cycle (Figure 1 – right) which, in turn, relies upon the Folate Cycle (Figure 1 – left).  Figure 1 below shows the critical steps in these cycles and their interreliance.

Figure 1: from Bradley and Loscalzo 2009

As medical research has determined the intricacies of our complicated metabolism methylation resistance has been repeatedly implicated as a factor in many diseases, including schizophrenia.

General Risk Factors

Folate and B12 are the two essential vitamins involved specifically in methylation, though many nutritional supplements participate in the process at one location or another.  These include:

            SAMe or S-Adenosyl Methionine

            Betaine HCl or Trimethylglycine

            Pyridoxine or B6

            Calcium, Magnesium and Zinc.

Poor methylation can occur for a number of reasons:

1)   Poor Intake – dietary shortage of vitamins and nutrients.

2)   Genetics – e.g., MTHFR gene abnormalities.

3)   Smoking – inactivates B6 and increases metabolic stress.

4)   Malabsorption – especially true with B12 which is poorly absorbed in digestive diseases and with aging as stomach acid decreases.

5)   Medications and Toxins – acid blockers, methotrexate, some anesthetics, mercury.

High Homocysteine Levels in Schizophrenia Imply Impaired Methylation

Homocysteine is a specific marker for methylation deficits that involve Folate, B12 and/or B6.  Homocysteine is a toxic metabolic step in the methylation cycle (and folate cycle) and high levels of homocysteine have been implicated in many diseases including Depression, Heart Disease, Stroke, Dementia, and Bone Loss.

High plasma homocysteine levels are also common in schizophrenia.   One case-control study reported mean plasma homocysteine levels that were almost 50% higher in schizophrenia compared to controls (16.1 versus 10.9 µmol/L; p=0.028).  Hyperhomocysteinemia with levels greater than 15 µmol/L was seen in 34.4% of subjects with schizophrenia compared to 15.2% of controls (Mabrouk et al. 2011).

Kemperman et al. (2006) reported that 28% of subjects were in the highest 97.5th percentile for homocysteine levels compared with only 2% of controls (p<0.001).  Feng et al. (2009) reported homocysteine levels in subjects with schizophrenia at almost double that of controls.

Table 1:  Feng et al. 2009

But while homocysteine is directly toxic to many tissues, it also acts as a quantitative marker signifying impairment in myriad essential biochemical processes related to methylation.

High homocysteine levels imply that myriad complex metabolic processes essential to physical and mental health are impaired

One example is Glutathione, an endogenous antioxidant that is often dangerously low in schizophrenia.  In building glutathione homocysteine is first converted to cysteine, the sulfur containing amino acid that acts as its limiting reagent.  Impairment in the complex methylation cycles illustrated in Figure 1 below (from Bradley and Lascalzo 2009) can help explain why glutathione levels are often so low in schizophrenia.  Regardless of whether this is due to genetic abnormalities (e.g., clutamate-cysteine ligase enzyme) or low levels of folate, B6 or B12, intervention is warranted.

For more information on Glutathione please see the section on N-Acetyl Cysteine on this website.

 Low Folate Levels in Schizophrenia

Two problems related to folate have been clearly identified in schizophrenia.  The first issue is clear.  Low plasma folate levels are quite common in this disorder.

One small double-blind study found that 37% of inpatients admitted for schizophrenia had folate levels below 200 µg/l (Godfrey et al. 1990).  A case-control study found high homocysteine levels in schizophrenia in conjunction with folate levels that were half that of controls (8.2 versus 4.2 µmol/L; p<0.001) (Mabrouk et al. 2011).

And these low folate levels appear to matter regarding symptom severity.  Goff et al. (2004) reported plasma folate levels in schizophrenia that are reduced by 43% compared to controls, and they correlated these lower levels to negative symptoms severity as measured by the Schedule for Assessment of Negative Symptoms (SANS) (r=–0.31, N=91, p<0.01).  In other words, there is a correlation between low folate levels and a worsening negative symptoms.

In a side note, Goff et al. (2004) also found a negative correlation between low levels of Glycine and SANS scores (r=–0.29, N=91, p<0.001).  For further discussion of the connection between glycine and negative symptoms please see in the section on this website dedicated to Sarcosine.

Kale et al. (2010) reported 36% reductions in plasma folate and 53% reductions in red blood cell folate in individuals with a first episode of psychosis compared to healthy controls.  This study clearly demonstrates that low levels are not the result of antipsychotic medication use.

Table 2 – Kale et al. (2010)

Genetic Problems with Folate Activation

In addition to generally low levels of folate, genetic problems related to activating or recharging folate also appear to be common in schizophrenia.  The enzyme 5,10-Methylene Tetrahydrofolate Reductase (MTHFR) converts inactive folate to its active form, namely 5-Methyltetrahydrofolate, or MethyFolate.  Genetic abnormalities in this enzyme have been implicated in many diseases and mental health conditions, including schizophrenia.

In schizophrenia, the poorly functioning C677T variant or allele of the MTHFR gene is reported to be associated with negative symptoms (Roffman et al. 2008).  The A1298C allele is reported to be associated with schizophrenia in general (Zhang et al. 2010), and other MTHFR alleles genes have been implicated as well (Roffman et al. 2011)

In the C677T variant or allele of MTHFR, an alanine is replaced by a valine at a specific place in the protein.  This alteration reduces enzymatic efficiency so greatly that individuals with two copies of this allele (homozygous) have only 40-50% of mean enzyme activity compared to homozygous wild-type (Feng et al. 2009 quoting Rosen 1997).

In their study of 123 Han Chinese, Feng et al. (2009) reported that subjects with schizophrenia were more than twice as likely to have two copies of the C677T allele of MTHFR compared with controls (31.7% versus 14.6% in controls with p<0.001).  The presence of two copies was associated with significantly increased homocysteine levels in controls and in schizophrenia.  Particularly notable however was that this adverse effect on homocysteine was especially pronounced in schizophrenia, perhaps due to other overlapping genetic risk factors.

Figure 1 – Feng et al. 2009

Vares et al. (2009) examined the genetics of two populations – 820 Scandinavians with schizophrenia, and 243 Chinese with schizophrenia and with two or more siblings with schizophrenia spectrum disorders.  They report that homozygosity for the C677T allele was associated with earlier age of onset of schizophrenia in both populations (p=0.0015 and p=0.008 respectively).

Figure 1: Vares et al. 2009 – Time to development of schizophrenia separated by genetic status in Scandinavian subjects.

Figure 2: Vares et al. 2009 – Time to development of schizophrenia separated by genetic status in Chinese subjects.

Kempisky et al. (2006) reported that individuals with schizophrenia were 1.8 times more likely to carry at lease one copy of the C677T allele compared to controls (OR 1.796; P = 0.0020), and 2.8 times more likely to carry two copies (OR 2.758; p = 0.0071).

There is still work to be done in this area however.  One research group presents conflicting findings in two separate studies. Muntjewerff et al. (2006) report in a meta-analysis of eight retrospective case-control studies that having two copies of C677T versus having none is associated with 36% higher risk of schizophrenia.  They also report 70% increased risk for 5 µmol/l higher homocysteine levels.  A year later they found no evidence for increased rates of transmission of this allele to offspring with schizophrenia in large family studies (Muntjewerff et al. 2007).

Similarly, Yoshimi et al. (2010) reported that despite finding strong support for an association between C677T and schizophrenia in a meta-analysis of 18 studies, they failed to find an association in their own genetic survey.

Folate Trials in Schizophrenia

The studies are clear.  Individuals with schizophrenia are at risk for low plasma folate levels and these low levels are likely to impact symptom severity.  At the same time, there is also risk for carrying folate-related genetics that reduce folate activity by over 50%.  In fact, both issues can exist within the same individual because both are common.

Studies using inactive folate in schizophrenia are likely to increase chances of false negative outcomes.  The use of methyfolate is likely to be a more effective treatment approach in general.   

Unfortunately, there is only one study using MethylFolate in treatment of schizophrenia to date, and it is a small one at that.

In blinded fashion, Godfrey et al. (1990) gave 15 mg of methylfolate versus placebo for 6 months to individuals with schizophrenia and low plasma folate levels.  They reported 57% improvement on clinical rating scales with active treatment compared to essentially no change with placebo (p<0.05).  These findings are very hopeful, but this study has not been replicated in any of its critical design features.  This was a long study using methylfolate in individuals with low folate levels.

Over two decades after Godfrey at al. (1990) there has been no follow-up study using Methylfolate in treatment of schizophrenia.

Godfrey et al. 1990

Levine et al. (2006) did report positive outcomes in a crossover study comparing active treatment for three months with 2 mg of folate, 25 mg or pyridoxine (B6) and 400 µg of B-12 to placebo in individuals with schizophrenia and high plasma homocysteine (greater that 15 µmol/L).  They saw homocysteine levels decrease as expected, and also report significant decreases in PANSS Total (p=0.034) and Positive subscales (p<0.009).

Figure 1: Levine et al. 2006

Hill et al. (2011) reported no changes in negative symptom scores measured with the SANS in 42 stable adult schizophrenia outpatients who were given folate at 2 mg/day versus placebo for 3 months.  Negative results may stem from study design which:

1) only used 2 mg/day of folate,

2) used the inactive form of folate,

3) included individuals with normal folate levels, and

4) limited outcomes measures to negative symptoms only with the Schedule for Assessment of Negative Symptoms (SANS).

Hopefully future studies in this area will be careful to use active methyfolate in treatment of schizophrenia.

Schizophrenia and Folate or Methylfolate – Bibliography and Research Abstracts

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