Monday, March 11, 2013

Folate and Negative Symptoms in Schizophrenia

The psychiatric symptoms of schizophrenia are defined in two major categories, "positive" and "negative." So-called positve symptoms are called so because they are an addition that people without psychosis don't experience, such as hallucinations and delusions and disorganized behavior. The negative symptoms represent functions being taken away from the brain and can be apathy, social withdrawal, and loss of motivation and emotional expressiveness.

Earlier today, a paper (free full text) was released from JAMA Psychiatry detailing a multi-center trial of placebo vs 2 mg folate and 400 micrograms of B12 for folks diagnosed with schizophrenia.  All the patients (140, aged 18-68)  had residual symptoms but were stabilized on antipsychotic medications for at least 6 months and on a stable dose for at least 6 weeks.

All the patients had genetic evaluations of their folate systems and measurements of red blood cell levels of folate. Red blood cell levels of folate don't necessarily correlate with levels in the central nervous system, which is just something to keep in mind. However, in other studies, folate metabolite measurements in the central nervous system seem to flatten and be maintained at a relatively moderate level of red blood cell folate, and levels correlate more closely at lower levels of folate.

The folate cycle is complicated. Please see this article and several articles linked from that one for more detail. However, in short, folate is an important nutrient necessary to make neurotransmitters, DNA, and also to help with the activation or deactivation of DNA via a process called methylation (which is basically just adding groups of -CH3 molecules).

Folate deficiency has long been linked to schizophrenia. Certain groups of people with hereditary deficits in their folate cycle metabolism are more likely to be schizophrenic than the general population, and cohorts of babies born during famines are more likely to develop schizophrenia a few decades later.  A few of the particular genes include the C77T variant of the MTHFR gene (the young man in the case study of B12 deficiency and psychosis had this variation of this gene). MTHFR is needed to make folate from food into the kinds of folate we use in the body, and many of us have a less efficient version of this enzyme. Each copy (we have two) of the C77T version (rather than C77C, the more typical version) reduces MTHFR activity by 35%. Other missense variants in genes coding for FOLH1 (a peptide that sits on the intestinal brush border and helps dietary folate be absorbed into the body), COMT, and methionine synthase also confer a higher risk of schizophrenia. More interestingly, problems with these genes will predict a greater negative symptom burden in schizophrenia but seem to have no relationship to the positive symptoms.

Back to the current study. Folate (in rather large doses, 2mg) and B12 were used together as the B12 would facilitate the action of the folate in helping the folate cycle… cycle through. In more biochemical terms, B12 is a cofactor for methionine synthase (MTR), which remethylates homocysteine into methionine, which is then converted into the universal methyl donor S-adenosylmethionine (SAMe). 

The long and the short of it…supplementation failed to separate from placebo for the general study group. HOWEVER, among those with the (more efficient) version of the FOLH1 gene and to a lesser degree among other folate cycle genetic variants, folate and B12 supplementation did seem to significantly help negative symptoms in schizophrenia, but not the positive ones.

An important point to make is that negative symptoms are extremely difficult to treat. It is, relatively speaking, fairly straightforward to decrease positive symptoms of hallucinations and disorganized behavior with medications in most people with psychosis. Apathy, social withdrawal, and flattened emotions tend to remain and be very debilitating. (In addition, the medicine can also cause a flattened affect). Therefore finding any intervention, particularly one with presumably far fewer side effects than antipsychotic medication that might help the negative symptoms is an exciting finding.

Genetic testing in psychiatry is still in its infancy. In many cases (such as finding if someone is a rapid metabolizer of certain antidepressants) the tests have modest usefulness in the Real World where such tests are generally paid for out of pocket. But with this study we are really starting to unlock some real clinical utility, and as genetic testing becomes cheaper and more readily available, it might help us design personalized treatments. 


  1. I noticed in the study that they didn't actually supplement with folate but with folic acid. I have read that folate is often more bioavailable than folic acid. (

    Do you think that a greater effect would been seen if a different form of folate was used?

    1. I was thinking the same, folic acid is not nearly as good as folate. Chris Kresser notes that in his suggestions for women who want to get pregnant too.

    2. Yes, I've written some posts on methylfolate vs. folic acid. The literature is actually very mixed.

    3. It makes one wonder what the results would have been like using methylcobalamin instead of cobalamin and a form of folate that bypasses the MTHFR polymorphism for those patients who could not fully metabolize folic acid. At least they were able to separate the results based on MTHFR status.

  2. Hi Emily,
    Nice post, thanks.
    This is reminiscent of the studies out of the UK a few years back that showed nutrient supplementation + omega3 fatty acids reduced violent outbursts in prisoners. The notion that schizophrenia and violent behavior could be truly related to poor nutrition is highly disturbing imho. We’ve GOT to start eating better.

    1. I covered a lot of that literature in this post:

      Gesch is working on a much larger study, which should be published some time this year.

  3. The antiviral Ribavirin depletes tetrahydrobiopterin (the active form of biopterin). People using it (in combination with interferon-alpha) speak of "Riba rage".

  4. "The notion that schizophrenia and violent behavior could be truly related to poor nutrition is highly disturbing imho"

    it is not a new notion, and, to make things worse, it is also related to your *mothers* nutrition. From Ch19 of Weston Price's Nutrition and Physical Degeneration (1940);

    "...more recently Clouston has recorded a large number of observations which show conclusively that, although deformed palates occur in the normal, they are far and away more frequent in neuropaths and the mentally defective. He states that deformed palates are present in 19 per cent of the ordinary population, 33 per cent of the insane, 55 per cent of criminals, but in no less than 61 per cent of idiots. Petersen, who has made a most exhaustive study of this question, and has compiled an elaborate classification of the various anomalies found palatal deformities present in no less than 82 per cent of aments, (mental defectives), in 76 per cent of epileptics, and in 80 per cent of the insane."

    Fascinating reading about prenatal malnutrition and the consequences of such. Entirely in keeping with the observation that babies born in periods of famine are more likely to develop schizophrenia (or other mental and physical defects) decades later.

  5. Emily, I love your blog!! I have learned so much from your posts and enjoy your matter of fact approach, backed by clinical perspective/experience.

    Are there any recommendations out there on how best to test vitamin/mineral deficiencies, that may be causing and/or contributing to one’s mental ails? What type of Dr. would be best to help research/address underlying deficiencies (e.g., nutritional, gastrointestinal, metabolic, genetic, etc.)?

    I suspect I am deficient in magnesium (and possibly other micro-nutrients), as for one example, I have been able to exhibit Chvostek's sign for a long time (learning only recently of it serving as a crude indicator of mag deficiency!). In addition, I have also suffered from significant anxiety (to the level of OCD - pureO) for many years, but this did not develop until several years after already having Chvostek’s sign (among other mag-def related symptoms). I'm wondering in my situation how best to go about researching the potential connection (magnesium/micronutrient deficiencies and anxiety/OCD). And, if a positive causal connection is found, depending on the source, how best to treat it.

    I have looked at EMP+ and a newer product TrueHope is releasing called DEN (daily essential nutrients - which interestingly enough includes 500 mcg folic acid/serving, 50% as L-methylfolate calcium). I would be willing to try the micronutrient approach (along with a paleo diet), but would like to better understand where/if any deficiencies and/or connections exist before guessing at solutions.



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