Folic Acid, Vitamin B12 and Negative Symptoms of Schizophrenia

[In Brief: Folic acid and vitamin B12 help a subset of individuals with schizophrenia by decreasing negative symptoms. Side effects are no different than with placebo. Adding folate and vitamin B12 is a low risk strategy for symptoms that are very difficult to treat.]


Negative symptoms play an important role in the disability caused by schizophrenia. Symptoms in schizophrenia are divided into 4 main types: positive, negative, cognitive (impaired concentration, poor planning and problem solving, etc.) and mood. Use of the terms positive and negative has nothing to do with whether the symptoms are good or bad. Positive symptoms refers to hallucinations, delusions and disorganization. Negative symptoms are some of the most disabling, and play a larger role in impaired functioning than positive symptoms. Negative symptoms include loss of interest (apathy), loss of pleasure (anhedonia), decreased motivation (avolition), decreased emotional expression (affective flattening) and decreased speech (alogia). These are sometimes referred to as the 5 A’s.

Negative symptoms are hard to treat. When the newer antipsychotics (Risperdal, Zyprexa, Seroquel, Abilify, and others) became available in the mid-90’s and later, they were promoted as superior to older antipsychotics, in part because of a purported greater ability to decrease negative symptoms. It took quite awhile, but we now know that these second-generation antipsychotics are no better at decreasing negative symptoms than first-generation antipsychotics. It is possible that the older antipsychotics are more likely to increase negative symptoms, particularly when used in high doses.

An article published in the May, 2013 issue of JAMA Psychiatry studied the effect of adding folate and vitamin B12 on negative symptoms, taking into account the role of genetic variation in several genes involved in folate absorption and metabolism. The study was double-blind, placebo controlled and enrolled 140 patients with chronic schizophrenia. Participants were stable but still symptomatic. Doses were 2mg/day of folate and 400micrograms/day of vitamin B12.

The authors were particularly interested in studying folate because of the epidemiological, biochemical and genetic association studies that have identified folate deficiency as a risk factor for schizophrenia. Findings of prior investigations include the following:

* After famines in China and The Netherlands, rates of schizophrenia doubled, presumably as a result of dietary deficiencies.

* Low folate levels in the 3rd trimester of pregnancy are associated with more than a 2 fold increased risk in the development of schizophrenia in offspring.

* Low folate levels have been found in patients with schizophrenia.

* In patients with schizophrenia, low folate levels are associated with more severe negative symptoms, but do not correlate with positive symptoms.

* 2 small studies found that adding a folate supplement benefited patients with schizophrenia, if they had low folate levels.

* In patients with prominent negative symptoms, folate supplements were helpful in the subgroup with a specific genotype.

The author’s hypothesis was that folate and vitamin B12 supplementation would decrease negative symptoms, but only in those patients with hypofunctioning (low functioning) genes involved in the absorption and metabolism of folate. In other words, only some people would have more emotional expression, talk more, and be more motivated, and it would be those with genes that were less effective at absorbing and metabolizing folate.

I should have mentioned earlier that this is a difficult paper. I do not recommend reading the whole thing, unless you like struggling with genotypes, alleles and vague statements, while in search of limited conclusions, of uncertain value.

That being said, the study found (as predicted) that folate and vitamin B12 supplementation did help negative symptoms, but only “modestly”, and only in a subset of patients. Other symptoms of schizophrenia did not benefit. There was no difference in side effects between those taking the vitamins and those taking placebo. When genotype was taken into account, there was a 27% difference in negative symptoms between those receiving folate and B12 and those receiving placebo. Is there any practical significance of this finding?                                                                                                                                                                                                                       

In the authors words:  “Even small effects of folate and vitamin B12 supplementation could be clinically meaningful, though, given the disability associated with negative symptoms, the lack of available treatments,35 and the minimal apparent adverse effects of vitamin supplementation.”

In my slightly optimistic interpretation: negative symptoms interfere with the ability to function, they are hard to treat, these doses of vitamins are safe, and even a small improvement in negative symptoms might mean a lot to the individual and their family. There is little to lose and possibly something small but important to gain.                                                                                                                        I could not find anything in the article that would allow one to estimate the proportion of patients likely to benefit from supplementation.


For those looking for a punishing read, the full article can be found in the May, 2013 issue of JAMA Psychiatry.





Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia


Joshua L. Roffman, MD, MMSc; J. Steven Lamberti, MD; Eric Achtyes, MD, MS; Eric A. Macklin, PhD; Gail C. Galendez, BS; Lisa H. Raeke, MA; Noah J. Silverstein, BA; Jordan W. Smoller, MD, ScD; Michele Hill, MD; Donald C. Goff, MD


JAMA Psychiatry. 2013;70(5):481-489. doi:10.1001/jamapsychiatry.2013.9


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