Psychopharmacology
https://doi.org/10.1007/s00213-018-5095-1
LETTER TO THE EDITOR
Folic acid and its congeners in the treatment of schizophrenia
Jacob Peedicayil 1
Received: 20 September 2018 / Accepted: 25 October 2018
# Springer-Verlag GmbH Germany, part of Springer Nature 2018
I read with interest the article by Sakuma et al. (2018) in which
they reviewed and analyzed data on the use of folic acid and
its congeners methylfolate and folinic acid for the treatment of
psychopathology in patients with schizophrenia. The authors
included 10 randomized controlled trials (RCTs), 7 using folic
acid, 2 using methylfolate, and 1 using folinic acid in a sys-
tematic review, and 7 RCTs in a meta-analysis. The authors
found that pooled folic acid (all three congeners, namely, folic
acid, methylfolate, and folinic acid) + antipsychotic treatment
is not superior to placebo + antipsychotic treatment in the
improvement of total, positive, general, or depressive symp-
toms of schizophrenia. However, pooled folic acid + antipsy-
chotic treatment was more effective than placebo + antipsy-
chotic treatment for the treatment of negative symptoms of
schizophrenia. The authors concluded that pooled folic acid
+ antipsychotic treatment improves negative symptoms in pa-
tients with schizophrenia, and is well tolerated by patients.
I would like to discuss some aspects of the differences be-
tween folic acid, folinic acid, and methylfolate in the treatment
of patients with schizophrenia. Folic acid is the synthetic form of
the vitamin folate (vitamin B9) (Stahl 2008). In the body, after
ingestion, folic acid and folate are converted to tetrahydrofolic
acid (THF) (Kaushansky and Kipps 2018). Folinic acid is the 5-
formyl derivative of THF (Kaushansky and Kipps 2018). THF
is metabolized to methylenetetrahydrofolic acid (MTHF).
MTHF can be reduced to methylfolate (Anderson et al. 2012),
which is the fully active form among the congeners, and which
readily enters the brain (Stahl 2008; Roffman et al. 2018). The
reduction of MTHF to methylfolate is catalyzed by methylene-
tetrahydrofolate reductase (MTHFR) (Peedicayil 2012). The
gene encoding MTHFR is known to have polymorphisms in
the general population, resulting in variations in the activity of
MTHFR between individuals (Mathews 2002). This can lead to
* Jacob Peedicayil
jpeedi@cmcvellore.ac.in
1
Department of Pharmacology and Clinical Pharmacology, Christian
Medical College, Vellore, India
reduced levels of methylfolate in the body. Indeed, meta-
analyses of studies have found that polymorphisms in this gene
are associated with schizophrenia (Muntjewerff et al. 2006;
Yadav et al. 2016). Hence, methylfolate, rather than folic acid
or folinic acid, is the preferred congener for the treatment of
psychiatric disorders like schizophrenia (Peedicayil 2012).
Sakuma et al. (2018) did not discuss these aspects of folic acid
and its congeners in their article. It is interesting that in the list of
RCTs investigated by Sakuma et al. (2018), two trials (Godfrey
et al. 1990; Roffman et al. 2018) used methylfolate, rather than
folic acid or folinic acid for the treatment of schizophrenia. In
both these trials, there was overall improvement of symptoms of
schizophrenia, and not just the negative symptoms.
The main commercially available preparations of these
congeners are folic acid and methylfolate, in tablet form or
as an aqueous solution for injection, and in combination with
other vitamins and minerals (Kaushansky and Kipps 2018). In
the light of the above data, I suggest that future studies inves-
tigating the use of folic acid or its congeners for treating
schizophrenia should use methylfolate, rather than folic acid
or folinic acid, since methylfolate is the most effective conge-
ner for treating this disorder.
Compliance with ethical standards
Conflicts of interest The author declares that there is no conflict of
interest.
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