Cerebral Folate Deficiency In Treatment Resistant Psychiatric Illness  Terrence Early MD 


This is an overview of some recent developments that indicate possible treatments for

many forms of treatment resistant psychiatric illness. There is a biochemical pathway called

‘the methylation cycle’ that has a role in the manufacture of neurotransmitters. Several

vitamins and metabolites implicated in depression, such as vitamins B12 and B6, folic acid,

and SAM-e are involved in this cycle. Some people have variants of the some of the

enzymes involved in this pathway, such as the MTHFR enzyme, which slow the pathway

down and cause decreased neurotransmitter production as well as an increase in an amino

acid called homocysteine. You can read about this in an online article PDF called “The

Homocysteine Hypothesis of Depression”.

The next part of the story involves the blood-brain barrier, which protects the brain from

fluctuations in intermediate products of metabolize that might alter brain function, by

blocking many substances from entry, except through a transport mechanism. There are

three main forms of folic acid – regular folate or folic acid, folinic acid, and methyfolate.

When the brain’s main mechanism for folate transport, the folate receptor alpha, is

blocked, regular folic acid or folate may not get into the brain. Folinic acid can enter if used

at a higher dose, using the low affinity folate transporter. Methylfolate can also get in if

used in a high enough dose. Usually, measuring substances in the brain involves a

procedure called a lumbar puncture, which involves sticking a needle into the spine under X-

ray fluoroscopy and measure the cerebral spinal fluid (CSF).

In 2005, Dr. V.T. Ramaeker described cerebral folate deficiency as any neuropsychiatric

disorder involving problems getting enough folate into the brain. This was initially

described in infants with severe neurological illness, but many of them responded to high

dose of folinic acid.

In 2013, Dr. Richard Frye, a child neurologist, studied 93 patients with autism and found

that 75.3% had cerebral folate deficiency. In addition to CSF studies, he found that the

patients who had cerebral folate deficiency had antibodies to the folate receptor alpha. Dr.

Frye’s results have been replicated at least a couple of times, both the finding of cerebral

folate deficiency and the response to high dose folinic acid.

This test, the folate receptor antibody test or FRAT is commercially available now through a

company called Ilead Neuroscience for $250. Contact information is Dr. Sri Ganeshan MD,

(917) 907-2404, email sganeshan@iliadneuro.com, kits can be ordered at


In 2014, Dr. Ramaeker and his colleagues measured cerebral folate and FRAT in 18 patients

patients with treatment resistant schizophrenia and found that 15 patients had cerebral

folate deficiency. 8 of these patients were treated with high dose folinic acid, and 7


In 2017, Dr. Lisa Pan published on metabolomic abnormalities in 33 patients with treatment

resistant unipolar depression. Surprisingly, 12 of these patients had cerebral folate

deficiency demonstrated by lumbar puncture, and 10/12 had some improvement with high

dose folinic acid. She did not measure FRAT results. Although there have been no attempts

to replicate her results so far, taken within the context of the other findings in autism and

schizophrenia it seems highly likely that a substantial minority of patients with treatment

resistant depression might have cerebral folate deficiency as a factor. Dr. Pan has a very

informative video on u-tube discussing her results in 50 cases of treatment resistant

depression. 19 /50 or 38% had cerebral folate deficiency, and 11/50 additional cases had

other identifiable inborn errors of metabolism, indicating that overall, 60% had a

metabolomic cause of treatment resistance. Four patients had a biopterin deficiency, and

treatment with sapropterin was helpful in some of these cases. Seven had abnormal

acylcarnitine profile. One had Fabry disease, and another had another genetic disorder.

Normally, the concentration of folic acid in the brain is 1.5 times the serum level.

According to Dr. Sri Ganeshan, the medical director of Ilead Neuroscience, the company

that makes the FRAT, the rate of false positive FRAT for the blocking antibody is 1.4%, with

2.7% false negatives. The rate of false positives for the binding antibody was 1.4% and false

negatives 0%. In normal controls not screend for neuropsychiatric disorders, the rate of

positive FRAT has been below 2% in children less than age 16, 4-7% of healthy women in

Spain, 9-13% of healthy people in Ireland, and 10-15% in US normals. There is some

tendency for the FRAT to vary over time in infantile onset cases, and repeating the FRAT at

6-9 months in selected cases may be indicated (Sri Ganeshan MD, personal communication).

One of the criticisms of the studies in normal is that most were not screened for

neuropsychiatric disease. At this point we do not know what the rate of positive FRAT is in

non-treatment resistant depression, attention deficit disorder, or most other psychiatric

disorders. In one study of children with autism in Ashkenazic Jews, (Berrocal-Zaragoze MI J

Nutr), children had a rate of positive FRAT of 60-65% but family members also had a high

rate of positive FRAT. Unaffected siblings had a rate of 75%, fathers had a rate of 69%, and

mothers had a rate of 59%, and controls without autism had a rate of 29%. This has made

me wonder whether family members of individuals with autism should be routinely

screened for cerebral folate deficiency if they are seen for any psychiatric disorder.

A lumbar puncture is the definitive method of demonstrating cerebral folate deficiency, and

has the advantage that some of the other metabolic disorders can be identified with this.

But it is a more invasive test, and insurance is not yet reliably covering this (Lisa Pan MD,

personal communication.