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E H Reynolds
It is becoming clear that folic acid affects mood and thinking, especially in older individuals.
Folic acid is important for functioning of the nervous system for everyone. In the fetus the relation between maternal folate status and the risk of neural tube defects is well established. Clinical trials have shown that preventive treatment prior to conception with 400 µg or higher of folic acid significantly reduces the risks of such defects.
In neonates, infants, children, and adolescents, inborn errors of folate transport and metabolism are associated with a variety of overlapping syndromes that are influenced by age of clinical presentation. These include:
- Developmental delay,
- Cognitive deterioration,
- Motor and gait abnormalities,
- Behavioral or psychiatric symptoms,
- Seizures,
- Signs of demyelination or failure of myelination, and
- Vascular changes seen on magnetic resonance imaging or postmortem examination.
- Less commonly, subacute combined degeneration and peripheral neuropathy may also occur.
In adult patients presenting with anemias due to folate deficiency, approximately two thirds have neuropsychiatric disorders which overlap considerably with those associated with anemia due to vitamin B-12 deficiency.
The degree of anemia is poorly correlated with the presence of neuropsychiatric disorders, but if these anemias were left untreated nearly all patients would eventually develop neuropsychiatric complications.
Over the past 35 years numerous studies have shown a high incidence of folate deficiency correlated with mental symptoms, especially depression and cognitive decline in epileptic, neurological, psychiatric, geriatric, and psychogeriatric populations. Furthermore, recent studies in elderly people suggest a link between folic acid, homocysteine, ageing, depression, and dementia, including Alzheimer's disease and vascular disease.
Patients with Epilepsy
Many studies of folate in serum, red cells, or cerebrospinal fluid have shown a consistent association between drug induced deficiency and mental changes, especially depression, apathy, psychomotor retardation and dementia.
Treatment of 26 folate deficient epileptic patients with 5 mg of folic acid daily for one to three years resulted in:
- Improved drive,
- Initiative,
- Alertness,
- Concentration,
- Mood, and
- Sociability in most.
This contradicted the prevailing view that folic acid was harmful only to the nervous system, although that concept was reinforced by the additional observation that seizure control deteriorated in several of the patients.
Although short term clinical trials of folic acid for one to three months produced conflicting results with respect to mental changes and seizure control, there is abundant experimental evidence now of the excitatory properties of folate derivatives, especially when the efficient blood-brain barrier mechanism for the vitamin is circumvented. In addition, folic acid influences DIlantin metabolism, leading to a fall in blood concentrations of this drug.
Neurological Patients
Several of the earliest reports of neurological disease associated with severe folate deficiency emphasize the importance of dementia and depression reversible with vitamin therapy. On the basis of clinical, neuropsychological, computed tomography, and radionuclidecisternographic findings, researchers concluded that chronic folate deficiency could induce cerebral atrophy.
Psychiatric Patients
On the basis of serum or red cell assays, folate deficiency has been reported in up to one third of psychiatric outpatients or inpatients, more so in the former.
Depressed patients with folate deficiency had higher depression scores, higher affective morbidity indices, and a poorer response to standard treatment with antidepressants.
The few controlled clinical trials of vitamin therapy in addition to standard psychotropic medication have all reported positive effects on patients' mental state. In a double blind placebo controlled trial in depressive patients treated with lithium, the addition of 200 µg of folic acid for one year significantly improved affective morbidity. Similarly, the addition of 500 µg of the vitamin to Prozac for 10 weeks significantly improved antidepressant response, especially in women.
Geriatric and Psychogeriatric Patients
The highest incidence of folate deficiency as measured by serum and red cell folate concentrations is in elderly populations, especially psychogeriatric patients. A close association with dementia and depression, apathy, withdrawal, and lack of motivation has been noted.
One reason for the apparently high incidence of folate deficiency in elderly people is that folate concentrations in serum and cerebrospinal fluid fall and plasma homocysteine rises with age, perhaps contributing to the ageing process.
In a prospective community based study of 370 healthy elderly Swedish subjects, folate or vitamin B-12 deficiency doubled the risk of subsequently developing Alzheimer's disease. Recently the much larger and longer Framingham community based study confirmed that a raised plasma homocysteine concentration doubled the risk of developing Alzheimer's and non-Alzheimer's dementia.
Neurochemical Aspects
Concentrations of folate in serum and cerebrospinal fluid decline and those of plasma homocysteine rise with age, which contributes to the apparently high incidence of the vitamin deficiency in geriatric and psychogeriatric populations. Low concentrations of folate in serum, red cells, and cerebrospinal fluid are associated with depression and dementia in a wide range of clinical neuropsychiatric settings, as is raised plasma homocysteine.
There is also increasing evidence of an association between plasma homocysteine and vascular disease, and the increased risk of dementia, including Alzheimer's disease, associated with raised plasma homocysteine may be mediated by a vascular or possibly a neurotoxic mechanism.
Mood and some cognitive functions may be related to methylation processes in the brain. With respect to depression, this hypothesis is supported by the similar effect of S-adenosylmethionine to that of folates on mood, and by the influence of folates and S-adenosylmethionine on monoamine metabolism, which is also incriminated in depression. The lowest concentrations of folate and S-adenosylmethionine in cerebrospinal fluid are found in dementia, including Alzheimer's disease.
British Medical Journal June 22, 2002;324:1512-1515 Full Text Article
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