Nutrition and Depression: The Role of Folate

Jonathan E. Alpert, MD, PhD, Maurizio Fava, MD

Medscape Psychiatry & Mental Health eJournal. 1997;2(1)

Folate and the Prediction of Antidepressant Response

A relationship between folate levels and treatment outcome among 101 depressed adults admitted to a clinical research unit was suggested by Reynolds and colleagues.^[8] These investigators found that depressed inpatients with low serum folate levels at admission had significantly higher ratings of depression and neuroticism at discharge following treatment with electroconvulsive therapy (ECT), antidepressants, or tryptophan than patients with normal folate levels. Patients with low folate levels were also more severely depressed at admission than those with normal folate levels. Interpretation of the difference observed in treatment outcome between patients with low and normal folate levels is, therefore, confounded by the differences in depressive severity at baseline between the 2 groups. Also, most patients in this study were on antidepressant regimens at the time of study admission, such that baseline folate levels were, in effect, interim rather than pretreatment values potentially altered by ongoing treatment.

More recently, we have found that among 213 adult outpatients presenting with major depressive disorder (MDD), those individuals who had low serum folate levels prior to initiation of antidepressant treatment were less likely to respond to 8 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (20mg/day) than were patients with normal folate levels.^[10] Assessment of treatment response was performed by clinical investigators blind to patients' folate status. This relationship with treatment outcome did not appear to be related to baseline difference in depression severity. Moreover, the relationship appeared to be specific for folate, since pretreatment serum B12 or homocysteine levels did not correlate with antidepressant response. In our study, the proportion of depressed individuals with low folate levels was larger in those with melancholic depression compared with nonmelancholic depressive subtypes (eg, atypical depression). This finding supports the stronger association between folate deficiency and endogenous depression compared with its relationship to neurotic depression as described by Carney and associates.^[7]

The relationship between low folate levels and response to antidepressant treatment has been further supported by a recent study of RBC folate and response to sertraline and nortriptyline.^[15] Among 22 patients with MDD who were over the age of 60 and randomly assigned to receive either of the 2 antidepressants, there was a significant correlation between folate and antidepressant response in the sample overall and within the subgroup of patients receiving sertraline in particular. The correlation with treatment response did not reach significance for the patients receiving nortriptyline. Since the number of patients in each treatment group was small, it would be premature to suggest that low folate at baseline may be a predictor of partial or nonresponse to some kinds of treatment (SSRIs) but not others (tricyclic antidepressants). A similar caveat applies to a study of serum 5-methyltetrahydrofolate levels in depressed patients in whom there was no difference in pretreatment values between responders and nonresponders to a subsequent course of ECT.

Overall, recent evidence suggests that low serum and RBC folate levels may predict poorer response to some forms of antidepressant treatment. Further studies are needed to replicate this finding and to clarify the degree to which the association between low folate and treatment outcome with the SSRIs can be generalized to other classes of medications and other treatment modalities including ECT, phototherapy, and psychotherapy.

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Cite this: Nutrition and Depression: The Role of Folate - Medscape - Jan 30, 1997.

Abstract & Introduction
Folate Deficiency and Depression
Folate and the Prediction of Antidepressant Response
Folate in the Treatment of Depression
The Basis for Folate Deficiency in Depression
Conclusion
References
Sidebar: Folate and Metabolism

Sidebar: Folate and Metabolism

The biochemical mechanisms through which folate exerts an influence on neuropsychiatric status are likely to involve the 1-carbon cycle, a pathway essential to many transmethylation reactions within the CNS, including the metabolism of neuroactive substances such as the monoamine neurotransmitters and melatonin; the formation of membrane phospholipids; and the synthesis, repair, and recombination of nucleic acids.

^[1,2,3]

Folate plays an integral role in the 1-carbon cycle (Fig. A). It is first converted to 5-methyltetrahydrofolate (MTHF) and then combines with homocysteine, in a reaction catalyzed by vitamin B12-dependent methionine synthetase, to produce L-methionine. Methionine produced through this cycle, and also furnished directly but in insufficient amounts as a dietary amino acid, is combined with adenosine triphosphate (ATP) in a reaction catalyzed by methionine adenosine transferase (MAT) to form S-adenosyl-methionine (SAMe, or ademetionine). SAMe, in turn, is widely distributed throughout the CNS as an intermediary of over 35 transmethylation reactions.

^[3,4]

In 1963, Smythies

^[5]

hypothesized a defect in the mechanism of the 1-carbon cycle as an underlying factor in some psychotic and mood disorders. Although the "transmethylation hypothesis" of schizophrenia as outlined by Smythies has not been well supported by subsequent research, evidence for a role of the 1-carbon cycle in processes relevant to the expression of affective disorders continues to accrue. This includes the work of Tolbert and colleagues,

^[6]

who observed that the RBCs of unipolar depressives had lower levels of activity of MAT compared with erythrocytes from controls. Moreover, following antidepressant treatment, a significant increase in the Vmax of the MAT activity of patients with major depression was observed.

^[7]

Similarly, low cerebrospinal fluid levels of SAMe have been reported among a sample of depressed adults,

^[8]

and parenteral doses of SAMe and some oral formulations of the compound have been associated with antidepressant efficacy greater than placebo and comparable to standard antidepressants, though, quite interestingly, with a more rapid onset.

^[9]

As would be predicted from the utilization of folate in 1-carbon metabolism, reduction in brain levels of SAMe has been reported in rats maintained on a folate-deficient diet,^[10] and lowered levels of SAMe have been reported in animal studies following treatment with the antifolate agent methotrexate and in children with inborn errors of folate metabolism.^[11] Thus, at least some of the important neuropsychiatric effects of folate and methylfolate are likely to be mediated through their direct impact on synthesis of this principal methyl donor.

Among the myriad transmethylation reactions involving the 1-carbon cycle, which are most relevant to the relationship between folate and depressive disorders remains a matter of speculation. Both folates and SAMe appear to influence the rate of synthesis of tetrahydrobiopterin (BH4), the cofactor in the hydroxylation of phenylalanine and tryptophan.^[11,12,13] Since this is the rate-limiting step in the biosynthesis of dopamine, norepinephrine, and serotonin--neurotransmitter systems that are thought to be involved in the pathophysiology and treatment of depressive disorders--alterations in the rate of synthesis of this important cofactor may be relevant to depression.^[14]

In support of this hypothesis, BH4 synthesis in brain preparations from depressed patients has been reported to be lower than in preparations from controls,^[15] and exogenous BH4 may have antidepressant properties.^[16,17] Given the diversity of neural processes influenced by alterations in 1-carbon metabolism--from gene transcription to membrane fluidity--these observations point to one of many potential mechanisms underlying the observed relationships between folate and depression, an intriguing area that requires further study.

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Bottiglieri T, Hyland K, Reynolds EH: The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 48:137-152, 1994.
Cantoni GL: S-adenosylmethionine: A new intermediate formed enzymatically from L-methionine and adenosine triphosphate. J Biol Chem 204:403-416, 1953.
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Nutrition and Depression: The Role of Folate

Folate and the Prediction of Antidepressant Response

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