Nutrition and Depression: The Role of Folate

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


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

In This Article

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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