Lower Folate Levels Increase Risk for Depressive Symptoms, Particularly in Women

Caroline Cassels

September 24, 2010

September 24, 2010 — Lower serum folate levels appear to be associated with an increased risk for depressive symptoms, a large population-based, cross-sectional study suggests.

Data on US adults from the National Health and Nutrition Examination Survey (NHANES) show elevated depressive symptoms were inversely associated with folate status, particularly among women.

"We found that the odds of having elevated depressive symptoms among individuals with the highest serum folate levels were about half that of those with the lowest levels," lead investigator May A. Beydoun, PhD, MPH, National Institute on Aging, told Medscape Medical News.

The study was published online September 14 in Psychosomatic Medicine.

First Nationally Representative Study

Previous research indicates that high levels of total homocysteine (tHcy) and low levels of folate and vitamin B12 are associated with depression or elevated depressive symptoms in adults.

However, investigators note that earlier studies examining the impact of low folate, low vitamin B12, and elevated tHcy status simultaneously on depressive symptoms did not examine interaction among those 3 risk factors and have had inconsistent findings as to the individual associations.

"To our knowledge this is the first nationally representative study conducted among U.S. adults after mandatory fortification of food with folic acid that examines associations of serum folate, vitamin B12, and tHcy levels with depressive symptoms," they write.

For the study the researchers used cross-sectional data from NHANES from 2005 to 2006 by assessing interactions (2 way and 3 way) among the 3 exposures and testing effect modification of the associations by sex.

The study sample included 2524 adults aged 20 to 85 years with complete data on demographics, diet, plasma folate, vitamin B12, and tHcy status, as well as information on physical activity, smoking status, blood pressure, and depressive symptoms.

Depressive symptoms were measured using the Patient Health Questionnaire (PHQ), and elevated symptoms were defined as a PHQ total score of 10 or greater.

Study Underpowered to Detect Effect in Men

With an odds ratio of 0.52 (95% confidence interval [CI], 0.35 – 0.76), adjusted analyses revealed that among the total population the odds of having elevated depressive symptoms was close to half that in the lowest tertile.

Further, with an odds ratio of 0.37 (95% CI, 0.17 – 0.86), the likelihood of women in the highest tertile of serum folate (mean ± SE, 21.1 ±0.29 ng/mL) to experience elevated depressive symptoms was about a third that of their counterparts in the lowest tertile (7.02 ± 0.08 ng/mL).

The study showed no relationship between B12 and tHcy levels and elevated depressive symptom risk — a finding that is consistent with previous research the researchers note.

In addition, researchers report that B12 and tHcy did not interact with folate status to affect its inverse association with depressive symptoms among women.

However, elevated homocysteine level was positively associated with elevated depressive symptoms in adults 50 years and older.

Although a significant association between folate levels and risk for elevated depressive symptoms was only observed in women, the investigators believe this is because the study was underpowered to detect the effect in men.

Boosting Folate Levels

The investigators point out that although the study has several strengths, it also has limitations, including its cross-sectional design, which prevents examination of the relationship between depression and serum folate levels over time.

Therefore, they note, it is possible that reverse causality is at play such that depressed individuals may be more likely to have a poor diet and therefore lower folate intake than nondepressed individuals.

Future interventions to improve mental health outcomes among US adult should focus on increasing levels of serum folate say investigators.

For instance, said Dr. Beydoun, clinicians should consider screening patients with depressive symptoms for serum folate and, if indicated, consider supplementation in addition to standard antidepressant therapy.

In addition, dietary and lifestyle advice to enhance serum folate should also be considered. Such counseling, she said, should include education about folate-rich foods, the beneficial effect of physical activity on folate levels, and the negative impact of cigarette smoking.

Diet Important in Mental Health

Commenting on the study, Felice Jacka, PhD, a researcher from the University of Melbourne in Australia, who has conducted a number of studies examining the impact of diet on mental health status, said given the fact that previous studies have reported this relationship the results are not surprising.

"However," she said, "the NHANES data are very good quality and, therefore, a very good vehicle to examine the relationships between nutritional status and mental health."

"This is the first large-scale population-based study in the US to show that folate status is associated with the presence of depressive symptoms since the fortification of foods with folate became mandatory," she added.

Dr. Jacka said this study also lends further support to the premise that diet is an important factor for mental health in the general population.

"It also suggests that blood tests to examine folate and homocysteine levels (and levels of other nutrients) in individuals with depressive symptoms may be of utility in clinical settings. If nutrient deficiencies and/or excess homocysteine are identified, dietary and/or supplementation strategies could then be considered," she said.

The study authors have disclosed no relevant financial relationships.

Psychosom Med. Published online September 14, 2010.

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