Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression

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Abstract

Background: Folate and B12 deficiencies may result in macrocytic anemia, and are common in major depression; hypofolatemia may result in poorer antidepressant response. We wished to determine whether anemia or macrocytosis predict hypofolatemia, low B12, or refractoriness to antidepressants.

Methods: After obtaining serum folate, B12, and hematological indices, 213 depressed adults were treated with fluoxetine 20 mg/day. Amelioration of depressive symptoms was measured.

Results: Neither macrocytosis nor anemia predicted low serum folate/B12, or antidepressant refractoriness. Among 39 patients with hypofolatemia, none had macrocytosis; 28% had low HCT; 41% had low RBC. Among 25 patients with low B12, none had macrocytosis; 24% had low HCT; 28% had low RBC. Among non-responders, 3% had macrocytosis; 24% had low HCT; 25% had low RBC.

Conclusion: Anemia and macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness to antidepressants. Measurement of folate and B12 should be considered when evaluating treatment refractoriness.

Introduction

Deficiencies of folate and vitamin B12 (cobalamin) are relatively uncommon but clinically important medical conditions. Although the actual prevalence of folate and B12 deficiency is not clear, studies suggest that low or deficient folate levels in the general population may range from 4% to 25% [1], [2], [3], [4], [5], and B12 deficiency may range from 3% to 13% [6], [7] and up to 15% in the elderly [8]. Folate and B12 deficiency may be caused by a number of factors including dietary deficiency, malabsorption, and increased requirement for these vitamins during stress [9]. Primary folate and B12 deficiency may result in macrocytic anemia, characterized by increased mean corpuscular volume (MCV), decreased red blood cell (RBC) count, and low hematocrit (HCT) [10]. Other primary causes of macrocytic anemia may include alcohol abuse, liver disease, hypothyroidism, and the use of medications such as antiretroviral agents, phenytoin or azathioprine [10]. Not all of these conditions involve folate or B12 deficiency. Consequently, a patient with macrocytic anemia may not necessarily be folate or B12 deficient, and, conversely, a folate or B12 deficient patient may not have macrocytic anemia.

It has long been recognized that folate and vitamin B12 may have an important role in regulating mood, presumably due to their relationship to methyl group donation pathways involved in the synthesis of central nervous system neurotransmitters [11]. Depressed patients have been shown to have low levels of folate and/or vitamin B12 in their serum and RBCs [12], [13], [14], [15]. The depressed state may contribute to these vitamin deficiencies through decreased appetite and dietary intake, poor choice of food, gastrointestinal disturbances that may decrease absorption of vitamins in the gut, and increased utilization of vitamins [9], [16].

Approximately 10–30% of depressed patients may have a low folate level [9], which may be higher than in the general population and is postulated to be of some relevance to the course of depression. Unless corrected, this condition may prove an obstacle to response to treatment among certain patient populations. For example, Fava et al. [15] recently found that patients with lower serum folate levels respond less well to fluoxetine than those with normal levels of folate; likewise, Alpert et al. [17] have reported that elderly patients with lower serum folate levels respond less well to sertraline. Folate-deficient individuals who become depressed may have increased duration of their disorder [18], and high folate levels may delay the age of onset of depression [18]. Correction of folate deficiency may improve depressive symptoms and/or response to antidepressant therapy [16], [19], [20], and folate supplementation may protect against recurrence of mood disturbance among individuals with unipolar or bipolar mood disorders if their baseline folate levels are low [21], [22].

B12 deficiency has been linked to various neuropsychiatric disorders including affective illness [23], [24]. Low or deficient B12 may be found in as many as 8–14% of depressed patients [1], [15], [25], though Vitamin B12 levels have not been shown to correlate as clearly or significantly with the response rate to antidepressant treatment [15].

Despite the strong evidence linking folate and B12 abnormalities to depressive states, levels of serum folate and B12 are not routinely obtained in the outpatient psychiatric setting. Given the relationship of these vitamin deficiencies to anemia and macrocytosis, and given that a complete blood count (CBC) is more routinely obtained among depressed outpatients, we were interested in determining the usefulness of RBC count, HCT, and MCV for detecting low serum folate or B12, and for predicting refractoriness to antidepressant treatment. We hypothesized that in depressed patients, low RBC count and other abnormal red cell indices would be predictive of abnormal serum folate and B12 levels, and would also be predictive of non-response to antidepressant treatment.

Section snippets

Method

The study was approved by the Massachusetts General Hospital Institutional Review Board. Our 213 subjects were adult participants ages 18–65 (mean age 39.9; SD=10.5; 119 women, 94 men), consecutively enrolled in an outpatient depression treatment study at the Massachusetts General Hospital. The mean duration of the current (index) depressive episode of our study subjects was 3.4 years (SD=5.5). Some patients were self-referred, after seeing advertisements for the study in newspapers,

Results

Complete data on pre-treatment blood cell indices, folate, and B12 were available from 209 of 213 patients (91 men, 118 women). In a few cases, complete data on baseline red cell indices, folate, and B12 were missing because certain lab tests were not done (reasons may include a difficult blood draw, reticence on the part of the patient, or lab error). Among our 209 subjects, 39 (19%) had low serum folate and 25 (12%) had low B12. Fifty-six (27%) had a low RBC count, 59 (28%) had a low HCT, and

Discussion

In this study, we found that low serum folate and Vitamin B12 occurred in 19% and 12% of our study population, respectively. Although both these prevalences were on the higher ends of the prevalence ranges found in the general population, they were not accurately predicted by an individual's RBC count, HCT, or MCV. These observations are consistent with those of Lindenbaum et al. [24], who found that anemia or macrocytosis may be absent in up to 28% of patients with B12 deficiency and related

Acknowledgements

This study was supported in part by NIMH Grant MH-48483.

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