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Nutrición Hospitalaria

versión On-line ISSN 1699-5198versión impresa ISSN 0212-1611

Nutr. Hosp. vol.28 no.3 Madrid may./jun. 2013 




A pilot study of folic acid supplementation for improving homocysteine levels, cognitive and depressive status in eating disorders

Estudio piloto sobre el efecto de la suplementación con ácido fólico en la mejora de los niveles de homocisteína, función cognitiva y estado depresivo en trastornos de la conducta alimentaria



Viviana Loria-Kohen1, Carmen Gómez-Candela1, Samara Palma-Milla1, Blanca Amador-Sastre2, Angel Hernanz3 and Laura M. Bermejo1

1Nutrition Department. La Paz University Hospital. Health Research Institute IdiPAZ. Madrid. Spain.
2Psychiatry Department. La Paz University Hospital. Health Research Institute IdiPAZ, Madrid. Spain.
3Biochemistry Department. La Paz University Hospital. Health Research Institute IdiPAZ, Madrid. Spain.





Background & aims: Several authors have reported low folate intake in patients with eating disorders (ED). This vitamin plays an essential role in synthesis reactions for neurotransmitters and structural elements of neurons, and therefore its deficiency has been associated with the presence of different disorders linked to mental function. The aim of this study was to determine the effect of folic acid supplementation on homocysteine levels and the cognitive and depressive status of a group of patients with eating disorders with low folate intake.
Subjects/methods: The study was designed as a randomised, prospective clinical trial, which included 24 participants assigned to two treatment groups for six months: supplemented group (SG) (10 mg/day of folic acid [ACFOL®]) and a placebo group (PG). Both groups maintained their medical, dietary and psychological treatment. At baseline and end of the intervention, anthropometric, dietary and biochemical parameters (plasma homocysteine [Hcy], serum and red blood cell folate) were recorded. Cognitive and depressive status questionnaires were administered (Stroop Test, Trail Making Test and Beck Depression Inventory).
Results: Twenty-two patients completed the study (SG: 12, PG: 10, mean age: 24.2 ± 8.8 years, BMI 18, ± 3.5 kg/m2). The SG significantly increased their serum and red blood cell folate levels and lowered Hcy levels (9.4 ± 2.4 µmol/l vs. 7.5 ± 1.7 µmol/l, P < 0.01). The SG also significantly improved most of their test scores for cognitive and depressive status. The PG showed no significant changes in any of the evaluated variables.
Conclusions: The results show that folic acid supplementation may be used as another tool within the comprehensive and multidisciplinary treatment applied to patients with ED.

Key words: Folate. Cognitive function. Eating disorders. Depression. Homocysteine.


Introducción y objetivo: Diferentes autores han reportado una baja ingesta de ácido fólico en pacientes con Trastornos de la Conducta Alimentaria (TCA). Esta vitamina desempeña un papel esencial en las reacciones de síntesis de neurotransmisores y elementos estructurales de las neuronas y, por lo tanto, su deficiencia se ha asociado con la presencia de diferentes trastornos relacionados con la función mental. El objetivo de este estudio fue determinar el efecto de la suplementación con ácido fólico sobre los niveles de homocisteína y sobre marcadores de función cognitiva y depresión en un grupo de pacientes con TCA con baja ingesta de ácido fólico.
Sujetos y métodos: Estudio clínico randomizado y prospectivo en el que se incluyeron 24 pacientes asignados a dos grupos de tratamiento durante un período de 6 meses: grupo suplementado (SG) (10 mg/día de ácido fólico [ACFOL®]) y grupo placebo (PG). Ambos grupos mantuvieron su tratamiento médico, dietético y psicológico. Al inicio del estudio y tras la intervención se evaluaron parámetros antropométricos, dietéticos y bioquímicos (homocisteína plasmática [Hcy], folato sérico y eritrocitario). Como marcadores de función cognitiva y depresión se administraron diferentes cuestionarios (Test de Stroop, Trail Making Test, BDI: Cuestionario de percepción de función cognitiva).
Resultados: Completaron el estudio 22 pacientes (SG: 12, PG: 10, edad media: 24,2 ± 8,8 años, IMC 18, ± 3,5 kg/m2). El grupo SG incrementó de forma significativa sus niveles de folato sérico y eritrocitario y redujo el de homocisteína (9,4 ± 2,4 /µmol/l vs. 7,5 ± 1,7 µmol/l, P < 0,01). Además, el grupo SG también mejoró significativamente las puntuaciones de los test de función cognitiva y depresión. En el grupo PG, en cambio, no se observaron cambios significativos en ninguna de las variables evaluadas.
Conclusiones: Los resultados obtenidos demuestran que la suplementación con ácido fólico podría emplearse como una herramienta más dentro del complejo y multidisciplinario tratamiento que requieren estos pacientes.

Palabras clave: Folato. Función cognitiva. Trastorno alimentario. Depresión. Homocisteína.

ED: Eating Disorders.
RA: Restrictive Anorexia Nervosa.
EDNOS: Eating Disorder Not Otherwise Specified.
PG: Placebo group.
SG: Supplemented group.
Hcy: Homocysteine.
ST: Stroop test.
TMT: Trail Making Test.
BDI: Beck Depression Inventory.



Folate deficiency is a common nutritional problem in many populations groups. This deficiency may be due to absorption disorders, genetic factors, drug interactions and inadequate diet.1

Several authors have reported low folate intake in patients with eating disorders (ED).2,3 The severe food restriction of that patients, especially those with Restrictive Anorexia Nervosa (RAN), causes them to have diets deficient in both energy and micronutrients, among them folate.

Folate is the generic term for the various chemical forms of folic acid that can only be synthesised by plants and microorganisms, thus requiring it to be ingested through diet.4,5 This vitamin plays an essential role in synthesis reactions for neurotransmitters and structural elements of neurons,6 and therefore its deficiency has been associated with the presence of different disorders linked to mental function such as depression6-8 and cognitive function impairment9. The effect of folic acid supplementation has been studied as a tool for improving these disorders, with conflicting results.10-13

Some authors have identified the presence of increased homocysteine levels in eating disorders patients,14-17 and attempts have been made to find some association between this and the high rates of depression18,19 and cognitive function impairment recorded in these patients.20,21 It is still not known what causes this increase in homocysteine levels, whether the levels return to normal after the nutritional state is normalised and what strategies must be employed to carry out this normalisation.22

The aim of this study was to determine the effect of folic acid supplementation on homocysteine levels in an ED group of patients. The secondary objectives were to evaluate the outcome on cognitive and depressive status after the intervention.



Study participants

This study was designed as a prospective, randomised, double-blind, parallel-placebo clinical study, developed by the Nutrition Department of "La Paz University Hospital" in the period between January 2008-June 2010. Twenty-four males and females diagnosed with eating disorders (RAN: Restrictive Anorexia Nervosa and EDNOS: Eating Disorder Not Otherwise Specified) through clinical interviews with the Psychiatry Department and measured for low folate intake, based on the recommended daily intake in terms of age,23 were included consecutively. Exclusion criteria were: hypersensitivity to folic acid or anemia due to lack of B12, patients who routinely used drugs that interfere with folic acid absorption (analgesics, anticonvulsants, hydantoin, carbamazepine, antacids, antibiotics, cholestyramine, methotrexate, pyrimethamine, triamterene, trimethoprim and sulphonamides) and patients taking vitamin and mineral supplements.

All participants or their relatives, in the case of minors, signed an informed consent for participation. The study was approved by the Ethics Committee of the La Paz University Hospital and conformed to the ethical standards of the Declaration of Helsinki. Registered under Identifier no. NCT0143674.


Patients were randomly assigned to two treatment groups. The treatment groups consisted of a supplemented group (SG) using two 5-mg tablets of folic acid (ACFOL®), and a placebo group (PG) using two tablets that were identical to those of SG, but composed of crystalline cellulose, lactose and food colouring. Groups were treated for six months. Patients continued the standard medical, dietary and psychological treatment established for these patients within the Nutrition Department.



The following data were collected at baseline and at the end of the study:

- Anthropometric parameters: height (SECA stadiometer [range: 80 cm to 200 cm]) and weight (TANITA BC-420MA, Biologica Tecnologia Medica S.L, Barcelona, Spain) were measured. BMI was calculated using the equation: weight (kg)/[height (m)]2.

- Dietary parameters: all food and beverages consumed were recorded using a food frequency questionnaire and a "3-day food and drink record", validated for Spanish population.24 The food's energy and nutritional content was then calculated using nutrition software (DietSource® 3.0, Novartis, Spain). The values obtained were compared to the recommended values to determine the diets' nutritional adequacy.23,30

- Blood variables: hematology determinations were performed using an ABX Pentra 120 autoanalyser (Horiba). Serum and red blood cell folate and vitamin B12 levels were determined by a Modular Analytics E 170 autoanalyser (Roche). Plasma homocysteine was quantified by nephelometry using a Prospec autoanalyser (Siemens). The following reference values were used for the diagnosis of folate deficiency: serum folate < 3 ng/ml, red blood cell folate < 140 ng/ml, Hcy > 8 µmol/l and vitamin B12 < 258 pmol/l.25

- Depressive and cognitive status:

• Depressive symptomatology was assessed using the Beck Depression Inventory (BDI).26 The BDI is a 21-item self-report scale measuring the depression severity (range 0-63). Depression absence is defined as a total score below 12, moderate depressive symptoms as a score between 12 and 17 and a clinically relevant depression, 18 or above.

• Selective attention and executive function was measured using the Stroop colour-word interference test.27 The first part of the test (named P) consists of reading the names of colours printed in black ink, and measures verbal ability and attention. In the second part of the test (named C), participants have to name the colour (blue, green or red) of a series of printed dashes. In the third part (named PC), participants have to name the colour of coloured words printed in incongruent ink colours instead of reading the name. Interference (I) is calculated using the scores from the three test parts and measures the ability to adapt to changing demands and suppress habitual responses in favour of unusual ones [I = PC-(C*P)/(C + P)]. The T score was determined by crossing the variables in the score calculation table.27 Normal limits for T scores ranged from 35 to 65 points. To assess the various parts of the test, the following scales were used for Spanish population:28



• Trail Making Test,29 evaluates visual search speed, attention, visuospatial sequencing, mental flexibility and motor function. The test has two parts: tMT-A (participants have to connect digits from 1 to 25 in ascending order after they have performed a similar training task with only 8 digits), and TMT-B [participants have to connect digits and letters sequentially (1-A, 2-B, ... 13-L)]. The test variable was the time in seconds needed to correctly complete the task. In accordance with Frieling et al. (2005), TMT values were scored as paired or unpaired (Cutoff: TMT-A > 40s; TMT-B > 85s).

Prior to completing the cognitive function questionnaires, the patient was checked to make sure they were not fasting and were getting a regular amount of sleep, in order to minimise the effects of these factors on the results.

Other interesting medical parameters were recorded at baseline: age and time of disease diagnosis.

Statistical analysis

Analysis was performed using the SPSS .0 programme (SPSS Inc., Chicago, IL, USA). Continuous variables are shown as mean (standard deviation [SD]). Qualitative variables are shown as absolute frequencies and percentages. Due to the sample size, the Shapiro-Wilk test was used for performing normality tests. When the distribution of the results was normal, the Student t test was used to compare the mean values of the studied variables recorded for the two treatment groups. The Mann-Whitney U test was used when the distribution was not normal. Differences within groups at the beginning and end of the study were examined using the Student paired t test when the distribution of the results was normal, and the Wilcoxon test when it was not. We also calculated linear correlation coefficients using the Pearson's test when at least one of the variables was normally distributed, or the Spearman's test when both were not normal. Values of p < 0.05 were considered significant for all statistical tests.



Twenty-four patients were recruited (SG: 14, PG: 10). Two patients in the SG withdrew from the Nutrition Department's standard treatment, so the data from their last visit could not be obtained and they were excluded (PG: 12, PG: 10). No side effects were reported during treatment.

At the start of the study there were no significant differences in the values of any of the variables studied (table I). After assessing folate intake by means of the food record, we observed that half of the group did not meet 30% of the recommended daily intake for their age (400 µg/day).



The total study sample presented baseline serum and red blood cell folate and vitamin B12 levels within reference values: 9.7 ± 3.3 ng/ml; 725.6 ± 306.1 ng/ml and 654.0 ± 30.1 µg/ml, respectively. Mean Hcy values were 9.4 ± 2.4 µmol/l. The only male included in the study had 7.8 µmol/l.

In terms of the correlation between Hcy levels and the specific variables linked to metabolism of this amino acid (folate, vitamin B12), only an inverse and weak correlation between homocysteine and vitamin B12 was found (r = -0.412 P < 0.05).

About cognitive function results at baseline, 8.3% of participants scored below the mean of the reference in P, and 33.3% in C and CP test cards for Stroop test (ST). Some 33.3% scored below the I mean. Only one patient (4%) had a T score outside normal ranges.27 Regarding TMT, 8.4% scored above the reference cutoff used in part A and 20.8% in part B.21 About depression symptoms assessment at baseline, 20.8% scored in the moderate range of depression and 58.3% scored in relevant or severe ranges on the BDI.26

After six months of intervention, there were no significant changes in caloric or macronutrient intake. In terms of micronutrients, significant differences were only observed in the total folate intake. The SG had a greater increase of this nutrient as a result of supplementation (28.0 ± 65.5 vs. 5.2 ± 58.8 µg/day; P < 0.001).

Biochemical parameters evolution after the intervention is shown in table II. The SG significantly increased their serum and red blood cell folate levels and lowered Hcy levels. There were no significant changes in vitamin B12 levels in either treatment group.



The evolution of scores from the different questionnaires is shown in table III. The SG significantly lowered the time spent resolving part B of the TMT and increased the number of words read in the ST test cards P, C and CP. BDI scores were also significantly lower (figs. 1, 2). There were no significant changes in any of the tests assessed for the PG.





The increase in total folate intake in SG correlated significantly and inversely with the change in BDI scores (r = -0.581, P < 0.05), but not with other questionnaires.

In terms of BMI evolution, the SG significantly increased their BMI (18. ± 3.2 vs. 20.1 ± 2.6 kg/m2; P < 0.05). PG did not change this parameter (18.8 ± 3.9 vs. 18.6 ± 4.0 kg/m2). Also, the differences between the variations of the groups were significant (SG: 1.4 ± 1. vs. PG: -0.2 ± 1.2 kg/m2; P < 0.05). There were no significant correlations between BMI changes and in the questionnaires scores changes or in the Hcy changes. The coefficients of determination R2 indicated that only a low and insignificant percentage of the change in the variation of studied variables may be attributed to the variation in BMI (Stroop P: R2 = 0.004, P = 0.788; Stroop C: R2 = 0.03, P = 0.806; Stroop PC: R2 = 0.035, P = 0.406; TMT-A: R2 = 0.07, P = 0.206; TMT-B: R2 = 0.044, P = 0.347; BDI: R2 = 0.15 P = 0.066; Hcy R2 = 0.009, P = 0.077).

When studying the relationship between patient age and time of diagnosis of the disease with the changes at the end of the intervention, there were no significant correlations in any of them.



After six months of a 10-mg/day folic acid supplementation in EDs patients, there was an improvement in folate status and a significant reduction in Hcy levels. Additionally, there were significant and favourable changes in most cognitive function and depression test scores.

At baseline of the study, folate intake of all patients was deficient (< 67% RDI), and did not achieve 30% of the recommended daily intakes.30 These values are similar to previous studies.2,31

Folate is involved in various biological functions necessary for achieving a healthy state. Some studies suggest that deficient folate status is associated with high levels of Hcy.9,32 Hcy levels above 10 µmol/l are linked to a poor cognitive state and depression.33

The median for Hcy in our groups [9.6 µmol/l (range: 5.2 to 14.4)] was greater than reference values for the Spanish population [7.7 µmol/l (range: 4.3 to 17.7)].32 Some 66% of the sample had baseline Hcy levels greater than the reference value considered for indicating folate deficiency (> 8 µmol/l).1 Moreover, it has been observed that 42% of all the patients had baseline Hcy levels greater than the value indicative of a health risk.33

The presence of high Hcy levels has been reported in ED patients.14-17 However, we should take into account the significant variability in the data collection and analysis methods, such as the control markers used, which must be considered when interpreting and comparing these data.32,34

Despite ED patients have a high nutritional risk for some nutrients,3 both groups in our study had normal blood vitamin B12 and serum and red blood cell folate levels, an observation found in other studies.14,16

Vitamin B12 deficiency is rare since the ratio of cobalamin body reserves to its normal daily requirements is approximately 1000:1, which makes it difficult to develop a deficiency in this vitamin based solely on a deficient diet. Its deficiency is caused more by congenital errors in metabolism or by gastrointestinalv problems related to surgery, age, etc.1 Previous studies have not found vitamin B6 deficits in patients with ED, and Hcy levels were not reduced after supplementing with this vitamin.15 However, some authors suggest that conventional criteria for the folate deficiency diagnosis may be inadequate to identify individuals who may benefit from dietary supplements,9 since finding appropriate levels would not reflect the actual situation. Therefore, to understand the exclusive effect of folate on the study variables, we decided to perform folic acid supplementation and not in combination with B6 and B12, as was done in many previous studies.10-12 Before carrying out an intervention with folic acid, vitamin B12 deficiency had to be ruled out since both nutrients use common metabolic pathways, and supplementation with folic acid may mask B12 deficiency.9 In our study, folic acid supplementation in the doses and times used did not cause a significant reduction in vitamin B12 levels whose baseline values were within normal ranges.

After the intervention, SG showed significant changes in various parameters linked to folate status, increasing both serum and red blood cell folate. Moreover, only SG experienced a drop in Hcy values. Other interventions with folic acid, mainly on elders, also achieved improvements in folate nutritional state as well as significant reductions in Hcy levels.11-13,35

EDs are associated with cognitive function impairment.20,21 Based on studies performed on Alzheimer's patients, which associate increased Hcy with cognitive impairment,36 it is hypothesised that high Hcy levels may contribute to cognitive impairment in ED patients.

Baseline cognitive status of participants assessed with the Stroop test showed that almost a third of them were below the mean scores for the same age Spanish population.28 However, baseline Hcy levels were not significantly correlated to test scores. Frieling et al. (2005) assessed the cognitive function of patients with ED using this test and obtained scores and percentages similar to those found at baseline in our study. They also did not find a relationship between Hcy levels and Stroop test scores. These results suggest that Hcy levels may not immediately reflect cognitive function impairment.

After the intervention, only SG improved their cognitive state, significantly increasing the number of words read in the P, C and CP test sheets. The changes in scores for PG were not significant.

After the intervention, SG improved their cognitive state, significantly reducing the time spent in solving TMT part B. As in the previous test, despite the fact that a reduction in test times was expected due to repetition of the test, the changes in the times for the PG were not significant.

It has been suggested that depression symptoms in patients with ED occur due to neuroendocrinological disorders induced by food restriction.19 According to scores obtained for the BDI, more than three quarters of all participants achieved scores indicative of depression. The prevalence rates for depression reported in ED patients ranged from 35% to 85%, and are greater in patients with RAN.18,19 Frieling et al. (2008), using the same test, obtained baseline scores that were equal to those of our study and found a significant correlation between baseline Hcy levels and test scores,19 which was not observed in our study or other recently performed study.22

After the intervention, SG improved their depressive state by significantly reducing BDI scores, which was not observed in PG. Although only 7.1% of the SG scored in normal ranges at baseline, the percentage increased to 41.7% after the intervention. The percentage of those who scored in the severe ranges also decreased (78.6% to 33.3%). The evolution of the percentages in the normal range in the PG was from 40% to 60%, and fell 10% for severe cases. We should note that for this analysis both groups received routine psychiatric and psychological treatment, which explains the positive evolution of PG. In addition, it was observed that BDI scores changes were significantly correlated with total folate intake changes. Therefore, oral supplementation with folic acid may prove to be beneficial in the treatment of this type of disorder in patients with ED.

We have not found previous studies on ED patients who supplemented with folic acid. However, we can find extensive literature with conflicting results on the influence of folate and folic acid supplementation on cognitive function in individuals with cognitive impairment due to age and dementia. A review by Cochrane concludes that there was no evidence of benefit from folic acid supplementation with or without the addition of B12 compared to placebo in some of the measures of cognition and mood in healthy individuals with cognitive impairment or dementia. However, in a trial that recruited healthy elderly people with high Hcy levels, the administration of folic acid supplements for three years was associated with a significant benefit in overall function, memory capacity and information processing speed. The authors suggest that more studies are necessary in this area9. It should be noted that most of the review studies are on elders, which means that some of the neurological lesions may be irreversible despite supplementation.

About the anthropometric parameters evolution after intervention, SG significantly increased their BMI, a condition not observed in PG. Previous studies have shown that nutritional rehabilitation (without vitamin B complex supplementation) may significantly reduce Hcy levels.14 In contrast, a recent study observed that after nutritional treatment (not specified by the authors) there was a significant increase in BMI and yet Hcy, folate and B12 levels did not change and there were no changes in most of the cognitive function tests used.22 In our study, the increase in BMI after the intervention was not associated with improved results in both Hcy levels and test scores.

Other determinants of the evolution of cognitive and depressive status, may include age and time of diagnosis of the disease.16 However, in our study there was no association between them.

This study is the first clinical trial, to our knowledge, that used folic acid supplements to assess changes in cognitive and depressive status in EDs patients. Another strength was the exclusive folic acid supplementation, not in combination with other B vitamins. This allowed us to isolate the results for this vitamin and to verify the folic acid supplementation use in participants without prior deficiencies does not cause negative effects on vitamin B12 levels. It is also noteworthy that an extensive battery of tests was used to assess the evolution in cognitive and depression status (Stroop, TMT, and BDI), since current evidence suggests that Hcy levels alone cannot report on the clinical repercussion in cognitive and depressive status.

One of the limitations of this study was the small sample size. Nevertheless, other EDs patients publications have similar sample sizes. The small size is consequence of the low prevalence of this disease coupled with the strict exclusion criteria. The small sample size precludes a proper analysis by subgroups, which would have been of great interest. Moreover, the inclusion of a healthy control group would have been of significant value for comparing baseline test results with a reference population.

Positive evolution of the cognitive and depressive status observed in SG may contribute to improving their quality of life and recovery. This fact demonstrates the scientific importance of this study, since folic acid supplementation may be used as tool within a comprehensive and multidisciplinary treatment for ED patients.



Supplementation with 10 mg/day of folic acid for six months in patients with EDs (RAN and EDNOS) and low folate intake produced an improvement in folate status, as well as, significant reduction in Hcy levels and significant and favourable changes in most test scores for cognitive and depressive status. Supplementation was safe and vitamin B12 levels were not affected.

Further studies with larger sample sizes are needed to expand and support these results.



We thank the study participants and the staff of the Nutrition Department at La Paz University Hospital who contributed to its successful completion.

This study was made possible thanks to the donation of study tablets and placebos from the laboratory ITALFARMA S.A.

The authors declare no conflict of interest.



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Viviana Loria-Kohen.
Nutrition Department. La Paz University Hospital.
Health Research Institute IdiPAZ.
Paseo de la Castellana, 261.
28046 Madrid, Spain.

Recibido: 22-XI-2012.
1.a Revisión: 22-XI-2012.
Aceptado: 2-XI-2012.

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