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A Systematic Review of Randomized Trials

Ethan M. Balk, MD, MPH; Gowri Raman, MD; Athina Tatsioni, MD; Mei Chung, MPH; Joseph Lau, MD; Irwin H. Rosenberg, MD

Arch Intern Med. 2007;167(1):21-30.

ABSTRACT
Background  Despite their important role in cognitive function, the value of B vitamin supplementation is unknown. A systematic review of the effect of pyridoxine hydrochloride (hereinafter "vitamin B₆"), cyanocobalamin or hydroxycobalamin (hereinafter "vitamin B₁₂"), and folic acid supplementation on cognitive function was performed.

Methods  Literature search conducted in MEDLINE with supplemental articles from reviews and domain experts. We included English language randomized controlled trials of vitamins B₆ and/or B₁₂ and/or folic acid supplementation with cognitive function outcomes.

Results  Fourteen trials met our criteria; most were of low quality and limited applicability. Approximately 50 different cognitive function tests were assessed. Three trials of vitamin B₆ and 6 of vitamin B₁₂ found no effect overall in a variety of doses, routes of administration, and populations. One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels. Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function. Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements. The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes.

Conclusion  The evidence does not yet provide adequate evidence of an effect of vitamin B₆ or B₁₂ or folic acid supplementation, alone or in combination, on cognitive function testing in people with either normal or impaired cognitive function.

INTRODUCTION

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Globally, 24 million people have some form of dementia, with 4.6 million new cases diagnosed each year.¹ It is estimated that the number of people affected will double every 20 years and reach 81 million by 2040. Pharmacotherapy of Alzheimer disease and other dementias can provide only modest cognitive or disease-modifying benefits.² However, even modest benefits may have significant effects on quality of life, caregiver burden, and societal economic costs. Increased homocysteine levels in conjunction with low levels of folate, vitamin B₆, and vitamin B₁₂, which interact to control homocysteine, have been reported to correlate with decreased performance on cognitive tests.^3-5 For these reasons, B vitamin supplementation has been proposed to prevent or reverse cognitive decline.

This systematic review examines whether supplementation with pyridoxine hydrochloride (hereinafter "vitamin B₆"), cyanocobalamin or hydroxycobalamin (hereinafter "vitamin B₁₂"), and folic acid can prevent, decrease the progression rate of, or reverse the neurologic changes associated with age-related neurodegenerative conditions such as Alzheimer disease in humans. The review was conducted as part of a larger evidence report on the association between B vitamins and berries and neurocognitive function.⁶

METHODS

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STUDY ELIGIBILITY

We conducted a comprehensive literature search for publications on B vitamins in MEDLINE and Commonwealth Agricultural Bureau (CAB) Abstracts from inception through February 2, 2005; an update limited to randomized trials and systematic reviews was performed on August 17, 2006. Search terms included the common and chemical names for the B vitamins (folic acid, folate, pteroylglutamic, folacin, riboflavin, lactoflavin, thiamin(e), cobalamin, cyanocobalamin, pyridoxine, pyridoxal, pyridoxamine, and vitamins B₁, B₂, B₆, and B₁₂) and neurocognitive terms including nervous system diseases, cognitive disorders, delirium, amnestic, neurodegeneration, dementia, Alzheimer, Lewy body, brain, neuron, and nerve cell. Additional studies were sought from neurology and vitamin research experts and from reference lists of selected articles, review articles, and meta-analyses.

Study eligibility criteria included peer-reviewed reports of randomized controlled trials of clearly defined B vitamin supplements (B₆, B₁₂, and folic acid), where specific type of vitamin, dose, and route of administration were reported. We included English language publications of trials of adult participants with outcomes related to diagnosis or severity (degree) of Alzheimer disease, other age-related neurocognitive disorders, cognitive impairment, or tests of cognitive function. We excluded studies of mental retardation, encephalopathies, peripheral neuropathy and other lower motor neurodegeneration, subacute combined degeneration, vascular dementia, and mixed causes of dementia lacking separate analyses for disease types. We also excluded studies of "multivitamins" that included vitamins other than B vitamins.

STUDY SELECTION AND DATA EXTRACTION

All citations identified through the literature search were screened according to the eligibility criteria, and retrieved articles were evaluated against the same criteria. Each accepted study was extracted by a single reviewer, and a second reviewer independently verified the extracted data. Data extraction issues were resolved by consensus.

METHODOLOGIC QUALITY GRADE

We used a 3-category grading system to denote the methodologic quality of each trial^6-7: (1) Good quality studies had the least bias. These studies mostly adhered to the commonly held concepts of good quality: they were formal and randomized with a clear description of the population, setting, interventions, and comparison groups; they used appropriate outcome measurements, statistical and analytic methods, and reporting conventions; and they contained no reporting errors, less than a 20% dropout rate, clear reporting of dropouts, and no obvious bias. (2) Fair quality studies were susceptible to some bias. They had some deficiencies but none likely to cause major bias. (3) Poor quality studies had significant bias. They had serious errors in design, analysis, or reporting or may have had a large amount of missing information or discrepancies in reporting. Each included study was graded by at least 2 people. When there were disagreements, additional reviewers graded the studies, and consensus was reached.

APPLICABILITY GRADE

Applicability addresses the relevance of a given study that is distinct from the question of the study's methodologic quality. The applicability of a study is dictated by the questions and populations that are of interest to those analyzing the studies.

We categorized studies within a target population into 1 of 3 levels of applicability^6-7: (1) In widely applicable studies, the sample was representative of individuals at increased risk for, or diagnosed as having, age-related neurocognitive disorders. They included both sexes, an appropriate age range, and other important features of the target population (eg, general health status). At least 30 participants were analyzed. (2) For moderately applicable studies, the sample was representative of a relevant subgroup of the target population but not the entire population. Limitations included such factors as a narrow age range and a setting that applied to only a portion of the general population (eg, nursing home). At least 10 participants were analyzed. (3) In narrowly applicable studies, the sample was representative of a narrow subgroup of participants only and was of limited applicability to other subgroups.

On review of the literature, we determined that studies of short-term B vitamin supplementation (ie, 1 or 3 months), but longer-term cognitive testing (ie, at 3 or 12 months), were of lesser relevance to the question of whether B vitamin supplementation should be recommended to prevent cognitive decline. These studies were included but deemed to be of limited applicability.

OUTCOMES AND METRICS REPORTED

We evaluated all outcomes relevant to neurocognitive function that were reported in studies. In all included trials, this involved the use of one or more cognitive function tests or subtests.

Three sets of data were evaluated: (1) the mean baseline levels in both intervention and control arms, (2) within-cohort changes (ie, final minus baseline values), and (3) the net change of the outcome (change in intervention cohort minus control cohort). In addition, we included the reported P values of both the within-cohort change and the net change. We reported P value less than .10; those above .10 and those reported as nonsignificant were described as "NS."

RESULTS

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The literature searches yielded 6914 citations, of which 185 articles were retrieved. An additional 16 studies were identified in review articles and study reference lists or were forwarded by domain experts. From these 202 articles, 14 randomized controlled trials of vitamins B₆, B₁₂, and folic acid supplementation qualified for this review (these included 18 comparisons of B vitamins with placebo).^8-19 Among the rejected studies, 146 were studies of correlations between B vitamin levels or dietary intake and cognitive function; 32 were other nonrandomized studies; and 9 randomized trials did not evaluate either interventions or outcomes of interest (Figure). One trial reported separate data for different age groups of cognitively normal women.⁹ After reviewing all studies, we included only the data from the older cohort of women, aged 65 to 92 years, to be consistent with the other trials, which all included only older participants. Table 1 lists the number of studies, number of participants, quality, applicability, and summarized results of the evidence for the effects of B vitamin intervention on neurocognitive conditions.

View larger version (43K): [in this window] [in a new window] [as a PowerPoint slide]   Figure. Flow diagram of study selection process. CAB indicates Commonwealth Agricultural Bureau.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 1. Summary of Intervention Studies Evaluating the Effect of B Vitamins on Neurocognitive Outcomes

VITAMIN B₆

Three trials of either good, fair, or poor quality and of narrow to moderate applicability investigated the effect of B₆ intervention on cognitive function in people with either normal cognitive function or limited to those with ischemic vascular disease (Table 2).^8-10 Sample sizes ranged from about 19 to 88 participants taking vitamin B₆ supplements; doses ranged from 12 to 75 mg/d, considerably higher than the US Recommended Daily Allowance (RDA) dose of 1.3 to 1.7 mg/d. Vitamin B₆ supplementation was given for 5 or 12 weeks; however, notably, 1 study performed follow-up cognitive testing at 1 year, 9 months after the vitamin supplementation stopped.⁸

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 2. Effect of Pyridoxine Hydrochloride (Vitamin B6) Intervention on Cognitive Function Tests

Across studies, among 9 different cognitive function subtests used in the 3 trials, no statistically significant difference in testing was found after vitamin B₆ supplementation in all but 1 test (Deijen et al¹⁰), where there was a significant improvement in long-term memory with vitamin B₆ compared with placebo. Among all the subtests, there was no consistent direction (net improvement vs net worsening) of effect with supplementation.

There is inadequate evidence to support any dose effect of vitamin B₆ on the outcomes. There was insufficient evidence from the trials regarding differences in effect on tests of different cognitive domains. No other interactions were reported in the studies.

VITAMIN B₁₂

Six trials of variable quality assessed the effect of vitamin B₁₂ intervention on cognitive function in humans (Table 3).^{9, 11-14,29} All studies had narrow to moderate applicability. Sample sizes ranged from 18 to 70 participants receiving vitamin B₁₂. Two trials each recruited cognitively intact participants with normal or low vitamin B₁₂ levels; 1 trial included participants with cognitive impairment; and 1 included people with a range of cognitive function. The 6 trials used different doses and administration routes of vitamin B₁₂ interventions ranging from 0.01 mg/d orally to 1 mg/wk intramuscularly. Three trials used oral vitamin B₁₂, and 3 used intramuscular vitamin B₁₂. Doses were higher than the US RDA of 2.4 µg/d. The duration of supplementation ranged from 4 weeks to 6 months. Notably, Hvas et al¹¹ retested cognitive function 2 months after stopping vitamin B₁₂ supplementation. There was large heterogeneity among trials in the cognitive function assessment instruments used.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 3. Effect of Cyanocobalamin or Hydroxycobalamin (Vitamin B12) Intervention on Cognitive Function Tests in Randomized Controlled Trials

For most of the cognitive tests performed, no effect was found for vitamin B₁₂. Only 3 of the 35 cognitive function tests and subtests showed a statistically significant difference between participants receiving vitamin B₁₂ compared with placebo. Notably, statistically significant net worsening on cognitive functioning tests was found in 2 studies (Hvas et al¹¹ and Eussen et al²⁹). However, in 1 of these tests, the effect was driven primarily by a statistically significant improvement in the placebo arm that was not seen in the treatment arm.¹¹ Neither study considered the effects to be clinically significant. In contrast, a large nonsignificant improvement was reported in 1 test,¹³ in which a statistically significant change compared with baseline was found with treatment, but the net change failed to reach statistical significance.

Seal et al¹² directly evaluated the effect of vitamin B₁₂ oral supplementation in 2 intervention arms, one receiving double the dose of the other, and compared these groups with placebo. No significant change was found in Mini-Mental State Examination²⁶ scores when the 3 groups were compared.

There is large heterogeneity among trials in terms of dose, administration route, and duration of treatment, and it would be difficult to support any conclusion about a potential dose effect. Overall, half of the tests found a net improvement in cognitive function and half a net worsening of cognitive function with vitamin B₁₂ supplementation. There was no evidence across trials of differences in effect in tests of different cognitive domains.

FOLIC ACID

Three trials of moderate to poor quality reported data on folic acid supplementation and the effect on cognitive function or therapeutic benefit in a total of 39 people who received folic acid (Table 4).^{9, 15-16} Two trials were conducted among participants with dementia or cognitive impairment, and 1 among normal participants. The trials tested various doses of folic acid ranging from 0.75 to 20 mg/d. In comparison, the US RDA for folate is 0.4 to 1 mg/d. Trial durations ranged from 5 to 10 weeks.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 4. Effect of Folic Acid Intervention on Cognitive Function Tests

The 3 trials had discordant results in 3 different populations. In a trial of relatively low-dose folic acid supplementation (0.75 mg/d) in women with normal cognitive function,⁹ no significant effects were found across 5 measured tests, with 3 showing a net improvement and 2 a net worsening. In a very small trial of folic acid, 20 mg/d, in 7 people with dementia and normal baseline folate levels,¹⁶ no statistically significant difference was found in the results of 8 cognitive function tests, although there was a trend toward a net worsening of associate learning and a trend toward a net improvement in 1 concentration test (Trails B³²). Overall, 5 tests found a net improvement and 3 a net worsening of cognitive function. In the third trial of cognitively impaired individuals with low baseline folate levels,¹⁵ supplementation with folic acid, 15 mg/d, resulted in a net benefit in all 6 cognitive tests used, 4 of which were statistically significant. The study found that the cognitive improvement after folic acid intervention was correlated in a linear fashion with the low levels of folate at baseline.

Owing to the paucity of evidence evaluating the effect of folic acid on the outcomes, any conclusions remain tentative. Nevertheless, the limited evidence may suggest a benefit from folic acid supplementation for people with both cognitive impairment and serum folate levels lower than 3 ng/mL (<6.8 nmol/L).

COMBINED B VITAMINS

Six trials of varying quality reported data on the effect of combined B vitamin intervention in participants with dementia, normal cognitive function, or ischemic vascular disease (Table 5).^{8, 17-19,29, 44} All trials used different daily doses of various B vitamins; all substantially higher than the US RDA for each vitamin. Studies tested combination B vitamins in from 17 to 128 participants. Two studies used a combination of folic acid, vitamin B₆, and vitamin B₁₂^{17, 44}; the other 4 trials combined folic acid and vitamin B₁₂.^{8, 18-19,29} One study used vitamin B₁₂ injections and oral folic acid,¹⁹ while the other trials used oral vitamin B₁₂. One study lasted 2 years⁴⁴; in the others, the B vitamin supplements were given for either 3 or 4 months; though 1 trial tested cognitive function 9 months after ending treatment.⁸

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 5. Effect of Combination Interventions on Cognitive Function

For most of the cognitive tests, no effect was found with B vitamin treatment. In 2 studies,^{17, 29} participants in the placebo arm performed better than those receiving B vitamins in 5 of the 25 tests. In contrast, McMahon et al⁴⁴ found a significant improvement in 1 of 8 cognitive tests with a combination of all 3 B vitamins. The remaining 3 trials of combination folic acid and vitamin B₁₂ found no significant effects on cognitive testing, although 2 did not report quantitative data.^{8, 18-19}

There were no dose-related responses discussed in the trials. There was no evidence across trials of differences in effect on tests of different cognitive domains.

COMMENT

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The limited evidence from the short-duration randomized controlled trials suggests that supplementation with vitamins B₆ or B₁₂ or folic acid among either elderly cognitively intact individuals or those with dementia or cognitive impairment does not improve cognitive function as measured by a wide battery of tests. The 1 exception to this may be folic acid supplementation in people with both cognitive impairment and serum folate levels lower than 3 ng/mL (<6.8 nmol/L). However, any conclusions about the effect of folic acid treatment are greatly limited because there are only 3 trials with 39 people who received folic acid. Further clarification may be available soon because a large, 3-year trial of folic acid in elderly people with hyperhomocysteinemia has been presented at an international conference.⁵² The abstract, which has not yet been peer reviewed, preliminarily reported a net improvement in global cognitive function including memory, sensorimotor speed, and informational processing speed.

Notably, in a minority of studies of both vitamin B₁₂ and combinations of B vitamins that include vitamin B₁₂ compared with placebo, the B vitamin treatment resulted in worse performance on a small number of cognitive tests. The clinical significance of this effect, though, is questionable, in that those receiving placebo had statistically significant improvements from baseline among these tests.

Overall, the data are sparse, and firm conclusions are not possible. Importantly, no trial evaluated the risk of developing dementia, clinical symptoms, neurological imaging tests, or clinical outcomes beyond ability to perform cognitive function tests. About 50 different tests or subtests were used across the trials, measuring different or overlapping domains of cognitive function; thus, comparisons across studies were difficult. In addition, studies did not explicitly report the clinical importance of the changes in cognitive function test results. Consequently, clinical inferences based on the reported scores alone would be problematic.

Only 1 trial compared different doses of vitamin B₁₂, and only 2 directly compared the different B vitamins.^8-9 No trial directly compared populations, routes of administration of vitamin B₁₂, or different durations. In addition, the small number of available trials limited our ability to assess the impact of these factors. The quality of the trials was often compromised by incomplete reporting of methodology and results, lack of blinding, small sample size, short duration, and other factors. Two of the trials also implicitly tested the effect of short-term intervention (1 or 3 months) on longer-term cognitive function (3 or 12 months).^{8, 11} Interpretation of the clinical value of this type of trial is unclear.

Future well-performed, well-analyzed, sufficiently powered, long-term, randomized controlled trials are necessary to address whether B vitamin supplementation is effective to slow cognitive decline or improve cognitive function. No peer-reviewed trial has addressed the question of whether these B vitamins can prevent or delay clinical dementia or can affect clinical symptoms of dementia. However, further standardization is clearly needed both in the field of vitamin research and for the assessment of cognitive function. Future studies should use only well-established diagnostic criteria for neurocognitive disorders and only measures of cognitive function that have been verified and accepted by the neurocognitive research community. Studies that use nonstandard diagnostic definitions or neurocognitive tests are of lesser value to clinicians, policy makers, and other researchers. Researchers should also preferentially use cognitive function tests that adequately differentiate between different cognitive domains and should evaluate how B vitamin supplementation differentially affects different cognitive domains. In addition, imaging studies such as magnetic resonance imaging and positron-emission tomography may prove to be of value to assess how B vitamin supplementation affects cognitive function.

In conclusion, the few available randomized controlled trials of vitamins B₆, and B₁₂ and folic acid supplementation, alone or in combination, do not provide adequate evidence for a beneficial effect of supplementation on cognitive function testing in people with either normal or impaired cognitive function, although 1 very small trial found an improvement with folic acid supplementation in patients with low baseline folate levels. However, the poor quality and the small number of trials and participants preclude a firm conclusion. Additional trials are needed to determine which populations, if any, would benefit from B vitamin supplementation and to determine whether B vitamin supplementation would affect clinical signs and symptoms of dementia.

AUTHOR INFORMATION

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Correspondence: Ethan M. Balk, MD, MPH, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, 750 Washington St, NEMC No. 63, Boston, MA 02111 (ebalk{at}tufts-nemc.org).

Accepted for Publication: September 15, 2006.

Author Contributions: Dr Balk had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Balk, Chung, Lau, and Rosenberg. Acquisition of data: Balk, Raman, and Chung. Analysis and interpretation of data: Balk, Raman, Tatsioni, and Rosenberg. Drafting of the manuscript: Balk. Critical revision of the manuscript for important intellectual content: Balk, Raman, Tatsioni, Chung, Lau, and Rosenberg. Statistical analysis: Balk and Chung. Obtained funding: Balk and Lau. Administrative, technical, and material support: Raman, Chung, and Lau. Study supervision: Balk and Lau.

Financial Disclosure: None reported.

Funding/Support: This evidence report was prepared by the Tufts-New England Medical Center Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (contract No. 290-02-0023), Rockville, Md. Funding was provided by the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine, National Institutes of Health.

Author Affiliations: Tufts-New England Medical Center Evidence-based Practice Center, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center (Drs Balk, Raman, Tatsioni, and Lau and Ms Chung), and Nutrition and Neurocognition Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (Dr Rosenberg), Boston, Mass.

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