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Almedia , et al. "B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial.". Trials. 2014. 205(6):450-7.
PubMedFull text

Clinical Question

In middle-aged or older adults with depression, do B vitamins enhance and/or sustain an antidepressant response?

Bottom Line

B vitamins do not improve depression related outcomes in patients within 12 weeks. Over 52 weeks, however, they increase the odds of remission and reduce the risk of relapse.

Major Points

Antidepressants are the first line therapy for the management of depression, but many patients fail to respond adequately to therapy. The B vitamin to enhance treatment response to antidepressants in middle aged or older adults (B-VITAGE) trial evaluated whether adding vitamins B6, B12, and folic acid to an antidepressant therapy (citalopram) had an effect on the efficacy of therapy.

They found that while there was no significant difference in efficacy over a 12 week period between B vitamin supplementation or placebo (measured as a 50% or greater reduction in MADRS score), there was an increased rate of remission and a reduced number of relapses over 52 weeks in the supplementation group. There was no significant difference in adverse events between groups, and no significant difference in the change of antidepressants.


  • No available guidelines reference using B vitamins in the management of depression


  • Single site, double-blind, parallel-group, randomized, controlled trial
  • N=153
    • Treatment (n=77)
    • Control (n=76)
  • Setting: Royal Perth Hospital, Australia
  • Enrollment: March 2009 to September 2012
  • Mean follow-up: 52 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Remission of DSM-IV-TR major depressive episode after 12, 26, and 52 weeks of treatment, as assessed by MINI.


Inclusion Criteria

  • Age 50 years or over
  • Major depressive episode in the context of a major depressive disorder according to DSM-IV-TR criteria
  • A MADRS score >20
  • Fluency in written and spoken english
  • Alcohol Use Disorders Identification Test (AUDIT) <15
  • Mini-Mental State Examination (MMSE) >24

Exclusion Criteria

  • Clinical history of stroke or neurodegenerative disorders (Parkinson’s, etc.)
  • Clinical history of allergic reactions to citalopram or escitalopram
  • Clinical history of life-threatening illnesses likely to compromise 1-year survival
  • Evidence of prominent psychotic symptoms or suicidal intent
  • Clinical history for schizophrenia, schizoaffective disorder or bipolar disorder
  • Currently undergoing electroconvulsive therapy or using antidepressants at baseline assessment

Baseline Characteristics

  • All data presented is in the order of B vitamin group versus placebo
  • Mean age: 63.4 vs. 61.7 years
  • Mean MMSE: 29 vs. 29
  • Mean MADRS: 26 vs. 27


  • Randomized to citalopram (10mg) plus placebo once daily or citalopram (10mg) plus vitamin B12 (0.5mg), folic acid (2mg), and vitamin B6 (25mg) once daily
    • In both groups, dose of citalopram was increased to 20mg after 2 weeks, with further increase to 40mg by week 8 to patient tolerance
  • After 12 weeks, the decision to maintain citalopram therapy or switch antidepressants was devolved to the patient’s primary care provider
  • Patients were encouraged to continue B-vitamins for 52 weeks or as long as tolerated
  • Patients were encouraged to not use any supplements or vitamins except the tablet given
  • Reduction of MADRS scores were monitored at 2, 8, 12, 26, and 52 weeks
  • Remission of major depressive episodes as measured by the MINI were monitored at weeks 12, 26, and 52
  • Relapse was measured in patients who reached remission after 12 weeks


Comparisons are placebo vs. vitamin B supplementation.

Primary Outcomes

Remission of major depressive episode after 52 weeks as assessed by MINI
75.8% vs. 85.5% (OR 2.49; 95% CI 1.12-5.51) NNT=11

Secondary Outcomes

>50% reduction in MADRS score after 12 weeks
76.7% vs. 64.4% (OR 0.59; 95% CI 0.28-1.25; P=0.840)
Relapse by week 52
17.5% vs. 8.8% (OR 0.33; 95% CI 0.12-0.94) NNT=12

Subgroup Analysis

Odds of remission in patients with tHcy >10.4 umol/L
(OR = 3.47; 95% CI 1.22-9.84)
Odds of remission in patients with tHcy <10.4 umol/L
(OR = 1.09, 95% CI 0.32-3.75)

Adverse Events

  • All side effects presented were related to citalopram. No significant differences in adverse events were detected between groups.


  • Small sample size that did not meet requirement for 80% power
  • Limited demographic population may diminish external validity
  • Recruitment was stopped prior to the planned number of participants being recruited and an explanation was not provided as to why.
  • High homocysteine levels have been associated with increased symptoms of depression. This study indicated that using B vitamins in patients with hyperhomocysteinemia and depression is beneficial. Despite this, testing homocysteine levels is not a standard practice for patients with depression in a clinical setting.


  • Funded by a grant from the National Health and Medical Research Council of Australia.
  • No conflicts of interest were declared.

Further Reading