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Almedia OP, 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.". Br J Psychiatry. 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, but this affect was small. There was no significant difference in adverse events between groups, and no significant difference in the change of antidepressants.

Several limitations are that this is a small sample size and recruitment was stopped prior to reaching the required number of patients for their power calculation without explanation in the manuscript. The authors did not assess what dose of citalopram patients were receiving nor for contamination of the findings of patients supplementing other vitamins at home.


As of June 2018, no guidelines have been published that reflect the results of this trial.


  • Single centre, double-blind, parallel-group, randomized, controlled trial
  • N=153
    • Citalopram + B-Vitamins (n=77)
    • Citalopram + Placebo (n=76)
  • Setting: Royal Perth Hospital, Australia
  • Enrollment: 31 March 2009 to 11 September 2013
  • 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 the Mini-International Neuropsychiatric Interview (MINI).[1]


Inclusion Criteria

  • ≥ 50 years
  • Major depressive episode in the context of a major depressive disorder according to DSM-IV-TR criteria[2]
  • A MADRS score ≥ 20 [3]
  • Fluency in written and spoken english
  • Alcohol Use Disorders Identification Test (AUDIT) ≤ 15[4]
  • Mini-Mental State Examination (MMSE) ≥ 24[5]

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

B-vitamin Group displayed

  • Demographics: mean age 63.4, 49.3% female,
  • Marital status: Single 8%, Married 57%,Separated/divorced 27%, Widowed 8%
  • Anthropomorphics: BMI normal 20.8%, overweight 44%, Obese 35%
  • Comorbid diagnoses: Cardiovascular disease 12%, Chronic Respiratory disease 20%, Diabetes 13%, Hearing impairment 21%
  • Diagnostics: Past diagnosis of depression 78%, mean MMSE 29, mean MADRS 26
  • Labs: median Homocysteine 11.2 mcgmol/L, Red cell folate 1352 mol/L, Vitamin B12 351 pmol/L


  • Citalopram (10mg) plus vitamin B12 (Cyanocobalamin 0.5mg), folic acid (2mg), and vitamin B6 (Thiamin 25mg) once daily
  • Citalopram (10mg) plus placebo once daily
    • Dose of citalopram were increased to 20mg after 2 weeks
    • Further increase to 40mg by week 8 if symptoms persisted
  • After 12 weeks, the decision to maintain citalopram therapy or switch antidepressants was devolved to the patient’s primary care provider


Comparisons are placebo vs. vitamin B supplementation.

Primary Outcomes

Remission of major depressive episode after 52 weeks
65.8% vs. 68.8% (ARR 3, OR 1.76, 95% CI 0.81–3.82) NNT = 33, P=NS

Secondary Outcomes

≥ 50% reduction in MADRS score at 12 weeks
76.7% vs. 64.4% (OR 0.59, 95% CI 0.28-1.25) P = 0.84
Relapse after week 52
17.5% vs. 8.8% (OR 0.33, 95% CI 0.12-0.94) NNT=12
Mean change in plasma homocysteine at 52 weeks
-0.2 mcmol/L vs. -2.1 mcmil/L (Difference -1.1, 95% -1.4 to -0.7)
Mean change in Red cell folate at 52 weeks
-64.2 nmol/L vs. 864.7 nmol/L (Difference 608.4, 95% 487.8-729.1)
Mean change in plasma homocysteine at 52 weeks
23.1 pmol/L vs. 339.0 pool/L (Difference 196, 95% 147.2-244.9)

Subgroup Analysis

Remission of major depressive episode after 52 weeks after adjustment for sex and baseline total plasma homocysteine concentration
75.8% vs. 85.5% (OR 2.49; 95% CI 1.12-5.51) NNT = 16
Odds of remission in patients with total plasma concentration of homocysteine > 10.4 umol/L
(OR = 3.47; 95% CI 1.22-9.84)
Odds of remission in patients with total plasma concentration of homocysteine ≤ 10.4 umol/L
(OR = 1.09, 95% CI 0.32-3.75)

Adverse Events

  • 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.
  • Testing homocysteine levels is not a standard practice for patients with depression in a clinical setting.
  • contamination with self-selected vitamins was not assessed


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

Further Reading

  1. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59 (suppl 20): 22–33; quiz 4–57
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn, revised) (DSM-IV-TR). APA, 2000
  3. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9
  4. Bohn MJ, Babor TF, Kranzler HR. The Alcohol Use Disorders Identification Test (AUDIT): validation of a screening instrument for use in medical settings. J Stud Alcohol 1995; 56: 423–32.
  5. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98.