Walker 2012.

Methods	2 x 2 x 2 factorial design, parallel group, double‐blinded, multicentre, duration of treatment 24 months, duration of follow‐up 24 months
Participants	Location: Australia. 3 sites: 2 urban and 1 rural Recruitment: The population‐based sample was recruited by a direct mailing of a screening survey and consent form to 105,000 randomly selected adults aged from 60 to 74 years. Number randomised: 453 in intervention, 456 in comparison Participant (baseline) characteristics: Age, mean (±SD): overall: 65.94 ± 4.24 folic acid‐vitamin B12: 65.92 ± 4.30 placebo: 65.97 ± 4.18 Gender, male, n (%): overall: 358 (39.8) folic acid‐vitamin B12: 181 (40.5) placebo: 177 (39.1) Main diagnosis: elevated psychological distress (Kessler Distress 10 Scale > 15) Inclusion criteria: cohort of community‐dwelling older 60–74 y adults with elevated psychological distress (Kessler Distress 10–Scale; scores > 15); did not engage in physical activity at public health–recommended levels as indicated by International Physical Activity Questionnaire scores; did not take folic acid, vitamin B12, or vitamin B complex supplements; had no history of dementia, bipolar disorder, or current suicide risk; had competent literacy skills; and did not have a medical condition that would contraindicate exercise or folic acid use Exclusion criteria: High likelihood of a depressive disorder with K10 scores of ≥ 30 were excluded. Those individuals with low concentrations of red blood cell folate (< 250 nmol/L) and vitamin B12 (<130 nmol/L), and abnormal thyroid stimulating hormone concentrations (0.35‐5.0 mU/L) were excluded because participation may have led to potentially adverse outcomes.
Interventions	Intervention: 1) Daily oral dose of one tablet consisting of 400 µg folic acid + 100 µg vitamin B12 supplementation (Matchland Pty Ltd, t/a New Products Development –ABN57052101176, Brisbane, Australia) for 24 months The protocol changed to 2 daily oral doses (200 µg folic acid + 50 µg vitamin B12 each) from July 2007. Comparator group: Drug: placebo. Placebo tablets were manufactured by the same producers of the folic acid + vitamin B12 tablets and were identical except for the omission of the active substances under investigation. Use of additional interventions (common to both treatment arms): Due to the factorial design, in both vitamin and placebo groups, approximately half the participants received an intervention to promote physical activity and approximately half info about nutrition for older adults; and approximately half received a mental health literacy intervention and approximately half received arthritis and pain management info.
Outcomes	Outcomes of interest in the review: Primary outcomes: TICSm total score Secondary outcomes: TICSm subscores: 1) orientation; 2) registration, recent memory, and delayed recall (immediate and delayed recall reported separately); 3) attention/calculation; and 4) semantic memory, comprehension, and repetition Processing speed measured with BTACT IQCODE
Notes	Funding sources, quote:“Supported by beyond blue: the national depression initiative and the Australian Government Department of Health and Ageing. HC was supported by a National Health and Medical Research Council (NHMRC) fellowship no. 525411. JGW was supported by NHMRC Capacity Building Grant 418020". "The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript." Declarations of interest, quote: “None of the authors had any conflicts of interest." Treatment adherence "Adherence was monitored by telephone assessment at 14 time points and by blood assay at baseline and at 12‐ and 24‐mo assessments."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomisation followed the screening assessment with block size fixed at eight and using strata comprising location, gender and high (19) and low (16–18) K10 depression scores (conducted by A.J.M.) using an automated computerised system." Comment: adequate method of random sequence generation
Allocation concealment (selection bias)	Low risk	Quote: “using an automated computerised system". Comment: adequate method of allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “Participants, interviewers, investigators and the survey administrators were masked to active intervention and folic placebo (sic) allocation.” Comment: Participants and personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “Participants, interviewers, investigators and the survey administrators were masked to active intervention and folic placebo (sic) allocation.” Comment: Outcome evaluators were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Of those who were recruited into the trial, the dropout rate was low, with only 123 (13.5%) participants withdrawing from the time of randomisation to the 24‐mo assessment”. Comment: Reasons for withdrawal balanced across groups
Selective reporting (reporting bias)	High risk	Comment: All cognitive results were reported, but not all were reported in sufficient detail for inclusion. Results of this study were therefore missing from some analyses.
Other bias	Low risk	Comment: no other important risks identified