DepressionVITAL-DEPNCT01696435

VITAL-DEP: Depression Endpoint Prevention in the VITamin D and OmegA-3 TriaL

A study testing vitamin D3 and omega-3 fatty acids (fish oil) in people with Depression and Depressive Symptoms, run by Brigham and Women's Hospital at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 50 years and olderHealthy volunteers can take part
Conditions the study is for: Depression, Depressive Symptoms, Mood
What is being tested?: vitamin D3 and omega-3 fatty acids (fish oil)
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 18,353 participants
Where: 1 siteUnited States
Study dates: Jul 2010to 31 Mar 2025
Phase: Interventional
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 50 years and older
All sexes
Healthy volunteers accepted
Adult, Older adult

Participants in VITAL (NCT 01169259) who meet the following criteria are eligible to participate in this ancillary study. These are the criteria specific for testing of the primary aims in the VITAL-DEP ancillary study:

no current significant depressive symptoms
no core major depressive disorder symptoms for a period of two or more weeks in the past two years
no history of alcohol and/or substance abuse disorder active in the past 12 months, schizophrenia or other primary psychotic disorder, bipolar disorder, post-traumatic stress disorder or obsessive-compulsive disorder
no current psychotherapy or current use of psychotropics (including non-prescription agents for the treatment of mood disorders), except for limited use of mild sedatives/hypnotics
no history of major neurologic disorder or delirium episode in the past 12 months
no history of clinical (i.e., overt and not sub-clinical) hypothyroidism diagnosis

Trial locations and contacts

1 site in 1 country.

United States1 site

Brigham and Women's Hospital
Boston, Massachusetts, 02215

Other trials in United States

About this study

The VITamin D and OmegA-3 TriaL (VITAL; NCT 01169259) is an ongoing randomized clinical trial in 25,871 U.S. men and women investigating whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 gram) reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. This ancillary study is being conducted among participants in VITAL and will examine whether vitamin D or fish oil: 1) reduces risk of clinical depressive syndrome, 2) yields better mood scores over time, compared to placebo.

Read the detailed description

VITAL-DEP: Depression Endpoint Prevention in the VITamin D and OmegA-3 TriaL is a randomized clinical trial of vitamin D (in the form of vitamin D3 [cholecalciferol]) and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements in the prevention of depression in older adults. Existing data from laboratory studies, epidemiologic research, limited clinical trials research suggest that these nutritional agents may reduce risk of depression or improve mood, but large primary prevention trials with adequate dosing and lengthy treatment durations in general populations are lacking.

Eligible participants will be assigned by chance (like a coin toss) to one of four groups: (1) daily vitamin D3 and omega-3; (2) daily vitamin D3 and omega-3 placebo; (3) daily vitamin D placebo and omega-3; or (4) daily vitamin D placebo and omega-3 placebo. Participants have an equal chance of being assigned to any of these four groups and a 3 out of 4 chance of getting at least one active agent.

Participants in all groups will take two pills each day -- one softgel that contains either vitamin D3 or vitamin D placebo and one capsule that contains either omega-3 or omega-3 placebo. Participants will receive their study pills in convenient calendar packages via U.S. mail.

Participants will also fill out a short (15-20 minute) questionnaire each year. The questionnaire asks about health; lifestyle habits such as physical exercise, diet, and smoking; use of medications and dietary supplements; family history of illness, and new medical diagnoses. The questionnaire also includes specific questions pertaining to mood. Occasionally, participants may receive a phone call from study staff to collect information or to clarify responses on the questionnaire.

Primary aims of 1) reduction in risk of clinical depressive syndrome and 2) yielding of better mood scores over time will be address in the full VITAL cohort of 20,000. Secondary aims will be addressed in sub-set of participants. The secondary aims will address whether: 1) among a subset of 1,000 participants evaluated at a Clinical and Translational Science Center (CTSC), the agents reduce risk of depression and yield better mood scores among persons with known risk factors for late-life depression; 2) among a subset of 1,000 participants evaluated at a CTSC, the agents reduce risk of major depression and yield better mood scores among persons with sub-syndromal depressive symptoms; 3) among all VITAL participants, African-American race (African-Americans have high risk of Vitamin D deficiency) modifies effects of vitamin D3 supplementation on late-life depression risk and on mood scores; 4) among a subset of participants, baseline plasma levels of vitamin D and omega-3 fatty acids are related to depression risk and/or modify agent effects.

Thus, VITAL-DEP will address simultaneously the impact of both vitamin D and fish oil for universal, selective and indicated prevention of late-life depression.

Conditions: Depression, Depressive Symptoms, Mood
Being tested: vitamin D3, omega-3 fatty acids (fish oil), Fish oil placebo, Vitamin D placebo
Keywords: Depression, Depressive Symptoms, Mood, Geriatric, Prevention
Medical subject headings: Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

vitamin D3Dietary supplement
Also called cholecalciferol
Vitamin D3 (cholecalciferol), 2000 IU per day
omega-3 fatty acids (fish oil)Drug
Also called fish oil
Omacor, 1 capsule per day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]).
Fish oil placeboDietary supplement
Fish oil placebo
Vitamin D placeboDietary supplement
Vitamin D placebo

Study groups in NCT01696435
Study group	Role	What they receive
Vitamin D + fish oil placebo	Active comparator	Vitamin D3 (cholecalciferol), 2000 IU per day Fish oil placebo Receives: Dietary Supplement: vitamin D3; Dietary Supplement: Fish oil placebo
Vitamin D placebo + fish oil	Active comparator	Vitamin D placebo Omacor, 1 capsule per day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]) Receives: Drug: omega-3 fatty acids (fish oil); Dietary Supplement: Vitamin D placebo
Vitamin D placebo + fish oil placebo	Active comparator	Vitamin D placebo Fish oil placebo Receives: Dietary Supplement: Fish oil placebo; Dietary Supplement: Vitamin D placebo
Vitamin D + fish oil	Active comparator	Vitamin D3 (cholecalciferol), 2000 IU per day Omacor, 1 capsule per day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]) Receives: Dietary Supplement: vitamin D3; Drug: omega-3 fatty acids (fish oil)

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With a Depression Event
Depression syndrome will be determined by presence of clinical diagnosis, treatment and/or above-threshold symptoms on mood questionnaire (e.g., PHQ) items. This is an event outcome, where the depression event was defined as a new self-report of physician/clinician-diagnosed depression, treatment (medication and/or counseling) for depression, or presence of clinically relevant depressive symptoms (PHQ-8 total score >=10 points) on the annual study questionnaires that were administered over a median 5.3 years of randomized treatment and follow-up. Participants were followed for the depression event until the occurrence of the endpoint, death, or the end of the trial, whichever came first. The Outcome Measure table shows the counts of depression events in each randomized group by treatment.
Measured: From date of randomization until the date of the occurrence of the endpoint, death, or the end of the trial, whichever came first, assessed up to a median of 5.3 years of follow-up
Mood Scores
Mood scores are evaluated by the 8-item Patient Health Questionnaire (PHQ-8). The measured outcome was the total PHQ-8 score. The PHQ-8 includes items corresponding to the criteria for major depression. Each of the 8 items can be scored as 0, 1, 2, or 3 points (higher score means worse symptoms). The 8 items are summed to a total PHQ-8 score. The range for the PHQ-8 score is 0-24 points; higher scores denote worse mood or depressive symptoms. The PHQ-8 was measured annually at baseline and at up to 5 follow-up times (for a maximum of 6 time points). Data from all time points was used to determine the mean differences in change in mood scores over all follow-up by randomized treatment. Per protocol, the Statistical Analysis section shows the results for the primary outcome of mean difference in overall change in PHQ-8 scores comparing active and placebo groups (for each agent).
Measured: Baseline, follow-up year 1, follow-up year 2, follow-up year 3, follow-up year 4, and follow-up year 5

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 201031 Mar 2025

First posted1 Oct 2012 (estimated)
Study startJul 2010
Primary completion31 Dec 2021
Study completion31 Mar 2025

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (10)Papers the sponsor has linked to this study.
Other trials for DepressionStudies of the same condition, open and under way.
More trials run by Brigham and Women's HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Factorial
Masking: Triple blind
Who is masked: Participant, Investigator, Outcomes assessor
Enrolment: 18,353 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01696435
Sponsor's protocol ID: 2010-P-001881
Other IDs: R01MH091448, R56MH091448
Acronym: VITAL-DEP
Status last verified: Nov 2025
First submitted: 24 Sep 2012
Last updated: 10 Dec 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Vyas CM, Ostaszewski BL, Anderson AK, Cook NR, Kang JH, Mischoulon D, Reynolds CF 3rd, Chang G, Gatchel JR, Manson JE, Selkoe DJ, Okereke OI. Effects of long-term daily supplementation with vitamin D3 and marine omega-3 fatty acids on change in ADRD biomarkers: A secondary analysis of a randomized clinical trial. Alzheimers Dement (N Y). 2026 Sep 14;12(3):e70312. doi: 10.1002/trc2.70312. eCollection 2026 Jul-Sep.
PubMed 42746141
Vyas CM, Kang JH, Mischoulon D, Cook NR, Reynolds Iii CF, Chang G, Mora S, De Vivo I, Manson JE, Okereke OI. Apolipoprotein E and Its Association With Cognitive Change and Modification of Treatment Effects of Vitamin D3 and Omega-3s on Cognitive Change: Results From the In-Clinic Subset of a Randomized Clinical Trial. J Gerontol A Biol Sci Med Sci. 2024 Mar 1;79(3):glad260. doi: 10.1093/gerona/glad260.
PubMed 37952113
Vyas CM, Mischoulon D, Chang G, Cook NR, Weinberg A, Copeland T, Kang JH, Bubes V, Friedenberg G, LeBoff MS, Lee IM, Buring JE, Manson JE, Reynolds CF, Okereke OI. Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Indicated and Selective Prevention of Depression in Older Adults: Results From the Clinical Center Sub-Cohort of the VITamin D and OmegA-3 TriaL (VITAL). J Clin Psychiatry. 2023 Jun 26;84(4):22m14629. doi: 10.4088/JCP.22m14629.
PubMed 37378490
Vyas CM, Mischoulon D, Chang G, Reynolds CF 3rd, Cook NR, Weinberg A, Copeland T, Bubes V, Bradwin G, Lee IM, Buring JE, Mora S, Rifai N, Manson JE, Okereke OI. Relation of serum BDNF to major depression and exploration of mechanistic roles of serum BDNF in a study of vitamin D3 and omega-3 supplements for late-life depression prevention. J Psychiatr Res. 2023 Jul;163:357-364. doi: 10.1016/j.jpsychires.2023.05.069. Epub 2023 May 26.
PubMed 37267732
Vyas CM, Sadreyev RI, Gatchel JR, Kang JH, Reynolds CF, Mischoulon D, Chang G, Hazra A, Manson JE, Blacker D, De Vivo I, Okereke OI. Pilot Study of Second-Generation DNA Methylation Epigenetic Markers in Relation to Cognitive and Neuropsychiatric Symptoms in Older Adults. J Alzheimers Dis. 2023;93(4):1563-1575. doi: 10.3233/JAD-230093.
PubMed 37212116
Okereke OI, Vyas CM, Mischoulon D, Chang G, Cook NR, Weinberg A, Bubes V, Copeland T, Friedenberg G, Lee IM, Buring JE, Reynolds CF 3rd, Manson JE. Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2021 Dec 21;326(23):2385-2394. doi: 10.1001/jama.2021.21187.
PubMed 34932079
Kang JH, Vyas CM, Okereke OI, Ogata S, Albert M, Lee IM, D'Agostino D, Buring JE, Cook NR, Grodstein F, Manson JE. Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial. Sci Rep. 2021 Dec 1;11(1):23253. doi: 10.1038/s41598-021-02485-8.
PubMed 34853363
Okereke OI, Reynolds CF 3rd, Mischoulon D, Chang G, Vyas CM, Cook NR, Weinberg A, Bubes V, Copeland T, Friedenberg G, Lee IM, Buring JE, Manson JE. Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):471-480. doi: 10.1001/jama.2020.10224.
PubMed 32749491
Donneyong M, Reynolds C, Mischoulon D, Chang G, Luttmann-Gibson H, Bubes V, Guilds M, Manson J, Okereke O. Protocol for studying racial/ethnic disparities in depression care using joint information from participant surveys and administrative claims databases: an observational cohort study. BMJ Open. 2020 Jan 7;10(1):e033173. doi: 10.1136/bmjopen-2019-033173.
PubMed 31915172
Okereke OI, Reynolds CF 3rd, Mischoulon D, Chang G, Cook NR, Copeland T, Friedenberg G, Buring JE, Manson JE. The VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention (VITAL-DEP): Rationale and design of a large-scale ancillary study evaluating vitamin D and marine omega-3 fatty acid supplements for prevention of late-life depression. Contemp Clin Trials. 2018 May;68:133-145. doi: 10.1016/j.cct.2018.02.017. Epub 2018 Mar 8.
PubMed 29526608

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 10 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: VITAL-DEP: Depression Endpoint Prevention in the VITamin D and OmegA-3 TriaL
ClinicalTrials.gov ID: NCT01696435
Acronym / sponsor ID: VITAL-DEP / 2010-P-001881
Conditions: Depression, Depressive Symptoms, Mood
Keywords: Depression, Depressive Symptoms, Mood, Geriatric, Prevention
Study type: Interventional
Recruitment status: Completed
Enrolment: 18,353 participants (actual)
Lead sponsor: Brigham and Women's HospitalUniversity, hospital or other
Collaborators: National Institute of Mental Health (NIMH)
Study start: Jul 2010
Primary completion: 31 Dec 2021 (actual)
Study completion: 31 Mar 2025 (actual)
First posted: 1 Oct 2012 (estimated)
Results: Posted 14 Mar 2023

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Thus, VITAL-DEP will address simultaneously the impact of both vitamin D and fish oil for universal, selective and indicated prevention of late-life depression.

Study design

Primary purpose: Prevention
Allocation: Randomised
Intervention model: Factorial
Masking: Triple blind (participant, investigator, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
Vitamin D + fish oil placebo	Active comparator	Dietary Supplement: vitamin D3, Dietary Supplement: Fish oil placeboVitamin D3 (cholecalciferol), 2000 IU per day Fish oil placebo
Vitamin D placebo + fish oil	Active comparator	Drug: omega-3 fatty acids (fish oil), Dietary Supplement: Vitamin D placeboVitamin D placebo Omacor, 1 capsule per day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA])
Vitamin D placebo + fish oil placebo	Active comparator	Dietary Supplement: Fish oil placebo, Dietary Supplement: Vitamin D placeboVitamin D placebo Fish oil placebo
Vitamin D + fish oil	Active comparator	Dietary Supplement: vitamin D3, Drug: omega-3 fatty acids (fish oil)Vitamin D3 (cholecalciferol), 2000 IU per day Omacor, 1 capsule per day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA])

Who may qualify

Ages: 50 years and older
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
vitamin D3Also: cholecalciferolVitamin D3 (cholecalciferol), 2000 IU per day	Dietary supplement	Vitamin D + fish oil, Vitamin D + fish oil placebo
omega-3 fatty acids (fish oil)Also: fish oilOmacor, 1 capsule per day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]).	Drug	Vitamin D + fish oil, Vitamin D placebo + fish oil
Fish oil placeboFish oil placebo	Dietary supplement	Vitamin D + fish oil placebo, Vitamin D placebo + fish oil placebo
Vitamin D placeboVitamin D placebo	Dietary supplement	Vitamin D placebo + fish oil, Vitamin D placebo + fish oil placebo

Primary outcome

Number of Participants With a Depression Event
Time frame: From date of randomization until the date of the occurrence of the endpoint, death, or the end of the trial, whichever came first, assessed up to a median of 5.3 years of follow-up
Depression syndrome will be determined by presence of clinical diagnosis, treatment and/or above-threshold symptoms on mood questionnaire (e.g., PHQ) items. This is an event outcome, where the depression event was defined as a new self-report of physician/clinician-diagnosed depression, treatment (medication and/or counseling) for depression, or presence of clinically relevant depressive symptoms (PHQ-8 total score >=10 points) on the annual study questionnaires that were administered over a median 5.3 years of randomized treatment and follow-up. Participants were followed for the depression event until the occurrence of the endpoint, death, or the end of the trial, whichever came first. The Outcome Measure table shows the counts of depression events in each randomized group by treatment.
Mood Scores
Time frame: Baseline, follow-up year 1, follow-up year 2, follow-up year 3, follow-up year 4, and follow-up year 5
Mood scores are evaluated by the 8-item Patient Health Questionnaire (PHQ-8). The measured outcome was the total PHQ-8 score. The PHQ-8 includes items corresponding to the criteria for major depression. Each of the 8 items can be scored as 0, 1, 2, or 3 points (higher score means worse symptoms). The 8 items are summed to a total PHQ-8 score. The range for the PHQ-8 score is 0-24 points; higher scores denote worse mood or depressive symptoms. The PHQ-8 was measured annually at baseline and at up to 5 follow-up times (for a maximum of 6 time points). Data from all time points was used to determine the mean differences in change in mood scores over all follow-up by randomized treatment. Per protocol, the Statistical Analysis section shows the results for the primary outcome of mean difference in overall change in PHQ-8 scores comparing active and placebo groups (for each agent).

Results and safety

Results posted to the registry on 14 Mar 2023, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Vitamin D + Fish Oil Placebo	4,573	4,573
Vitamin D Placebo + Fish Oil	4,563	4,563
Vitamin D Placebo + Fish Oil Placebo	4,609	4,609
Vitamin D + Fish Oil	4,608	4,608

Primary outcome: Number of Participants With a Depression Event

Time frame: From date of randomization until the date of the occurrence of the endpoint, death, or the end of the trial, whichever came first, assessed up to a median of 5.3 years of follow-up. Count of participants. Unit: Participants

Measure	Active Vitamin D n = 9181	Vitamin D Placebo n = 9172	Active Fish Oil n = 9171	Fish Oil Placebo n = 9182
Value	609	625	651	583

Active Vitamin D vs Vitamin D Placebo: Hazard Ratio (HR): .97 (95% CI .87 to 1.09), p = 0.62, Regression, Cox
Active Fish Oil vs Fish Oil Placebo: Hazard Ratio (HR): 1.13 (95% CI 1.01 to 1.26), p = 0.03, Regression, Cox

Population analysed: Analysis population reflects the randomized groups by treatment agents, as all published analyses per protocol were conducted comparing active treatment to placebo. These groups were: n=9181 randomized to active vitamin D and n=9172 randomized to vitamin D placebo; n=9171 randomized to active fish oil and n=9182 randomized to fish oil placebo. Per intervention results are presented for active vitamin D vs. matching vitamin D placebo and for active fish oil vs. matching fish oil placebo.

Primary outcome: Mood Scores

Time frame: Baseline, follow-up year 1, follow-up year 2, follow-up year 3, follow-up year 4, and follow-up year 5. Mean (95% Confidence Interval). Unit: score on a scale

Measure	Active Vitamin D n = 9181	Vitamin D Placebo n = 9172	Active Fish Oil n = 9171	Fish Oil Placebo n = 9182
Baseline adjusted mean	1.08 (1.05 to 1.11)	1.13 (1.09 to 1.16)	1.09 (1.06 to 1.13)	1.11 (1.08 to 1.15)
Mean change at Year 1	0.03 (-0.01 to 0.07)	0.03 (0.00 to 0.07)	0.05 (0.01 to 0.09)	0.01 (-0.02 to 0.05)
Mean change at Year 2	0.07 (0.03 to 0.11)	0.04 (0.00 to 0.08)	0.07 (0.03 to 0.11)	0.04 (0.00 to 0.08)
Mean change at Year 3	0.09 (0.05 to 0.13)	0.07 (0.03 to 0.12)	0.10 (0.06 to 0.15)	0.06 (0.02 to 0.10)
Mean change at Year 4	0.06 (0.02 to 0.10)	0.07 (0.03 to 0.11)	0.08 (0.04 to 0.12)	0.05 (0.01 to 0.09)
Mean change at Year 5	0.20 (0.15 to 0.25)	0.16 (0.11 to 0.22)	0.18 (0.13 to 0.23)	0.19 (0.13 to 0.24)

Active Vitamin D vs Vitamin D Placebo: Mean Difference (Net): 0.01 (95% CI -0.04 to 0.05), Mixed Models Analysis
Active Fish Oil vs Fish Oil Placebo: Mean Difference (Net): 0.03 (95% CI -0.01 to 0.07), Mixed Models Analysis

Population analysed: Analysis population reflects the randomized groups by treatment agents, as all published analyses per protocol were conducted comparing active treatment to placebo. These were n=9181 randomized to active vitamin D; n=9172 randomized to vitamin D placebo; n=9171 randomized to active fish oil; n=9182 randomized to fish oil placebo. Per intervention results are presented for active treatment vs placebo. Each row shows exact number of participants providing responses to the PHQ-8 at that timepoint.

Adverse events

Time frame: Adverse event data were collected over the entire randomized treatment and follow-up period, which was a median of 5.3 years. VITAL-DEP is an ancillary study of the VITAL trial. For total adverse events reported by the parent VITAL trial, please see Results reported by VITAL, NCT01169259.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Vitamin D + Fish Oil Placebo	545 of 4,573 (11.9%)	2,803 of 4,573 (61.3%)	153 of 4,573
Vitamin D Placebo + Fish Oil	569 of 4,563 (12.5%)	2,789 of 4,563 (61.1%)	152 of 4,563
Vitamin D Placebo + Fish Oil Placebo	570 of 4,609 (12.4%)	2,876 of 4,609 (62.4%)	133 of 4,609
Vitamin D + Fish Oil	549 of 4,608 (11.9%)	2,825 of 4,608 (61.3%)	153 of 4,608

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Dec 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 42746141Vyas CM, Ostaszewski BL, Anderson AK, Cook NR, Kang JH, Mischoulon D, Reynolds CF 3rd, Chang G, Gatchel JR, Manson JE, Selkoe DJ, Okereke OI. Effects of long-term daily supplementation with vitamin D3 and marine omega-3 fatty acids on change in ADRD biomarkers: A secondary analysis of a randomized clinical trial. Alzheimers Dement (N Y). 2026 Sep 14;12(3):e70312. doi: 10.1002/trc2.70312. eCollection 2026 Jul-Sep.
Derived from this study: PubMed 37952113Vyas CM, Kang JH, Mischoulon D, Cook NR, Reynolds Iii CF, Chang G, Mora S, De Vivo I, Manson JE, Okereke OI. Apolipoprotein E and Its Association With Cognitive Change and Modification of Treatment Effects of Vitamin D3 and Omega-3s on Cognitive Change: Results From the In-Clinic Subset of a Randomized Clinical Trial. J Gerontol A Biol Sci Med Sci. 2024 Mar 1;79(3):glad260. doi: 10.1093/gerona/glad260.
Derived from this study: PubMed 37378490Vyas CM, Mischoulon D, Chang G, Cook NR, Weinberg A, Copeland T, Kang JH, Bubes V, Friedenberg G, LeBoff MS, Lee IM, Buring JE, Manson JE, Reynolds CF, Okereke OI. Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Indicated and Selective Prevention of Depression in Older Adults: Results From the Clinical Center Sub-Cohort of the VITamin D and OmegA-3 TriaL (VITAL). J Clin Psychiatry. 2023 Jun 26;84(4):22m14629. doi: 10.4088/JCP.22m14629.
Derived from this study: PubMed 37267732Vyas CM, Mischoulon D, Chang G, Reynolds CF 3rd, Cook NR, Weinberg A, Copeland T, Bubes V, Bradwin G, Lee IM, Buring JE, Mora S, Rifai N, Manson JE, Okereke OI. Relation of serum BDNF to major depression and exploration of mechanistic roles of serum BDNF in a study of vitamin D3 and omega-3 supplements for late-life depression prevention. J Psychiatr Res. 2023 Jul;163:357-364. doi: 10.1016/j.jpsychires.2023.05.069. Epub 2023 May 26.
Derived from this study: PubMed 37212116Vyas CM, Sadreyev RI, Gatchel JR, Kang JH, Reynolds CF, Mischoulon D, Chang G, Hazra A, Manson JE, Blacker D, De Vivo I, Okereke OI. Pilot Study of Second-Generation DNA Methylation Epigenetic Markers in Relation to Cognitive and Neuropsychiatric Symptoms in Older Adults. J Alzheimers Dis. 2023;93(4):1563-1575. doi: 10.3233/JAD-230093.
Derived from this study: PubMed 34932079Okereke OI, Vyas CM, Mischoulon D, Chang G, Cook NR, Weinberg A, Bubes V, Copeland T, Friedenberg G, Lee IM, Buring JE, Reynolds CF 3rd, Manson JE. Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2021 Dec 21;326(23):2385-2394. doi: 10.1001/jama.2021.21187.
Derived from this study: PubMed 34853363Kang JH, Vyas CM, Okereke OI, Ogata S, Albert M, Lee IM, D'Agostino D, Buring JE, Cook NR, Grodstein F, Manson JE. Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial. Sci Rep. 2021 Dec 1;11(1):23253. doi: 10.1038/s41598-021-02485-8.
Derived from this study: PubMed 32749491Okereke OI, Reynolds CF 3rd, Mischoulon D, Chang G, Vyas CM, Cook NR, Weinberg A, Bubes V, Copeland T, Friedenberg G, Lee IM, Buring JE, Manson JE. Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):471-480. doi: 10.1001/jama.2020.10224.
Derived from this study: PubMed 31915172Donneyong M, Reynolds C, Mischoulon D, Chang G, Luttmann-Gibson H, Bubes V, Guilds M, Manson J, Okereke O. Protocol for studying racial/ethnic disparities in depression care using joint information from participant surveys and administrative claims databases: an observational cohort study. BMJ Open. 2020 Jan 7;10(1):e033173. doi: 10.1136/bmjopen-2019-033173.
Derived from this study: PubMed 29526608Okereke OI, Reynolds CF 3rd, Mischoulon D, Chang G, Cook NR, Copeland T, Friedenberg G, Buring JE, Manson JE. The VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention (VITAL-DEP): Rationale and design of a large-scale ancillary study evaluating vitamin D and marine omega-3 fatty acid supplements for prevention of late-life depression. Contemp Clin Trials. 2018 May;68:133-145. doi: 10.1016/j.cct.2018.02.017. Epub 2018 Mar 8.
Welcome to the VITAL study websiteLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Olivia I Okereke, MD, SM principal investigator

Brigham and Women's Hospital

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A study testing vitamin D3 and omega-3 fatty acids (fish oil) in people with Depression and Depressive Symptoms, run by Brigham and Women's Hospital at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With a Depression Event (time frame: From date of randomization until the date of the occurrence of the endpoint, death, or the end of the trial, whichever came first, assessed up to a median of 5.3 years of follow-up). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01696435, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2025.