Disclosures Vitamin D and Omega 3 Fatty Acids: Do They Have Benefits - - PDF document

1

Olivia I. Okereke, MD, SM

Associate Professor of Psychiatry and Epidemiology, Harvard Medical School and Harvard T. H. Chan School of Public Health Director of Geriatric Psychiatry, Massachusetts General Hospital NAMS Plenary September 26, 2019

Vitamin D and Omega‐3 Fatty Acids: Do They Have Benefits for Mood, Depression,

• r Cognition?

Disclosures

 Funding from the NIH, Harvard University  Royalties (Springer publishing) for book on late‐life depression prevention  Funding relevant to this presentation: NIH – R01 MH091448 (PI: Okereke), R01 MH096776 (PI: Okereke), R01 AG036755 (PI: Kang), U01 CA138962 (PI: Manson), R01 CA138962 (PI: Manson)

• Review current evidence regarding omega‐3,

vitamin D and aging outcomes of late‐life depression and cognitive decline

• Introduce rationale and describe design of

VITAL‐DEP and VITAL‐COG ancillaries to the VITAL trial

• Summarize main study findings and clinical

implications

Objectives Mechanisms

2

Omega-3 Fatty Acids and Depression: Review of Evidence

 Observational

 Largely support high fish and omega‐3 intake as associated

with better mood

 Experimental

 Over a dozen trials, meta‐analyses; few with higher dose

range (≥1 g/d) and long duration; most <6 months

 Track record in depression treatment context; EPA>DHA  Largely null for prevention (including recent MooDFOOD

trial – Bot et al., JAMA 2019)

 Mendelian randomization study in ~500,000: no evidence

for association of n‐3 PUFA with depression (Milaneschi et al., Transl Psychiatry, 2019)

Omega-3 Fatty Acids and Cognition: Review of Evidence

 Observational

 Largely support high fish and omega‐3 intake as

associated with slower cognitive decline in older adults (prospective, community‐based)

 Experimental

 Few trials with large samples, >12 month duration;

fewer with very long duration (>4 years)

 Results largely null  Trials focused on higher‐risk groups such as with MCI

support benefit (e.g., OmegAD trial, JAMA/Archives Neurolgy)

Summary and Limitations of Current Evidence

 Observational Studies

 Bias and confounding  Variable exposure (fish, n‐3 from diet, etc.)

 Experimental Studies

 Short treatment durations  Variable dosing  Smaller sample sizes (very low power for primary or

universal prevention)

 Low diversity  Inconsistent use of biochemical nutrient markers

VITAL‐DEP: NAM Framework for Prevention

Modality Target

Indicated Presence of sub‐syndromal depressive symptoms Selective Presence of high‐risk factors: e.g., physical/ functional impairment, living alone, anxiety Universal General population, regardless of risk status

3

Summary of Characteristics: VITAL‐DEP

N 18,353 Mean age ± SD, years 67.5 ± 7.1 Sex, % female 9,023 (49.2) Race/ethnicity, % Non‐Hispanic White 13,097 (72.8) African American 3,407 (18.9) Hispanic (not African American) 708 ( 3.9) Asian/Pacific Islander 294 ( 1.6) American Indian/Alaskan Native 150 (0.8) Mean body mass index (kg/m2) ± SD 27.8 (5.5) Current smoking, % 1,121 ( 6.1) Hypertension, treated, % 9,198 (50.4) High cholesterol, treated, % 6,624 (36.3) Diabetes, % 2,308 (12.6)

Summary of Characteristics: VITAL‐COG

Table 1. Key Pre‐randomization characteristics (n=3583) Male/female ratio 49.6/50.4 Mean age ± SD, yrs 67.2 ±7.0 High school diploma/GED

• r higher, %

99.2 African American (AA), % 10.0 Current smoker, % 4.4 Mean body mass index, kg/m2 28.5 Obesity (BMI≥30 kg/m2), % 27.8 History of diabetes, % 11.9 History of hypertension, % 53.1 Lifetime history of diagnosed depression

• r having used antidepressants, %

18.6 409 AA added post‐randomization, for total of 767 (out of n=3,992)

Vitamin D Potential Confounding Paths: Role of Aging

Poor Nutrition: Low Intake of Vitamin D Low Sun Exposure Obesity Low 25(OH)D Low Physical Activity

Depression and Poor Cognition

Older Age

? ?

Vitamin D and Depression: Review of Evidence

 Observational (systematic reviews and meta‐ analyses)

 Majority of prospective studies show association

between 25(OH)D level and lower risk of depression (Okereke et al., J Affect Dis, 2016)

 Evidence of dose‐response: 12% ↓HR of depression per

10‐ng/ml increment 25(OH)D (Li et al., AJGP, 2019)

 Experimental/Quasi‐experimental

 Almost all RCTs null, including recent D‐Vitaal and

MooDFOOD (2019) – both at >800 IU/d for 12 months

 Mendelian randomization study in ~500,000: no

evidence for association of 25(OH)D with depression (Milaneschi et al., Transl Psychiatry, 2019)

4

Vitamin D and Cognition: Review of Evidence

 Observational (systematic reviews and meta‐ analyses)

 Long‐term (>4 years) prospective studies consistent with

favorable association, especially if clear contrast of >75 vs low 25(OH)D

 Experimental/Quasi‐experimental

 Longest term, large study to date in WHI – null

 Long treatment duration (7.8 y) but low dose (400 IU/d)

 Mendelian randomization study in >170,000: no evidence

for association of 25(OH)D with global memory composite score (Maddock et al., Sci Rep, 2017)

Summary: VITAL‐DEP and VITAL‐COG

 Strengths:

 Large‐scale nationwide racially/ethnically diverse cohort  Power to address universal prevention  Experimental design  High follow‐up rates and compliance  Validated measures for endpoints, strong follow‐up and

safety plans

 Limitations:

 Dosing – optimal match of dose for each outcome?

 Balance of EPA, DHA for mood or cognition

 Shorter follow‐up for cognitive outcome (2 years)  Questions about exposure timing for cognitive outcome  Generally sufficient biochemical levels in cohort

VITAL‐DEP: Schematic of Current and Future Plans

VITAL parent trial

25,871 initially healthy men (aged ≥50) and women (aged ≥55) randomized equally to vitamin D3 and/or marine

• mega‐3 fatty acids or placebos

VITAL blood n~17,000 VITAL CTSC N=1,054 VITAL‐DEP

Yearly questionnaires to identify incident and recurrent depression cases (18,353), PHQ‐8 scores (all)

• Biochemical nutrient

levels of vitamin D and

• mega‐3 and long‐

term depression

• utcomes (n~11,500)
• Bioavailable vitamin D

(N~1,000)

• High‐risk factors

(indicated and selective prevention)

• Serum BDNF, plasma

metabolomics

Testing effects of vitamin D3 and/or

• mega‐3 on long‐term mood outcomes;

CMS linkage; racial/ethnic disparities

Plasma 25(OH)D and omega‐3 assays in all participants with blood samples VITAL‐DEP CTSC Psychiatric interviews, self‐rated symptoms, cognitive tests at baseline and 2‐yr follow‐up (N~700) Okereke et al., Contemp Clin Trials, 2018

PRACTICAL PRACTICAL TIPS SUMMA TIPS SUMMARY

1

• Use substitutions
• Calories ≠ Quality

2

• Consider: Type vs. Total
• Sources: Plant vs. Animal

3

• Use color
• Healthy plate is varied

Available through AARP, GCBH

5

Clinical and Public Health Implications

 Omega‐3 Fatty Acids:

 No change to encouraging fish intake >2 servings/week  No change to existing guidelines or practices re: use of

• mega‐3 in treatment contexts (unipolar depression and

bipolar disorder)

 Vitamin D

 No clinical guidelines exist re: vitamin D and depression

prior to study

 No changes from current guidelines for daily intake in

• lder persons