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

Disclosures Vitamin D and Omega ‐ 3 Fatty Acids: Do They Have Benefits for Mood, Depression, or Cognition?  Funding from the NIH, Harvard University  Royalties (Springer publishing) for book on late ‐ life Olivia I. Okereke, MD, SM depression prevention Associate Professor of Psychiatry and Epidemiology, Harvard Medical School and Harvard T. H. Chan School of Public Health  Funding relevant to this presentation: NIH – R01 Director of Geriatric Psychiatry, Massachusetts General Hospital MH091448 (PI: Okereke), R01 MH096776 (PI: Okereke), R01 AG036755 (PI: Kang), U01 CA138962 (PI: NAMS Plenary Manson), R01 CA138962 (PI: Manson) September 26, 2019 Objectives Mechanisms • 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 1

Omega-3 Fatty Acids and Depression: Omega-3 Fatty Acids and Cognition: Review of Evidence Review of Evidence  Observational  Observational  Largely support high fish and omega ‐ 3 intake as associated  Largely support high fish and omega ‐ 3 intake as with better mood associated with slower cognitive decline in older adults (prospective, community ‐ based)  Experimental  Experimental  Over a dozen trials, meta ‐ analyses; few with higher dose range ( ≥ 1 g/d) and long duration; most <6 months  Few trials with large samples, >12 month duration; fewer with very long duration (>4 years)  Track record in depression treatment context; EPA>DHA  Results largely null  Largely null for prevention (including recent MooDFOOD trial – Bot et al., JAMA 2019)  Trials focused on higher ‐ risk groups such as with MCI support benefit (e.g., OmegAD trial, JAMA/Archives  Mendelian randomization study in ~500,000: no evidence Neurolgy) for association of n ‐ 3 PUFA with depression (Milaneschi et al., Transl Psychiatry, 2019) Summary and Limitations of Current VITAL ‐ DEP: NAM Framework for Evidence Prevention  Observational Studies Modality Target  Bias and confounding Indicated Presence of sub ‐ syndromal depressive  Variable exposure (fish, n ‐ 3 from diet, etc.) symptoms  Experimental Studies  Short treatment durations Selective Presence of high ‐ risk factors: e.g., physical/  Variable dosing functional impairment, living alone, anxiety  Smaller sample sizes (very low power for primary or universal prevention) Universal General population, regardless of risk status  Low diversity  Inconsistent use of biochemical nutrient markers 2

Summary of Characteristics: Summary of Characteristics: VITAL ‐ DEP VITAL ‐ COG N 18,353 Table 1. Key Pre ‐ randomization characteristics (n=3583) Mean age ± SD, years 67.5 ± 7.1 Male/female ratio 49.6/50.4 Sex, % female 9,023 (49.2) Mean age ± SD, yrs 67.2 ±7.0 Race/ethnicity, % High school diploma/GED Non ‐ Hispanic White 13,097 (72.8) or higher, % 99.2 African American 3,407 (18.9) African American (AA), % 10.0 Hispanic (not African American) 708 ( 3.9) Current smoker, % 4.4 Mean body mass index, kg/m 2 28.5 Asian/Pacific Islander 294 ( 1.6) Obesity (BMI ≥ 30 kg/m 2 ), % 27.8 American Indian/Alaskan Native 150 (0.8) History of diabetes, % 11.9 Mean body mass index (kg/m 2 ) ± SD 27.8 (5.5) History of hypertension, % 53.1 Current smoking, % 1,121 ( 6.1) Lifetime history of diagnosed depression Hypertension, treated, % 9,198 (50.4) or having used antidepressants, % 18.6 High cholesterol, treated, % 6,624 (36.3) Diabetes, % 2,308 (12.6) 409 AA added post ‐ randomization, for total of 767 (out of n=3,992) Vitamin D Potential Confounding Paths: Vitamin D and Depression: Review of Role of Aging Evidence Older Age  Observational (systematic reviews and meta ‐ Poor Nutrition: Low Intake of Low Sun Exposure analyses) Vitamin D  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 Low 25(OH)D 10 ‐ ng/ml increment 25(OH)D (Li et al., AJGP, 2019)  Experimental/Quasi ‐ experimental Low Physical Activity Obesity  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) Depression and Poor Cognition 3

Vitamin D and Cognition: Review of Summary: VITAL ‐ DEP and VITAL ‐ COG Evidence  Strengths:  Observational (systematic reviews and meta ‐  Large ‐ scale nationwide racially/ethnically diverse cohort  Power to address universal prevention analyses)  Experimental design  Long ‐ term (>4 years) prospective studies consistent with  High follow ‐ up rates and compliance favorable association, especially if clear contrast of >75 vs  Validated measures for endpoints, strong follow ‐ up and low 25(OH)D safety plans  Experimental/Quasi ‐ experimental  Limitations:  Longest term, large study to date in WHI – null  Dosing – optimal match of dose for each outcome?  Long treatment duration (7.8 y) but low dose (400 IU/d)  Balance of EPA, DHA for mood or cognition  Mendelian randomization study in >170,000: no evidence  Shorter follow ‐ up for cognitive outcome (2 years) for association of 25(OH)D with global memory composite  Questions about exposure timing for cognitive outcome score (Maddock et al., Sci Rep, 2017)  Generally sufficient biochemical levels in cohort VITAL ‐ DEP: Schematic of Current and PRACTICAL PRACTICAL TIPS SUMMA TIPS SUMMARY Future Plans VITAL parent trial 25,871 initially healthy men (aged ≥50) and women (aged ≥55) randomized • Use substitutions VITAL blood VITAL CTSC equally to vitamin D 3 and/or marine n~17,000 N=1,054 • Calories ≠ Quality 1 omega‐3 fatty acids or placebos Plasma 25(OH)D VITAL‐DEP VITAL‐DEP CTSC • Consider: Type vs. Total and omega‐3 Psychiatric interviews, Yearly questionnaires to identify incident • Sources: Plant vs. Animal assays in all self‐rated symptoms, 2 and recurrent depression cases (18,353), participants with cognitive tests at baseline PHQ‐8 scores (all) blood samples and 2‐yr follow‐up (N~700) • Use color • Biochemical nutrient Testing effects of vitamin D 3 and/or levels of vitamin D and • Healthy plate is varied omega‐3 on long‐term mood outcomes; 3 • High‐risk factors omega‐3 and long‐ CMS linkage; racial/ethnic disparities (indicated and term depression selective prevention) outcomes (n~11,500) • Serum BDNF, plasma • Bioavailable vitamin D metabolomics (N~1,000) Okereke et al., Contemp Clin Trials , 2018 Available through AARP, GCBH 4

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 omega ‐ 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 older persons 5