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.

BACKGROUND: Apolipoprotein E (APOE)-ε4 allele is associated with cognitive decline; however, its potential to modify effects of vitamin D3 and omega-3s supplementation on later-life cognition is unclear. Our objectives were to estimate among the in-clinic subset of a randomized trial: (1) associations between APOE-ε4 and global and domain-specific cognitive change, with exploration of potential sex and race differences; and (2) modification by APOE-ε4 of effects of vitamin D3 and omega-3s supplementation on cognitive change. METHODS: From an ancillary study of depression prevention within a completed 2 × 2 factorial trial testing vitamin D3 (2 000 IU per day), omega-3s (1 g per day), and/or placebos, we included 743 older adults with baseline in-person neuropsychiatric assessments and APOE genotyping data. The primary outcome was change in global cognition (averaging z-scores of 9 tests) over 2 years. Secondarily, episodic memory and executive function/attention z-scores were examined. General linear models of response profiles with multiplicative interaction terms were constructed; stratified results were reported. RESULTS: Mean age (standard deviation) was 67.1 (5.3) years; 50.6% were females; 24.9% were APOE-ε4 carriers. Compared to noncarriers, APOE-ε4 carriers had worse 2-year change in global cognition and episodic memory; differences were more apparent among females than males. There was no variation by race in APOE-ε4 associations with cognition. APOE-ε4 did not significantly modify effects of vitamin D3 or omega-3s, compared to placebo, on change in global cognition, episodic memory, or executive function/attention. CONCLUSIONS: APOE-ε4 was associated with worse cognition but did not modify overall effects of vitamin D3 or omega-3 supplementation on cognition over 2 years.

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).

Objective: To test vitamin D3 and omega-3 fatty acids (omega-3s) for late-life depression prevention under the National Academy of Medicine framework for indicated (targeting subthreshold depression) and selective (targeting presence of high-risk factors) prevention.Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a 2 × 2 factorial trial of vitamin D3 (2,000 IU/d) and/or omega-3s (1 g/d) for cardiovascular and cancer prevention (enrollment: November 2011-March 2014; end date: December 31, 2017). In this targeted prevention study, we included 720 VITAL clinical sub-cohort participants who completed neurobehavioral assessments at baseline and 2 years (91.9% retention). High-risk factors were subthreshold or clinical anxiety, impaired activities of daily living, physical/functional limitation, medical comorbidity, cognitive impairment, caregiving burden, problem drinking, and low psychosocial support. Coprimary outcomes were incident major depressive disorder (MDD), adjudicated using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), and change in mood (Patient Health Questionnaire-9 [PHQ-9]). We used exact tests to determine treatment effects on MDD incidence and repeated-measures models to determine treatment effects on PHQ-9.Results: A total of 11.1% had subthreshold depression, 60.8% had ≥ 1 high-risk factor, MDD incidence was 4.7% (5.1% among completers), and mean PHQ-9 score change was 0.02 points. Among those with subthreshold depression, the MDD risk ratio (95% confidence interval) was 0.36 (0.06 to 1.28) for vitamin D3 and 0.85 (0.25 to 2.92) for omega-3s, compared to placebo; results were also null among those with ≥ 1 high-risk factor (vitamin D3 vs placebo: 0.63 [0.25 to 1.53]; omega-3s vs placebo: 1.08 [0.46 to 2.71]). There were no significant differences in PHQ-9 score change comparing either supplement with placebo.Conclusions: Neither vitamin D3 nor omega-3s showed benefits for indicated and selective prevention of late-life depression; statistical power was limited.Trial Registration: ClinicalTrials.gov identifier: NCT01696435.

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.

This study: 1) examined cross-sectional and longitudinal relations of serum brain-derived neurotrophic factor (BDNF) to late-life depression (LLD); 2) tested effects of vitamin D3 and omega-3s on change in BDNF; 3) explored modifying or mediating roles of BDNF on effects of vitamin D3 and omega-3s for LLD. We selected 400 adults from a completed trial of vitamin D3 and omega-3 supplements for LLD prevention. BDNF was measured using an enzyme-linked immunosorbent assay. We administered semi-structured diagnostic interviews and Patient Health Questionnaire [PHQ]-9 to ascertain outcomes at baseline (depression caseness vs. non-caseness; PHQ-9) and at 2-year follow-up among baseline non-depressed individuals (incident vs. no incident MDD; change in PHQ-9). At baseline, while there were no significant differences in mean serum BDNF comparing depression cases and non-cases, being in the lowest vs. highest serum BDNF quartile was significantly associated with worse depressive symptoms. There were no significant longitudinal associations between serum BDNF and LLD. Neither supplement significantly affected change in BDNF; serum BDNF did not appear to modify or mediate treatment effects on LLD. In conclusion, we observed significant cross-sectional but not longitudinal associations between serum BDNF levels and LLD. Vitamin D3 or omega-3s did not alter serum BDNF over 2 years.

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.

Importance: Marine omega-3 fatty acid (omega-3) supplements have been used to treat depression but their ability to prevent depression in the general adult population is unknown. Objective: To test effects of omega-3 supplementation on late-life depression risk and mood scores. Design, Setting, and Participants: A total of 18 353 adults participated in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized trial of cardiovascular disease and cancer prevention among 25 871 US adults. There were 16 657 at risk of incident depression (no previous depression) and 1696 at risk of recurrent depression (previous depression, but not for the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017. Interventions: Randomized 2 × 2 factorial assignment to vitamin D3 (2000 IU/d), marine omega-3 fatty acids (1 g/d of fish oil, including 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid) or placebo; 9171 were randomized to omega-3 and 9182 were randomized to matching placebo. Main Outcomes and Measures: Prespecified coprimary outcomes were risk of depression or clinically relevant depressive symptoms (total of incident + recurrent cases); mean difference in mood score (8-item Patient Health Questionnaire [PHQ-8] depression scale). Results: Among 18 353 participants who were randomized (mean age, 67.5 [SD, 7.1] years; 49.2% women), 90.3% completed the trial (93.5% among those alive at the end of the trial); the median treatment duration was 5.3 years. The test for interaction between the omega-3 and the vitamin D agents was not significant (P for interaction = .14). Depression risk was significantly higher comparing omega-3 (651 events, 13.9 per 1000 person-years) with placebo (583 events, 12.3 per 1000 person-years; hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P = .03). No significant differences were observed comparing omega-3 with placebo groups in longitudinal mood scores: the mean difference in change in PHQ-8 score was 0.03 points (95% CI, -0.01 to 0.07; P = .19). Regarding serious and common adverse events, the respective prevalence values in omega-3 vs placebo groups were major cardiovascular events (2.7% vs 2.9%), all-cause mortality (3.3% vs 3.1%), suicide (0.02% vs 0.01%), gastrointestinal bleeding (2.6% vs 2.7%), easy bruising (24.8% vs 25.1%), and stomach upset or pain (35.2% vs 35.1%). Conclusions and Relevance: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with omega-3 supplements compared with placebo yielded mixed results, with a small but statistically significant increase in risk of depression or clinically relevant depressive symptoms but no difference in mood scores, over a median follow-up of 5.3 years. These findings do not support the use of omega-3 supplements in adults to prevent depression. Trial Registration: ClinicalTrials.gov Identifiers: NCT01696435 and NCT01169259.

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.

Importance: Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials. Objective: To test the effects of vitamin D3 supplementation on late-life depression risk and mood scores. Design, Setting, and Participants: There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up. Intervention: Randomized assignment in a 2 × 2 factorial design to vitamin D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo. Main Outcomes and Measures: The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points). Results: Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P = .62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, -0.04 to 0.05 points]). Conclusions and Relevance: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression. Trial Registration: ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435.

Effect of Osteopathic Obstetrical Management on the Duration of Labor in the Inpatient Setting: A Prospective Study and Literature Review.

CONTEXT: Several studies have investigated the effects of osteopathic manipulative treatment (OMT) on labor duration, but the outcomes remain ambiguous. Confounding the relationship between OMT and labor duration is the lack of standardization between treatment settings, gestational ages at the time of treatment, OMT techniques, and overall obstetrical management principles from foundational and modern osteopathic approaches. OBJECTIVE: To evaluate the effect of OMT on labor duration when applied in tandem with standard obstetrical management in the inpatient setting. METHODS: This pilot prospective observational study was conducted from June 2017 through September 2017. All patients who received OMT as part of their labor management were included. These patients were matched with controls who did not receive OMT. The OMT protocol involved once-daily administration of suboccipital decompression, thoracic inlet release, rib raising, paraspinal inhibition, and sacral inhibition. Obstetrical decisions regarding labor management were made by 1 senior attending osteopathic obstetrician. Labor management as well as OMT was carried out by osteopathic obstetricians in the OMT group, whereas allopathic obstetricians carried out labor management in the control group. RESULTS: A total of 100 patients were enrolled. Fifty patients who underwent adjunctive OMT in addition to standard labor management were matched to controls who received standard labor management only. Each group was represented by an ethnically diverse population. The mean (SD) labor duration for patients receiving OMT was significantly shorter than the labor duration for controls (11.34 [6.62] hours [range, 1.1-27.0 hours] vs 16.57 [4.39] [range, 1.0-58.8 hours], respectively; P=.03). All other measures studied did not achieve statistical significance. CONCLUSION: Pregnancy and labor present many musculoskeletal and neurovisceral challenges to obstetrical patients and, to the authors' knowledge, this is the first study to present an effective, efficient, and feasible approach to intrapartum osteopathic obstetrical management in the inpatient setting to reduce labor duration.

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.

RATIONALE: Depression is a leading cause of disease burden and disability for older adults; thus, prevention is a priority. Biologic and observational data support potential mental health benefits of vitamin D and omega-3 fatty acids; however, it is unclear whether these supplements can prevent late-life depression. DESIGN: We describe the novel methodology of a large-scale study: VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention), an ancillary to the VITAL trial. Primary Aims of VITAL-DEP are to determine effects on prevention of depression and on trajectory of mood symptoms of long-term (mean=5years) supplementation with vitamin D (vitamin D3 [cholecalciferol], 2000IU/day) and marine omega-3 fatty-acids (eicosapentaenoic acid + docosahexaenoic acid, 1g/day), in a 2×2 factorial design, among 25,874 older adults. Secondary Aims will evaluate: vitamin D's effects among African-Americans (an at-risk group for vitamin D deficiency); both agents' effects among those with high-risk factors or sub-syndromal depression in a sub-set of ~1000 participants with detailed examinations at baseline and 2-year follow-up; whether baseline nutrient levels influence depression risk and/or modify agents' effects. Additional planned analyses will use pre-randomization blood samples available in ~17,000 participants to address whether key biomarkers and factors influence long-term mood and depression risk and/or the agents' effects. CONCLUSION: VITAL-DEP applies all modalities of state-of-the-art prevention research - universal, selective and indicated. VITAL-DEP will clarify effects of supplemental vitamin D and/or omega-3 on mood, and inform clinical care and public health guidelines on the use of these agents for prevention of depression in mid-life and older adults.

The use of auricular acupuncture in opioid use disorder: A systematic literature review.

BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) is a chronic disease with significant personal, societal, and public health consequences. Even for the minority who receive the most effective evidence-based treatments, morbidity, and mortality remain significant. These facts, along with the recovery movement calling for individualized, holistic, culturally sensitive care, have led to the exploration of adjunctive interventions including acupuncture. Despite hundreds of international trials, however, there is a lack of consensus regarding its efficacy in OUD due in large part to methodological issues of trials to date. In response to these issues, the National Acupuncture Detoxification Association (NADA) developed an operationalized manual auricular acupuncture protocol that has since become the most widely used in the US. This systematic review is the first to focus explicitly on randomized trials utilizing the NADA protocol as a complementary intervention to address OUD. METHODS: The methods utilized to identify studies for inclusion are based on a 2009 protocol developed by the Cochrane Collaboration. RESULTS: Four trials met inclusion criteria. Despite methodological issues, results indicate that while the NADA protocol may not be effective in reducing acute opiate craving or withdrawal, it may be effectively utilized as an adjunctive treatment to increase treatment retention and decrease methadone detoxification and maintenance dosages in OUD. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Incorporation of the NADA protocol into existing evidence-based treatment approaches may facilitate recovery and, through its impact on treatment retention and completion, indirectly impact morbidity, and mortality in individuals with OUD. Given the limitations of the current review, conclusions are tentative and directions for future research are discussed. (Am J Addict 2016;25:592-602).

Substance use and survival after treatment for chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS).

BACKGROUND: Patients' substance use problems are a particularly understudied aspect of psychosocial variables in cancer treatment. OBJECTIVES: The specific hypothesis tested was that lifetime substance use disorders increased the risk of adverse outcome, in the context of other psychosocial and clinical characteristics demonstrated in other studies to have an impact on treatment outcome. METHOD: Prospective cohort study of 106 adults with chronic myelogenous leukemia or primary myelodysplastic syndrome. None satisfied criteria for current substance abuse or dependence, but the lifetime rates of substance use disorders in this sample were 28% for alcohol, 12% for cannabis, and 9% for cocaine. RESULTS: Participants received treatment as directed by their physicians, and were followed until death or the end of the study (median 1.5 years). Twenty-eight died. Multivariate survival analysis identified three predictors of outcome: lifetime cocaine use, associated with a six-fold increased risk of death (p = .04), and two protective variables, baseline hemoglobin (p = .002) and estimated intelligence quotient (IQ) (p = .04). CONCLUSION: The results of this study highlight the potential significance of substance use disorders, and lifetime cocaine diagnoses in particular, on treatment outcome for people with chronic myelogenous leukemia or myelodysplastic syndrome. Whereas neither lifetime alcohol nor cannabis use were associated with survival on either the univariate or multivariate models of survival, lifetime cocaine diagnoses were associated with significant six-fold increased risk of death (p = .04).

Alcohol use and religiousness/spirituality among adolescents.

BACKGROUND: Previous studies indicate that religiousness is associated with lower levels of substance use among adolescents, but less is known about the relationship between spirituality and substance use. The objective of this study was to determine the association between adolescents' use of alcohol and specific aspects of religiousness and spirituality. METHODS: Twelve- to 18-year-old patients coming for routine medical care at three primary care sites completed a modified Brief Multidimensional Measure of Religiousness/Spirituality; the Spiritual Connectedness Scale; and a past-90-days alcohol use Timeline Followback calendar. We used multiple logistic regression analysis to assess the association between each religiousness/spirituality measure and odds of any past-90-days alcohol use, controlling for age, gender, race/ethnicity, and clinic site. Timeline Followback data were dichotomized to indicate any past-90-days alcohol use and religiousness/spirituality scale scores were z-transformed for analysis. RESULTS: Participants (n = 305) were 67% female, 74% Hispanic or black, and 45% from two-parent families. Mean +/- SD age was 16.0 +/- 1.8 years. Approximately 1/3 (34%) reported past-90-day alcohol use. After controlling for demographics and clinic site, Religiousness/Spirituality scales that were not significantly associated with alcohol use included: Commitment (OR = 0.81, 95% CI 0.36, 1.79), Organizational Religiousness (OR = 0.83, 95% CI 0.64, 1.07), Private Religious Practices (OR = 0.94, 95% CI 0.80, 1.10), and Religious and Spiritual Coping--Negative (OR = 1.07, 95% CI 0.91, 1.23). All of these are measures of religiousness, except for Religious and Spiritual Coping--Negative. Scales that were significantly and negatively associated with alcohol use included: Forgiveness (OR = 0.55, 95% CI 0.42-0.73), Religious and Spiritual Coping--Positive (OR = 0.67, 95% CI 0.51-0.84), Daily Spiritual Experiences (OR = 0.67, 95% CI 0.54-0.84), and Belief (OR = 0.76, 95% CI 0.68-0.83), which are all measures of spirituality. In a multivariable model that included all significant measures, however, only Forgiveness remained as a significant negative correlate of alcohol use (OR = 0.56, 95% CI 0.41, 0.74). CONCLUSIONS: Forgiveness is associated with a lowered risk of drinking during adolescence.