Predictors of the placebo response in a nutraceutical randomized controlled trial for depression.

OBJECTIVE: The placebo response in depression studies is the change in symptoms amongst those who receive an inactive treatment. Many well-designed randomized controlled trials (RCTs) of depression have a high proportion of placebo responders, with little understanding as to why. The present study assesses characteristics associated with the placebo response in a nutraceutical trial with a large proportion of placebo responders. METHODS: This is a secondary analysis of a nutraceutical depression RCT which identified no overall treatment benefit relative to placebo (n = 69 in placebo group). We investigated participant characteristics such as socio-demographics, clinical features, and recruitment methods, and their association with the placebo response. Monoaminergic genetic polymorphisms were also assessed. Placebo response was measured based on change in Montgomery-Asberg Depression Rating Scale score. The association of these hypothesis-driven variables of interest and the placebo response was examined using linear mixed effects models. RESULTS: Greater levels of education, particularly pursuing post-high school education, better self-reported general health, marriage/de facto, greater improvement in the first trial week, and more failed antidepressant therapies in the current depressive episode were associated with greater placebo response. An increased placebo response was not found in those recruited via social media nor in those with concomitant antidepressant therapy. Single nucleotide polymorphisms from the tryptophan hydroxylase 1 (TPH1) gene (A779C and A218C) were weakly associated with greater placebo response, although the evidence was attenuated after accounting for multiple comparisons. CONCLUSION: This is, to our knowledge, the first study within nutraceutical research for depression to assess the association between participant characteristics and variation in the placebo response. Several variables appeared to predict the placebo response. Such findings may encourage future trial designs which could dampen placebo response, improve assay sensitivity, and allow for treatment effects to be potentially more detectable. Please cite this article as: Arnold R, Murphy-Smith J, Ng CH, Mischoulon D, Byrne GJ, Bousman CA, Stough C, Berk M, Sarris J. Predictors of the placebo response in a nutraceutical randomized controlled trial for depression. J Integr Med. 2024; 22(1): 46-53.

A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD.

BACKGROUND: PTSD may involve oxidative stress, and N-acetylcysteine (NAC) may reduce the impact of oxidative stress in the brain. This study aims to investigate the efficacy of adjuvant NAC in people with treatment-resistant PTSD. METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adults with PTSD unresponsive to first-line treatment. The intervention was either oral NAC 2.7 g/day or placebo for 12 weeks. The primary outcome was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks compared with baseline. Secondary outcomes included depression and substance craving. Follow-up measures were obtained at 16 and 64-weeks. RESULTS: 133 patients were assessed, with 105 randomised; 81 participants completed the 12-week trial, 79 completed week-16 follow-up, and 21 completed week-64 follow-up. There were no significant differences between those taking NAC and those taking placebo in CAPS-5 scores at week 12, nor in secondary outcomes. Significant between-group differences were observed at week 64 in craving duration (Cohen's d = 1.61) and craving resistance (Cohen's d = 1.03), both in favour of NAC. CONCLUSION: This was the first multicentre, double-blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. No benefit of NAC was observed in this group beyond that provided by placebo at end of the trial. TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.

Sex Differences in Atrial Fibrillation Risk: The VITAL Rhythm Study.

Importance: Women have a lower incidence of atrial fibrillation (AF) compared with men in several studies, but it is unclear whether this sex difference is independent of sex differences in prevalent cardiovascular disease (CVD), body size, and other risk factors. Objective: To examine sex differences in AF incidence and whether AF risk factors differ by sex in a contemporary cohort of men and women without prevalent CVD. Design, Setting, and Participants: This was a prospective cohort analysis within the Vitamin D and Omega-3 Trial (VITAL) Rhythm Study, a randomized trial that examined the effect of vitamin D and ω-3 fatty acid supplementation on incident AF among men 50 years or older and women 55 years or older without a prior history of prevalent AF, CVD, or cancer at baseline. Data were analyzed from September 29, 2020, to June 29, 2021. Exposures: Sex, height, weight, body mass index (BMI), body surface area (BSA), and other AF risk factors at study enrollment. Main Outcomes and Measures: Incident AF confirmed by medical record review. Results: A total of 25 119 individuals (mean [SD] age, 67.0 [7.1] years; 12 757 women [51%]) were included in this study. Over a median (IQR) follow-up of 5.3 (5.1-5.7) years, 900 confirmed incident AF events occurred among 12 362 men (495 events, 4.0%) and 12 757 women (405 events, 3.2%). After adjustment for age and treatment assignment, women were at lower risk for incident AF than men (hazard ratio [HR], 0.68; 95% CI, 0.59-0.77; P < .001). The inverse association between female sex and AF persisted after adjustment for race and ethnicity, smoking, alcohol intake, hypertension, diabetes (type 1, type 2, gestational), thyroid disease, exercise, and BMI (HR, 0.73; 95% CI, 0.63-0.85; P <.001). However, female sex was positively associated with AF when height (HR, 1.39; 95% CI, 1.14-1.72; P = .001), height and weight (HR 1.49, 95% CI, 1.21-1.82; P <.001), or BSA (HR, 1.25; 95% CI, 1.06-1.49; P = .009) were substituted for BMI in the multivariate model. In stratified models, risk factor associations with incident AF were similar for women and men. Conclusions and Relevance: In this cohort study, findings suggest that after controlling for height and/or body size, women without CVD at baseline were at higher risk for AF than men, suggesting that sex differences in body size account for much of the protective association between female sex and AF. These data underscore the importance of AF prevention in women.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.

OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.

Effects of a group-based lifestyle medicine for depression: A pilot randomized controlled trial.

Given the growing evidence that a range of lifestyle factors are involved in the etiology of depression, a 'lifestyle medicine' approach can be potentially safe and cost-effective to prevent or treat depression. To examine the effects and acceptability of a group-based, integrative lifestyle medicine intervention as a standalone treatment for managing depressive symptoms, a pilot randomized controlled trial (RCT) was conducted in a Chinese adult population in 2018. Participants (n = 31) with PHQ-9 score above the cut-off of ≥ 10, which was indicative of moderate to severe depression, were recruited from the general community in Hong Kong and randomly assigned to lifestyle medicine group (LM group) or care-as-usual group (CAU group) in a ratio of 1:1. Participants in the LM group received 2-hour group sessions once per week for six consecutive weeks, which covered diet, exercise, mindfulness, psychoeducation, and sleep management. Linear mixed-effects model analyses showed that the LM group had a significant reduction in PHQ-9 scores compared to the CAU group at immediate posttreatment and 12-week posttreatment follow-up (d = 0.69 and 0.73, respectively). Moreover, there were significantly greater improvements in anxiety, stress, and insomnia symptoms (measured by DASS-21 and ISI) at all time points in the LM group (d = 0.42-1.16). The results suggests that our 6-week group-based, integrative lifestyle intervention program is effective in lowering depressive, anxiety, stress, and insomnia symptoms in the Chinese population. Further studies in clinical populations with a larger sample size and longer follow-up are warranted.

Efficacy and Safety of Traditional Chinese Herbal Medicine for Antipsychotic-Related Constipation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Constipation is a common but often ignored side effect of antipsychotic treatment, although it is associated with adverse outcomes. The results of the efficacy and safety of traditional Chinese herbal medicine (TCM) in treating constipation are mixed across studies. This is a systematic review and meta-analysis of randomized controlled trials (RCTs) of the efficacy and safety of TCM compared to Western medicine (WM) in treating antipsychotic-related constipation. Methods: Major international electronic (PubMed, EMBASE, Cochrane Library, and Web of Science) and Chinese (Wanfang, WeiPu VIP, SinoMed, and CNKI) databases were searched from their inception to November 29, 2020. Meta-analysis was performed using the random-effects model. Results: Thirty RCTs with 52 arms covering 2,570 patients in the TCM group and 2,511 patients in the WM group were included. Compared with WM, TCM alone was superior regarding the moderate response rate [risk ratio (RR) = 1.165; 95% confidence interval (CI): 1.096-1.238; P < 0.001], marked response rate (RR = 1.437; 95% CI: 1.267-1.692; P < 0.001), and remission rate (RR = 1.376; 95% CI: 1.180-1.606; P < 0.001) for constipation, while it was significantly associated with lower risk of rash (RR = 0.081; 95% CI: 0.019-0.342; P = 0.001). For the moderate response rate, meta-regression analyses revealed that publication year (ß = -0.007, P = 0.0007) and Jadad score (ß = 0.067, P < 0.001) significantly moderated the results. For the remission rate, subgroup and meta-regression analyses revealed that the geographical region (P = 0.003), inpatient status (P = 0.035), and trial duration (ß = 0.009, P = 0.013) significantly moderated the results. Conclusions: The efficacy of TCM for antipsychotic-related constipation appeared to be greater compared to WM, while certain side effects of TCM, such as rash, were less frequent.

Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial.

Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. Design, Setting, and Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). Main Outcomes and Measures: The primary outcome was incident AF confirmed by medical record review. Results: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). Conclusions and Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.

Plant-based Medicines (Phytoceuticals) in the Treatment of Psychiatric Disorders: A Meta-review of Meta-analyses of Randomized Controlled Trials: Les médicaments à base de plantes (phytoceutiques) dans le traitement des troubles psychiatriques: une méta-revue des méta-analyses d'essais randomisés contrôlés.

OBJECTIVES: Plant-based medicines have had a long-standing history of use in psychiatric disorders. Highly quantified and standardized extracts or isolates may be termed "phytoceuticals," in a similar way that medicinal nutrients are termed as "nutraceuticals." Over the past 2 decades, several meta-analyses have examined the data for a range of plant-based medicines in the treatment of psychiatric disorders. The aim of this international project is to provide a "meta-review" of this top-tier evidence. METHODS: We identified, synthesized, and appraised all available up to date meta-analyses... of randomized controlled trials (RCTs) reporting on the efficacy and effectiveness of individual phytoceuticals across all major psychiatric disorders. RESULTS: Our systematic search identified 9 relevant meta-analyses of RCTs, with primary analyses including outcome data from 5,927 individuals. Supportive meta-analytic evidence was found for St John's wort for major depressive disorder (MDD); curcumin and saffron for MDD or depression symptoms, and ginkgo for total and negative symptoms in schizophrenia. Kava was not effective in treating diagnosed anxiety disorders. We also provide details on 22 traditional Chinese herbal medicine formulas' meta-analyses (primarily for depression studies), all of which revealed highly significant and large effect sizes. Their methodology, reporting, and potential publication bias were, however, of marked concern. The same caveat was noted for the curcumin, ginkgo, and saffron meta-analyses, which may also have significant publication bias. CONCLUSIONS: More rigorous international studies are required to validate the efficacy of these phytoceuticals before treatment recommendations can be made. In conclusion, the breadth of data tentatively supports several phytoceuticals which may be effective for mental disorders alongside pharmaceutical, psychological therapies, and standard lifestyle recommendations.

A Systematic Review of Nutraceuticals for the Treatment of Bipolar Disorder.

BACKGROUND: Certain nutrient supplements (nutraceuticals) may target neurobiological pathways perturbed in bipolar disorder (BD) such as inflammation, oxidative stress, and mitochondrial dysfunction. Nutraceuticals thus may have a potential role as adjunctive treatments for BD. METHODS: A search of Embase via embase.com, PubMed via PubMed, Cumulated index to nursing and allied health literature (CINAHL) Complete via EBSCO, and Cochrane Central Register of Controlled Clinical Trials via cochranelibrary.com was conducted to identify published randomized controlled trials assessing the efficacy of nutraceuticals on mood symptomatology in adults with BD. Search terms for BD, nutraceuticals, and clinical trials (total search terms = 75) were used to search from inception to February 20, 2020. The Cochrane Collaboration's tool for assessing the risk of bias in randomized trials was used to assess the risk of bias. RESULTS: A total of 1,712 studies were identified through the search. After rigorous screening, 22 studies were included in the review. There was large variability across the studies with 15 different nutraceutical agents assessed and as such insufficient homogeneity for a meta-analysis to be conducted (I2 > 50%). Studies revealed promising, albeit conflicting, evidence for omega-3 fatty acids and N-acetylcysteine. Isolated positive results were reported for coenzyme Q10. CONCLUSION: Given nutraceuticals are tolerable and accessible, they may be useful as potential adjunctive treatments for BD. Nutraceuticals targeting neuroinflammation or mitochondrial activity may have the most potential for the depressive phase. However, further studies are required to determine efficacy.

Moving Towards Optimized Noncommunicable Disease Management in the ASEAN Region: Recommendations from a Review and Multidisciplinary Expert Panel.

INTRODUCTION: Noncommunicable diseases (NCDs) are the leading cause of morbidity and mortality in the Association of Southeast Asian Nations (ASEAN) member states. Progress has been slow despite the World Health Organization action plan for the prevention and control of NCDs in the region. This paper presents recommendations focused on practical strategies for optimizing NCD management in the ASEAN region. METHODS: A multidisciplinary group of experts from six ASEAN member states convened for two face-to-face meetings to discuss barriers and possible recommendations for optimizing NCD management, focused on cardiovascular diseases and mental disorders, in the region. Multiple approaches, ie, analysis of insights from the meetings and a review of existing literature on NCD programs in the ASEAN region were followed. The proposed recommendations were also based on selected successful interventions in ASEAN member states, thus providing actionable strategies. RESULTS: The gaps identified in NCD management for cardiovascular diseases and mental disorders in the ASEAN region were classified into gaps relating to policies and to clinical and public health practice. The proposed solutions addressing policy gaps include fostering multisectoral public-private partnerships, employing "whole-of-government" and "whole-of-society" approaches and promoting "health-in-all policies approach" to manage issues with financing, accessibility, efficiency and quality of health services. Whereas proposed solutions to bridge clinical and public health practice gaps entail strengthening primary care services, building the capacity of trained healthcare workers and employing collaborative care for holistic management of patients. CONCLUSION: The scale of premature and preventable deaths from NCDs in the ASEAN region remains a serious public health concern and requires a "whole-of-system approach". The interventions proposed in this paper build on regional collaborations and knowledge sharing to help develop a concerted and targeted response to NCDs.

EPA and DHA as markers of nutraceutical treatment response in major depressive disorder.

PURPOSE: Depression clinical trials are increasingly studying biomarkers to predict and monitor response to treatment. Assessment of biomarkers may reveal subsets of patients who are responsive to nutraceutical treatment, which may facilitate a personalized approach to treating depression. METHODS: This is a post hoc analysis of an 8-week, double-blind, randomized, controlled trial (n = 158) investigating a combination nutraceutical comprising Omega-3 (EPA 1 g/DHA 656 mg), SAMe, zinc, 5-HTP, folinic acid, and co-factors versus placebo for the treatment of Major Depressive Disorder. The study explored levels of polyunsaturated fatty acids, folate, vitamin B12, zinc, homocysteine, and BDNF as possible predictors and correlates of response to nutraceutical supplementation. RESULTS: Concentrations of EPA and DHA in red cell membranes increased in response to treatment and were significantly correlated with a decrease in depressive symptoms during active treatment (p = 0.003 and p = 0.029; respectively). Higher baseline levels of omega-6 fatty acid also correlated with depression reduction in the active treatment group ( p = 0.011). No other biomarkers were associated with a lessening of depressive symptoms. CONCLUSION: Changes in fatty acid levels resulting from a nutraceutical combination containing EPA and DHA provide a response biomarker in treating depression.

Mindfulness-Based Interventions for Insomnia: A Meta-Analysis of Randomized Controlled Trials.

Objective: Mindfulness-based interventions (MBIs) are clinically effective for insomnia, but the research findings have been mixed. This meta-analysis of randomized controlled trials (RCTs) examined the effect of MBIs on insomnia. Method: Both English (PubMed, PsycINFO, Embase, and Cochrane Library databases) and Chinese (WanFang and CNKI) databases were systematically and independently searched. Standardized mean differences (SMDs) and risk ratio (RR) with their 95% confidence intervals (CIs) were calculated using the random effects model. Results: Five RCTs (n = 520) comparing MBIs (n = 279) and control (n = 241) groups were identified and analyzed. Compared to the control group, participants in the MBIs group showed significant improvement in insomnia as measured by the Pittsburgh Sleep Quality Index (n = 247; SMD: -1.01, 95% CI: -1.28 to -0.75, I2 = 0%, p < 0.00001) at post-MBIs assessment. Conclusion: In this comprehensive meta-analysis, MBIs appear to be effective in the treatment of insomnia. Further studies to examine the long-term effects of MBIs for insomnia are needed.

Physical Activity as a Predictor of Clinical Trial Outcomes in Bipolar Depression: A Subanalysis of a Mitochondrial-Enhancing Nutraceutical Randomized Controlled Trial.

OBJECTIVES: Individuals with bipolar disorder (BD) generally engage in low levels of physical activity (PA), and yet few studies have investigated the relationship between PA and change in BD symptom severity. The aim of this subanalysis of an adjunctive nutraceutical randomized controlled trial for the treatment of bipolar depression was to explore the relationship between PA, the active adjunctive treatments (a nutraceutical "mitochondrial cocktail"), and clinical outcomes. METHODS: Participants with bipolar depression were randomized to receive N-acetylcysteine alone, N-acetylcysteine with a combination of nutraceuticals (chosen for the potential to increase mitochondrial activity), or placebo for 16 weeks. Participants (n = 145) who completed the International Physical Activity Questionnaire-Short Form (IPAQ-SF; measured at Week 4) were included in this exploratory subanalysis. Assessments of BD symptoms, functioning, and quality of life were completed at monthly visits up until Week 20. Generalised Estimating Equations were used to explore whether IPAQ-SF scores were a moderator of treatment received on outcomes of the study. RESULTS: Week-4 PA was not related to changes in Montgomery Åsberg Depression Rating Scale scores across the study until Week 20. However, participants who engaged in more PA and who received the combination treatment were more likely to have a reduction in scores on the Bipolar Depression Rating Scale (P = 0.03). However, this was not consistent in all domains explored using the IPAQ-SF. Participants who engaged in higher levels of PA also experienced greater improvement in social and occupational functioning and less impairment in functioning due to their psychopathology and improvement in quality of life at Week 20, irrespective of treatment. CONCLUSIONS: This study provides novel evidence of the association between PA and reduction in BD symptoms in a nutraceutical clinical trial. However, further research assessing the potential synergistic effects of PA in BD is required.

Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive N-acetylcysteine and mitochondrial agents in adults with bipolar disorder: A sub-study of a randomised placebo-controlled trial.

AIMS: We aimed to explore the relationships between diet quality, dietary inflammatory potential or body mass index and outcomes of a clinical trial of nutraceutical treatment for bipolar depression. METHODS: This is a sub-study of a randomised controlled trial of participants with bipolar depression who provided dietary intake data (n = 133). Participants received 16 weeks adjunctive treatment of either placebo or N-acetylcysteine-alone or a combination of mitochondrial-enhancing nutraceuticals including N-acetylcysteine (combination treatment). Participants were followed up 4 weeks post-treatment discontinuation (Week 20). Diet was assessed by the Cancer Council Victoria Dietary Questionnaire for Epidemiological Studies, Version 2, converted into an Australian Recommended Food Score to measure diet quality, and energy-adjusted dietary inflammatory index score to measure inflammatory potential of diet. Body mass index was also measured. Generalised estimating equation models were used to assess whether diet quality, energy-adjusted dietary inflammatory index score and/or body mass index were predictors of response to significant outcomes of the primary trial: depression symptoms, clinician-rated improvement and functioning measures. RESULTS: In participants taking combination treatment compared to placebo, change in depression scores was not predicted by Australian Recommended Food Score, dietary inflammatory index or body mass index scores. However, participants with better diet quality (Australian Recommended Food Score) reported reduced general depression and bipolar depression symptoms (p = 0.01 and p = 0.03, respectively) and greater clinician-rated improvement (p = 0.02) irrespective of treatment and time. Participants who had a more anti-inflammatory dietary inflammatory index had less impairment in functioning (p = 0.01). Combination treatment may attenuate the adverse effects of pro-inflammatory diet (p = 0.03) on functioning. Participants with lower body mass index who received combination treatment (p = 0.02) or N-acetylcysteine (p = 0.02) showed greater clinician-rated improvement. CONCLUSION: These data support a possible association between diet (quality and inflammatory potential), body mass index and response to treatment for bipolar depression in the context of a nutraceutical trial. The results should be interpreted cautiously because of limitations, including numerous null findings, modest sample size and being secondary analyses.

Efficacy and safety of traditional Chinese medicine for Tourette's syndrome: A meta-analysis of randomized controlled trials.

BACKGROUND: Traditional Chinese medicine (TCM) has been widely used in the treatment of Tourette's Syndrome (TS). However, the efficacy and safety of TCM in treating TS are mixed across studies. This is a meta-analysis of studies on the efficacy and safety of TCM compared to placebo and Western medicine (WM). METHODS: PubMed, Cochrane Library, PsycINFO, Chinese National Knowledge Infrastructure, SinoMed, and WanFang databases were systematically searched from inception date to October 16, 2018. Randomized Controlled Trials (RCTs) on the efficacy and safety of TCM alone or TCM + WM combination for TS were included. RESULTS: A total of 15 studies comprising 21 treatment trials (n = 2824) were included. TCM alone was more efficacious than placebo in terms of response rate (Relative Risk, RR: 1.96, 95% CI: 1.55-2.47, P < 0.01, I2 = 45 %) and the change in the Yale Global Tic Severity Scale total score (Standard mean difference, SMDs: -0.67, 95% CI: -0.81, -0.53, P < 0.01, I2 = 0 %). The results remained positive when TCM alone was compared with WM alone (RR: 1.06, 95% CI: 1.00-1.12, P = 0.03, I2 = 29 %), and when TCM + WM were compared with WM alone (RR: 1.24, 95% CI: 1.08-1.43, P < 0.01, I2 = 0 %). Adverse drug reactions were more frequent in WM than in TCM groups (P < 0.05). WM type (P = 0.02), proportion of males (P = 0.03) and trial duration (P = 0.03) were significantly associated with response rate in TS patients when comparing TCM alone with WM alone. CONCLUSION: The results of this meta-analysis support the efficacy and safety of TCM alone and TCM + WM in TS patients.

Association of Bone Mineral Density With Fractures Across the Spectrum of Chronic Kidney Disease: The Regina CKD-MBD Study.

BACKGROUND: Recent studies have demonstrated that measurement of areal bone mineral density by dual-energy x-ray absorptiometry (DXA) predicts fractures in patients with chronic kidney disease (CKD). However, whether fracture risk prediction through bone mineral density (BMD) is enhanced due to the assessment of biochemical markers of chronic kidney disease and mineral and bone disease (CKD-MBD) or clinical risk factors is not clear. We hypothesized that in a select cohort of patients managed in a CKD clinic, that combining T-Scores with biochemical markers would optimize fracture discrimination than using DXA alone. OBJECTIVE: To examine the relationships among BMD, biochemical markers of CKD-MBD, and fracture risk across Kidney Disease Improving Global Outcomes (KDIGO) glomerular filtration rate (GFR) categories G3a to G5. DESIGN: Retrospective study. SETTING: Patients were recruited from the multidisciplinary CKD clinic, Regina General Hospital, Canada. PATIENTS: A total of 374 patients who received a DXA scan upon initial referral to Regina Multidisciplinary CKD Program from January 31, 2001 to January 31, 2010, were included in this study. The patients were followed for a total of 5 years. METHODS: We conducted a retrospective review of 374 consecutive patients who underwent DXA imaging at the point of entry into our multidisciplinary CKD program. Areal BMD, T- and Z-Scores were obtained at the lumbar spine, total hip, mean of left and right femoral neck, and the one-third radius. We collected data on demographic, cross-sectional biochemical markers of mineral metabolism and fractures (identified through self-reported questionnaires, hospital electronic medical records, and physician billing records). We were able to gather data on 8/11 variables of Fracture Risk Assessment (FRAX) tool. RESULTS: In our cohort, 14.3% of GFR categories G3a and G3b, 15.7% of GFR category G4, and 19.7% of GFR category G5 experienced a clinical fracture during the study period. On multivariate analysis, each decline of 1.0 SD in total hip BMD T-Score was associated with a significant increase in the risk of fracture (OR = 1.46, 95% confidence interval [CI], 1.12-1.89). Adding CKD-MBD markers and clinical risk factors did not further contribute to the model. Low BMD was the only independent risk factor for fracture in patients with CKD. LIMITATIONS: Self-reporting by patients and administrative records were used to identify fractures. We did not perform spine imaging to ascertain morphometric vertebral fractures. We were unable to gather all 11 variables of FRAX score and information on ethnicity. We were unable to capture site of fracture (hips, spine, etc) from billing records. Albumin excretion rates were not collected at baseline. Treatment of the underlying bone disease with pharmacotherapeutic agents may have attenuated patients' fracture risk and thus underestimated the association between BMD and future fracture. CONCLUSIONS: Our findings confirm that BMD predicts fracture. The addition of cross-sectional CKD-MBD parameters and clinical risk factors to BMD did not add to fracture prediction. Prospective studies should investigate the utility of longitudinal biochemical markers on improving fracture risk assessment.

CONTEXTE: Des études récentes ont démontré qu'il était possible de prédire les fractures chez les patients atteints d'insuffisance rénale chronique (IRC) avec une mesure de la densité minérale osseuse (DMO) surfacique par absorptiométrie biénergétique à rayons X (DXA). On ignore cependant si la valeur prédictive de la DMO est améliorée par l'analyze des biomarqueurs des troubles minéraux et osseux associés à l'IRC (TMO-IRC) ou des facteurs de risque cliniques. Nous avons émis l'hypothèse que, dans une cohorte choisie de patients suivis en clinique d'IRC, la combinaison des scores T et des marqueurs biochimiques optimiserait la discrimination des fractures par rapport à l'utilization de la DXA seule. OBJECTIF: L'étude visait à établir un lien entre la DMO, les biomarqueurs des TMO-IRC et le risque de fractures chez les patients présentant un débit de filtration glomérulaire (DFG) de catégories G3a à G5 selon la classification du KDIGO (Kidney Disease Improving Global Outcomes). TYPE D'ÉTUDE: Étude rétrospective. CADRE: Les patients ont été recrutés à la clinique multidisciplinaire d'IRC de l'hôpital général de Régina (Canada). SUJETS: Ont été inclus les 374 patients ayant passé un test d'imagerie DXA entre le 31 janvier 2001 et le 31 janvier 2010 lors de leur aiguillage vers le program multidisciplinaire d'IRC de Régina. Les patients ont été suivis sur une période de cinq ans. MÉTHODOLOGIE: Nous avons mené une étude rétrospective portant sur 374 patients consécutifs examinés par DXA à leur admission au program. La DMO surfacique et les scores T et Z ont été mesurés au rachis lombaire, à la hanche totale, à la moyenne des cols fémoraux droit et gauche, et au tiers du radius. On a recueilli les caractéristiques démographiques des patients, les données sur les marqueurs biochimiques transversaux du métabolisme minéral et les fractures subies (recensées à l'aide d'un questionnaire d'auto-déclaration et par consultation des dossiers médicaux électroniques et des registres de facturation des médecins). Nous sommes parvenus à rassembler des données sur huit variables des onze de l'outil FRAX (Fracture Risk Assessment tool). RÉSULTATS: Dans notre cohorte, 14,3 % des patients avec un DFG de catégorie G3a-G3b, 15,7 % des patients avec un DFG de catégorie G4 et 19,7 % des patients avec un DFG de catégorie G5 ont subi une fracture clinique au cours de la période d'étude. Dans l'analyze multivariée, chaque déclin d'un point d'écart-type au score T de la DMO à la hanche a été associé à une augmentation significative du risque de fracture (RR = 1,46; IC 95 %: 1,12-1,89). L'ajout des marqueurs des TMO-IRC et des facteurs de risque cliniques n'a pas contribué davantage au modèle. Une faible DMO s'est avérée le seul facteur de risque indépendant de subir une fracture chez les patients atteints d'IRC. LIMITES: Les fractures ont été identifiées à partir des dossiers administratifs et par auto-déclaration des patients. Nous n'avons pas procédé à l'imagerie de la colonne vertébrale pour confirmer les fractures vertébrales morphométriques. Nous n'avons pas été en mesure de rassembler les onze variables du score FRAX ni les informations sur l'origine ethnique des patients. Les registres de facturation ne nous ont pas permis d'établir le site de la fracture (hanche, rachis ou autre). Les taux initiaux d'excrétion de l'albumine n'ont pas été mesurés. Le traitement de l'ostéopathie sous-jacente à l'aide d'agents pharmacothérapeutiques pourrait avoir atténué le risque de fracture des patients et ainsi, sous-évalué l'association entre la DMO et de futures fractures. CONCLUSION: Nos résultats confirment que la DMO est prédictive du risque de fractures. L'ajout des paramètres transversaux des TMO-IRC et des facteurs de risque cliniques à la mesure de DMO n'en a pas amélioré la valeur prédictive. Des études prospectives devraient examiner l'intérêt des marqueurs biochimiques longitudinaux pour améliorer l'évaluation du risque de fracture.

Efficacy of adjunctive Garcinia mangostana Linn (mangosteen) pericarp for bipolar depression: study protocol for a proof-of-concept trial

Objective: Bipolar depression is characterized by neurobiological features including perturbed oxidative biology, reduction in antioxidant levels, and a concomitant rise in oxidative stress markers. Bipolar depression manifests systemic inflammation, mitochondrial dysfunction, and changes in brain growth factors. The depressive phase of the disorder is the most common and responds the least to conventional treatments. Garcinia mangostana Linn, commonly known as mangosteen, is a tropical fruit. The pericarp's properties may reduce oxidative stress and inflammation and improve neurogenesis, making mangosteen pericarp a promising add-on therapy for bipolar depression. Methods: Participants will receive 24 weeks of either 1,000 mg mangosteen pericarp or placebo per day, in addition to their usual treatment. The primary outcome is change in severity of mood symptoms, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), over the treatment phase. Secondary outcomes include global psychopathology, quality of life, functioning, substance use, cognition, safety, biological data, and cost-effectiveness. A follow-up interview will be conducted 4 weeks post-treatment. Conclusion: The findings of this study may have implications for improving treatment outcomes for those with bipolar disorder and may contribute to our understanding of the pathophysiology of bipolar depression. Clinical trial registration: Australian and New Zealand Clinical Trial Registry, ACTRN12616000028404.

Nutraceuticals and nutritional supplements for the treatment of bipolar disorder: protocol for a systematic review.

INTRODUCTION: First line pharmacological treatments for bipolar disorder (BD) can leave shortfalls in recovery leading to patients seeking alternative and adjunctive treatments such as nutraceuticals. This protocol for a systematic review and proposed meta-analysis aims to answer the research question: in patients with BD, how does use of nutraceutical treatments compare with placebo in reducing depressive and mania symptoms? METHODS AND ANALYSIS: Clinical trials will be identified through database searches using PubMed via PubMed, EMBASE via embase.com, Cochrane Central Register of Controlled Clinical Trials (CENTRAL) via cochranelibrary.com and CINAHL Complete via EBSCO. Search terms for BD and specific nutraceuticals (75 total search terms) will be used. Double-blind, randomised, controlled, clinical trials of adults with BD will be included in the review. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomised trials. ETHICS AND DISSEMINATION: This review will only look at published data (already reviewed for ethical compliance); therefore, ethical approval is not required. We aim to publish the systematic review in a peer-reviewed journal and present at conferences. PROSPERO REGISTRATION NUMBER: CRD42019100745.

The Therapeutic Potential of Mangosteen Pericarp as an Adjunctive Therapy for Bipolar Disorder and Schizophrenia.

New treatments are urgently needed for serious mental illnesses including bipolar disorder and schizophrenia. This review proposes that Garcinia mangostana Linn. (mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders. Research to date demonstrates that neurobiological properties of the mangosteen pericarp are well aligned with the current understanding of the pathophysiology of bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties, with animal studies demonstrating favorable pharmacotherapeutic benefits with respect to these disorders. This review summarizes evidence of its properties and supports the case for future studies to assess the utility of mangosteen pericarp as an adjunctive treatment option for mood and psychotic disorders.