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.

Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial.

OBJECTIVES: Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD. METHODS: The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial (n = 15) of enema-delivered FMT (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. RESULTS: Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD. CONCLUSIONS: All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.

Safety and feasibility of faecal microbiota transplant for major depressive disorder: study protocol for a pilot randomised controlled trial.

BACKGROUND: Mental disorders, including major depressive disorder (MDD), are a leading cause of non-fatal burden of disease globally. Current conventional treatments for depression have significant limitations, and there have been few new treatments in decades. The microbiota-gut-brain-axis is now recognised as playing a role in mental and brain health, and promising preclinical and clinical data suggest Faecal Microbiota Transplants (FMT) may be efficacious for treating a range of mental illnesses. However, there are no existing published studies in humans evaluating the efficacy of FMT for MDD. METHODS AND DESIGN: This protocol describes an 8-week, triple-blind, 2:1 parallel group, randomised controlled pilot trial (n = 15), of enema-delivered FMT treatment (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. There will be a further 26-week follow-up to monitor longer-term safety. Participants will receive four FMT or placebo enemas over four consecutive days. The primary aims of the study are to evaluate feasibility and safety of FMT as an adjunctive treatment for MDD in adults. Changes in gut microbiota will be assessed as a secondary outcome. Other data will be collected, including changes in depression and anxiety symptoms, and safety parameters. DISCUSSION: Modification of the microbiota-gut-brain axis via FMT is a promising potential treatment for MDD, but there are no published rigorous clinical trials evaluating its use. If this study finds that our FMT strategy is safe and feasible, a larger fully powered RCT is planned. Further high-quality research in this field is urgently needed to address unmet need. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12621000932864.

Identifying aroma-active compounds in coffee-flavored dairy beverages.

Coffee aroma is a complex mixture of volatile compounds. This study characterized the important aroma-active compounds associated with consumer liking in formulated coffee-flavored dairy beverages. Nine coffee-flavored dairy beverages were formulated: low fat-low coffee; medium fat-low coffee; high fat-low coffee; low fat-medium coffee; medium fat-medium coffee; high fat-medium coffee; low fat-high coffee; medium fat-high coffee; and high fat-high coffee. Regular coffee consumers, (n = 231) used a nine-point hedonic scale to rate acceptance of aroma. Volatile compounds were extracted by head space-solid phase micro-extraction (HS-SPME) and analyzed by gas chromatography-mass spectrometry-olfactometry (GC-MS-O) using a modified frequency (MF) approach. Fifty-two aroma-active compounds were detected. Thirty-one aroma-active compounds were considered important compounds with MF-value ≥ 50%. The total number of aroma-active compounds and their intensity were affected because of fat and coffee concentration. Partial least squares regression (PLSR) was performed to determine the relationship between aroma-active compounds and liking. PLSR analysis identified three groups of compounds regarding liking. Twenty-five compounds were associated with positive liking, for example, 2-(methylsulfanylmethyl) furan (coffee like). Sixteen compounds were negatively associated with liking, for example, 2-methoxyphenol (bacon, medicine like). Eleven detected compounds had no association with liking, for example, butane-2,3-dione (butter, fruit like). Practical Application: The result of this study may be applied to formulate coffee-flavored dairy beverages to maximize consumer acceptance and aroma-liking. This study suggested too low coffee concentration is not desirable. Too much fat affects aroma release and/or alters the characteristic coffee flavor which negatively affects consumer acceptance.

A placebo-controlled, randomised pilot trial of N-acetylcysteine or placebo for cessation of tobacco smoking.

Smoking represents a significant health threat to the population, however there remains a core group of consistent smokers that are largely unable to break the addiction. Novel therapies are required to assist this group with cessation. N-acetylcysteine (NAC) is a nutraceutical supplement that has shown efficacy compared to placebo in previous pilot studies for assisting smokers to quit or reduce their consumption of cigarettes. A double-blind, randomised trial with a treatment period of 16 weeks and a final follow-up at 42 weeks was conducted comparing 1.8g of effervescent NAC per day (n=47) with placebo (n=47) as an aide to smoking cessation. Both study arms received adjunctive online support through the QuitCoach program. Participants reported smoking at each timepoint (baseline and weeks 8, 16 & 42), which was confirmed through salivary cotinine and exhaled carbon monoxide testing. Primary and secondary analyses were undertaken using a modified intent-to-treat basis, including all participants with at least one valid post baseline outcome, regardless of treatment received or their withdrawal from the study. There was no significant difference in smoking outcomes between intervention groups among the 24 participants that competed follow-up. There were no significant differences in age, gender, or body mass index (BMI) between the groups lost to follow-up or recorded at follow-up. This study found no evidence to support NAC as a therapy for smoking cessation. The negative outcome could be the result of lack of treatment efficacy, or alternatively, small sample size, participant retention difficulties, dose, or duration of follow-up. Trial Registration: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303. Registered on 19 October 2017.

The effect of fat and coffee concentration on the consumer acceptance of iced-coffee beverages.

The fat content of a product has the potential to influence consumer liking via mouthfeel, taste, and aroma modification. This study aims to determine the effects of fat and coffee concentration on sensory attributes and consumer liking of iced-coffee beverages. Nine iced-coffee beverages were formulated: low fat-low coffee; medium fat-low coffee; high fat-low coffee; low fat-medium coffee; medium fat-medium coffee; high fat-medium coffee; low fat-high coffee; medium fat-high coffee; and high fat-high coffee. Fat content was adjusted using different concentrations of cream, and coffee using different concentrations of Nescafé Blend 43. Regular coffee consumers (n = 231) rated their overall liking using a 9-point hedonic scale and completed a ranked preference based on degree of liking of all samples. Consumers also rated liking for sensory attributes: appearance, aroma, sweetness, coffee intensity, mouthfeel, and aftertaste. There were significant relationships between 1/ fat and 2/ coffee and liking of iced-coffee beverages (p < 0.001). There were three clusters of consumers based on iced-coffee preferences. Response surface curve indicated that overall liking of iced-coffee beverages increased with the increase of fat and coffee concentration to a certain level, then continuing to increase the fat and coffee concentration decreases overall liking. The finding of this study provides valuable information on how fat and coffee concentrations can be adjusted to modify consumer acceptance of iced-coffee beverages. PRACTICAL APPLICATION: The results of this research could be applied to reformulate iced-coffee beverages, while ensuring consumer acceptance. In addition, this research provides evidence that sweetness, aftertaste, coffee-intensity, and mouthfeel are important sensory attributes associated with consumer liking of iced-coffee beverages.

Osteoporosis medication use among Australian women over two decades.

Despite the burden of osteoporosis and treatment availability, a treatment gap remains. Women in a population-based study were followed with respect to use of anti-fracture medication over two decades. Use increased over time but remained suboptimal, with less than 20% of those at high risk of fracture receiving treatment. PURPOSE: We examined trends in osteoporosis-related medication use over time using data from the Geelong Osteoporosis Study, an ongoing, population-based study. METHODS: Self-reported medication use data were available for 822 women (50-90 years) at time-1 (1993-1997), 575 women at time-2 (2004-2008), and 527 women at time-3 (2011-2014) participating in a longitudinal study. Prevalence of any osteoporosis-related medication use (pooled anti-fracture (bisphosphonates, raloxifene, denosumab, or strontium); hormone therapy; and supplements (calcium and/or vitamin D)) was calculated using bootstrapping methods for the whole group and those at risk of fracture, identified using FRAX Aus® (probability of major osteoporotic fracture ≥ 20% and/or ≥ 3% hip fracture) and BMD (osteoporosis indicated by a T-score of less than - 2.5 at either the femoral neck or spine). Time trend (age groups 50-59, 60-69, 70-79, 80+ years) and time-point effects were evaluated using mixed effects logistic models. RESULTS: The use of any osteoporosis-related medication increased over three time points (time-1, 25.9% (95% CI 23.1, 28.8); time-2, 32.5% (28.7, 36.3); time-3, 35.9% (31.9, 39.8)), driven by the use of supplements (time-1, 12.9% (95% CI 10.6, 15.1); time-2, 22.1% (18.8, 25.4); time-3, 30.9% (26.9, 35.5)) and anti-fracture medication (time-1, 0.9% (0.4, 1.6); time-2, 5.0% (3.3, 6.8); time-3, 4.4% (2.7, 6.3)). Women at high risk of fracture were identified by BMD (time-1, n = 231 (28.1%); time-2, n = 92 (16.0%); time-3, n = 51 (9.7%)) and FRAX criteria (time-1, n = 272 (33.1%); time-2, n = 105 (18.3%); time-3, n = 100 (19.0%)). The use of anti-fracture medication was low among these groups (BMD criteria: time-1, 1.7% (0.4, 3.7); time-2, 16.3% (8.7, 24.3); time-3, 15.7% (7.1, 26.1); FRAX criteria: time-1, 1.1% (0.0, 2.3); time-2, 18.1% (11.5, 25.5); time-3, 13.0% (6.5, 19.8)). CONCLUSION: Use of anti-fracture medication among women at risk of fracture remained low over time. Investment into systems approaches to correct the treatment gap is warranted.

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.

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.

Is trabecular bone score less affected by degenerative-changes at the spine than lumbar spine BMD?

It has been established that degenerative-changes at the spine elevate bone mineral density at the lumbar spine. This study in men reports that trabecular bone score may be less affected by spinal degenerative-changes. PURPOSE: A recent tool for assessing trabecular microarchitecture at the lumbar spine, trabecular bone score (TBS), provides information about bone health complementary to lumbar spine areal BMD (here referred to as BMD). In men, mean BMD increases with increasing age due to degenerative-changes at the spine including osteophytes and aortic calcification. The aim of this study was to investigate whether TBS is similarly affected by the presence of degenerative-changes in men. METHODS: This study included 728 men aged 40-90 years enrolled in the Geelong Osteoporosis Study. Lumbar spine DXA scans (Lunar Prodigy) were used to determine TBS retrospectively (TBS iNsight software, Version 2.2), and for identification of degenerative-changes. Using multivariable regression techniques, the relationships between TBS or BMD and degenerative-changes were assessed, further adjusting for age and weight. The difference between each of the two methods was examined through testing interactions between method, degenerative-changes and age. RESULTS: Of 728 men, 439 (60.3%) were identified as having one or more degenerative-changes at the lumbar spine. Adjusted mean TBS was 1.219 (1.203-1.232) and 1.196 (1.179-1.212) for those with and without degenerative-changes, respectively. Adjusted mean BMD was 1.317 g/cm2 (1.297-1.336) and 1.198 g/cm2 (1.173-1.223) for those with and without degenerative-changes, respectively. Partial r2 for degenerative-changes in the model for TBS was 0.076 and for BMD, 0.257 (both p < 0.05). The three-way interaction between method, degenerative-changes and age was significant (p = 0.05) indicating significant effect of artefacts on the standardised values, affected by age and method. CONCLUSION: This study suggests that TBS is less affected by degenerative-changes at the spine than is BMD. Thus, TBS may prove useful in the assessment of fracture risk in men with degenerative-changes at the spine.