The Impact of N-acetylcysteine on Major Depression: Qualitative Observation and Mixed Methods Analysis of Participant Change during a 12-week Randomised Controlled Trial.

Objective: N-acetylcysteine (NAC) is a novel therapeutic agent with multiple mechanisms of action in the central nervous system and a favourable side effect profile. Clinical evidence indicates that adjunctive NAC may reduce the severity of depressive symptoms in individuals with major depressive disorder (MDD). Methods: A 12-week randomised controlled trial of 2,000 mg/day adjunctive NAC for MDD found no significant improvement at the primary endpoint (week 12) but did see improvements at the post-discontinuation interview (week 16). Within the context of patient-centered treatment, mixed-methods qualitative analysis was also included to explore factors that may determine individual responses to adjunctive NAC treatment. These data were drawn, under blinded conditions, from clinician notes recorded in the case report form. Using the DSM-5 symptom profile for MDD as the initial framework, themes were developed and explored. Frequencies were compared between placebo and NAC groups. Results: Per protocol analysis of individual themes across the six interviews revealed group differences in favour of NAC for overall depressive affect, optimism, relationships and reduced functional impairment. Conclusion: This study provides further evidence for the utility of the mixed methods approach complimenting the primary findings using traditional quantitative analyses, as well as being able to capture additional, often more subtle, evidence of individual symptom-level change that reflects improvement in functional abilities in response to NAC supplementation. The use of mixed methods to explore outcomes from psychiatric studies should be considered in future to work towards improved patient-centred care and both confirm quantitative findings and generate novel hypotheses.

Effect of Glucocorticoid and 11ß-Hydroxysteroid-Dehydrogenase Type 1 (11ß-HSD1) in Neurological and Psychiatric Disorders.

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity is implicated as a moderator of the progression of multiple diseases and disorders in medicine and is actively subject to investigation as a therapeutic target. Here we summarize the mechanisms of the enzyme and detail the novel agents under investigation. Such agents modulate peripheral cortisol and cortisone levels in hypertension, type 2 diabetes, metabolic disorders, and Alzheimer's disease models, but there is mixed evidence for transduction into symptom management. There is inchoate evidence that 11ß-HSD1 modulators may be useful pharmacotherapies for clinical improvement in psychiatry and neurology; however, more research is required.

The Relationship Between Psychological Stress and Anxiety with Gastrointestinal Symptoms Before and During a 56 km Ultramarathon Running Race.

BACKGROUND: This study assessed relationships and sex differences between psychological state (recovery, stress, anxiety, and self-confidence) and gastrointestinal symptoms (GIS) prior to and during a 56 km ultramarathon running race and identified predictive factors of race GIS. Forty-four (26 males, 18 females) ultramarathon competitors completed anxiety, recovery, stress and GIS questionnaires for three days prior to the race and immediately pre-race. Race GIS were assessed immediately post-race. Spearman's rank order, Mann-Whitney U tests and regression analyses were used to determine correlations and identify sex differences between psychological state and GIS and determine predictors of race GIS. RESULTS: Race GIS were significantly correlated with recovery (rs = - 0.381, p = 0.011), stress (rs = 0.500, p = 0.001) and anxiety (rs = 0.408, p = 0.006), calculated as the mean of the three days preceding the race and on race morning. The correlation between anxiety and GIS was strongest in the 24 h immediately prior to the race (all rs > 0.400, and all p < 0.05), but unclear patterns were identified for stress and recovery. Regression analyses showed 36% and 40% of variation in the severity and number of race GIS was accounted for by body mass and measures of stress, anxiety, and GIS over the three days preceding the race and on race morning (both p < 0.001). There were no sex differences in the number and severity of GIS leading up to or during the race (all p > 0.05), however, females reported greater state anxiety (p = 0.018) and lower self-confidence than males (p = 0.006) over the three days preceding the race and on race morning. CONCLUSION: Endurance athletes that experience GIS during competition should investigate elevated stress and/or anxiety as a potential contributor and identify if management strategies can reduce the occurrence and severity of GIS.

The Effect of Adjunctive Mangosteen Pericarp on Cognition in People With Schizophrenia: Secondary Analysis of a Randomized Controlled Trial.

Background: Cognitive impairment is prevalent and often highly burdensome in people with schizophrenia. The aim of this study was to investigate if mangosteen (Garcinia mangostana Linn.) pericarp extract may be an effective intervention to improve cognitive performance in this population. Methods: This was a secondary analysis of a larger randomized placebo-controlled trial that investigated a 24-weeks intervention of mangosteen pericarp extract supplementation in people diagnosed with schizophrenia. A subset of n = 114 participants with completed cognitive outcomes at follow up were included in this analysis. Using the Cogstate Brief Battery, the following cognitive outcomes were assessed: psychomotor function, attention, visual learning and memory (visual and working). Subgroup analyses investigated whether baseline clinical parameters (baseline cognitive functioning, illness severity and duration, depressive symptoms) moderated the relationship between mangosteen pericarp extract intervention and change in cognitive outcomes. Results: There were no significant between-group changes in any cognitive outcomes assessed. Subgroup analysis based on baseline cognition and clinical characteristics did not reveal any significant between-group difference in change. Conclusions: Mangosteen pericarp extract did not affect cognitive outcomes in people with schizophrenia. Further investigation regarding optimal dosing strategies for mangosteen interventions and the testing of additional cognitive domains may be warranted. Trial Registration: ANZCTR.org.au identifier: ACTRN12616000859482, registered 30 June 3 2016.

Impact of a Secondary School Depression Prevention Curriculum on Adolescent Social-Emotional Skills: Evaluation of the Resilient Families Program.

School-based mental health intervention programs have demonstrated efficacy for the prevention and reduction of depressive symptoms, though the effect tends to be variable and is often unsustained longitudinally. However, it is possible that these intervention programs may have an indirect impact on adolescent functioning via positive mediators, and that this influence may predict more durable protective benefits. This study evaluated the efficacy of the Resilient Families program for improving social-emotional skills and depressive symptoms for adolescents over a two-year period. Twenty-four secondary schools in Melbourne, Australia were randomly allocated to either Resilient Families or a control condition. 1826 students (M= 12.3, SD = .05 years at W1; 56% female) completed the curricula and subsequent surveys. Inconsistent with hypotheses, analysis with Structural Equation Modelling revealed that the program had no significant effect on social-emotional skills and these skills had no significant effects on adolescent depressive symptoms. However, family attendance at parent education events within the intervention schools was associated with longitudinal reductions in depressive symptoms. The findings highlight the importance of increasing emphasis on family and community protective factors in adolescent social-emotional development and depression prevention programs.

Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies.

Post-Operative Cognitive Dysfunction (POCD) is a highly prevalent condition with significant clinical, social and financial impacts for patients and their communities. The underlying pathophysiology is becoming increasingly understood, with the role of neuroinflammation and oxidative stress secondary to surgery and anaesthesia strongly implicated. This review aims to describe the putative mechanisms by which surgery-induced inflammation produces cognitive sequelae, with a focus on identifying potential novel therapies based upon their ability to modify these pathways.

The effect of N-acetylcysteine (NAC) on human cognition - A systematic review.

Oxidative stress, neuroinflammation and neurogenesis are commonly implicated as cognitive modulators across a range of disorders. N-acetylcysteine (NAC) is a glutathione precursor with potent antioxidant, pro-neurogenesis and anti-inflammatory properties and a favourable safety profile. A systematic review of the literature specifically examining the effect of NAC administration on human cognition revealed twelve suitable articles for inclusion: four examining Alzheimer's disease; three examining healthy participants; two examining physical trauma; one examining bipolar disorder, one examining schizophrenia, and one examining ketamine-induced psychosis. Heterogeneity of studies, insufficiently powered studies, infrequency of cognition as a primary outcome, heterogeneous methodologies, formulations, co-administered treatments, administration regimes, and assessment confounded the drawing of firm conclusions. The available data suggested statistically significant cognitive improvements following NAC treatment, though the paucity of NAC-specific research makes it difficult to determine if this effect is meaningful. While NAC may have a positive cognitive effect in a variety of contexts; larger, targeted studies are warranted, specifically evaluating its role in other clinical disorders with cognitive sequelae resulting from oxidative stress and neuroinflammation.

The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial.

BACKGROUND: Some degree of cognitive decline after surgery occurs in as many as one quarter of elderly surgical patients, and this decline is associated with increased morbidity and mortality. Cognition may be affected across a range of domains, including memory, psychomotor skills, and executive function. Whilst the exact mechanisms of cognitive change after surgery are not precisely known, oxidative stress and subsequent neuroinflammation have been implicated. N-acetylcysteine (NAC) acts via multiple interrelated mechanisms to influence oxidative homeostasis, neuronal transmission, and inflammation. NAC has been shown to reduce oxidative stress and inflammation in both human and animal models. There is clinical evidence to suggest that NAC may be beneficial in preventing the cognitive decline associated with both acute physiological insults and dementia-related disorders. To date, no trials have examined perioperative NAC as a potential moderator of postoperative cognitive changes in the noncardiac surgery setting. METHODS AND DESIGN: This is a single-centre, randomised, double-blind, placebo-controlled clinical trial, with a between-group, repeated-measures, longitudinal design. The study will recruit 370 noncardiac surgical patients at the University Hospital Geelong, aged 60 years or older. Participants are randomly assigned to receive either NAC or placebo (1:1 ratio), and groups are stratified by age and surgery type. Participants undergo a series of neuropsychological tests prior to surgery, 7 days, 3 months, and 12 months post surgery. It is hypothesised that the perioperative administration of NAC will reduce the degree of postoperative cognitive changes at early and long-term follow-up, as measured by changes on individual measures of the neurocognitive battery, when compared with placebo. Serum samples are taken on the day of surgery and on day 2 post surgery to quantitate any changes in levels of biomarkers of inflammation and oxidative stress. DISCUSSION: The PANACEA trial aims to examine the potential efficacy of perioperative NAC to reduce the severity of postoperative cognitive dysfunction in an elderly, noncardiac surgery population. This is an entirely novel approach to the prevention of postoperative cognitive dysfunction and will have high impact and translatable outcomes if NAC is found to be beneficial. TRIAL REGISTRATION: The PANACEA trial has been registered with the Therapeutic Goods Administration, and the Australian New Zealand Clinical Trials Registry: ACTRN12614000411640 ; registered on 15 April 2014.