Exploring Clinical Subgroups of Participants with Major Depressive Disorder that may Benefit from Adjunctive Minocycline Treatment.

Objective: : To explore illness-related factors in patients with major depressive disorder (MDD) recipients of adjunctive minocycline (200 mg/day) treatment. The analysis included participants experiencing MDD from a 12-week, double blind, placebo-controlled, randomized clinical trial (RCT). Methods: : This is a sub-analysis of a RCT of all 71 participants who took part in the trial. The impact of illness chronicity (illness duration and number of depressive episodes), systemic illness (endocrine, cardiovascular and obesity), adverse effects and minocycline were evaluated as change from baseline to endpoint (12-week) using ANCOVA. Results: : There was a consistent but statistically non-significant trend on all outcomes in favour of the use of adjunctive minocycline for participants without systemic illness, less illness chronicity, and fewer adverse effects. Conclusion: : Understanding the relationship between MDD and illness chronicity, comorbid systemic illness, and adverse effects, can potentially better characterise those individuals who are more likely to respond to adjunctive anti-inflammatory medications.

Trauma and comorbid post-traumatic stress disorder in people with bipolar disorder participating in the Heinz C. Prechter Longitudinal Study.

BACKGROUND: It is estimated that up to 50 % of people with bipolar disorder (BD) also have comorbid post-traumatic stress disorder (PTSD). However, little is known about the presentation and treatment of people with this comorbidity. METHODS: Data from 577 individuals diagnosed with bipolar disorder participating in the Heinz C. Prechter Longitudinal Study of BD were explored at baseline, year two and four. Three trauma groups were created: (i) one trauma (n = 75), (ii) multiple traumas (n = 417), and comorbid PTSD (n = 85). Measures of depression, mania, sleep, number of hospitalisations, suicide attempts, and medication use were analysed using regression modelling to determine differences between the three trauma groups. RESULTS: There was an increase in depression, mania, and sleep scores and a higher number of hospitalisations in participants with comorbid PTSD compared to those experiencing one trauma. Additionally, increased mania and depression scores were reported in participants experiencing multiple traumas compared to those with one trauma. There was no difference in medication use between those who experienced one trauma compared to those with comorbid PTSD. LIMITATIONS: The trauma groups may include confounding with more participants experiencing PTSD than reported in this study due to screening processes. Additionally, the severity of trauma was not recorded, therefore number of traumas was utilised as a proxy. CONCLUSION: Comorbid BD and PTSD is associated with worse symptom scores compared to participants reporting one trauma. Clinical implications include the addition of trauma-informed care to clinical settings to identify PTSD to provide appropriate treatments.

Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Does Post-traumatic Stress Disorder Impact Treatment Outcomes within a Randomised Controlled Trial of Mitochondrial Agents for Bipolar Depression?

Objective: Bipolar disorder often co-occurs with post-traumatic stress disorder, yet few studies have investigated the impact of post-traumatic stress disorder in bipolar disorder on treatment outcomes. The aim of this sub-analysis was to explore symptoms and functioning outcomes between those with bipolar disorder alone and those with comorbid bipolar disorder and post-traumatic stress disorder. Methods: Participants (n = 148) with bipolar depression were randomised to: (i) N-acetylcysteine alone; (ii) a combination of nutraceuticals; (iii) or placebo (in addition to treatment as usual) for 16 weeks (＋4 weeks discontinuation). Differences between bipolar disorder and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning at five timepoints, as well as on the rate of change from baseline to week 16 and baseline to week 20, were examined. Results: There were no baseline differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder apart from the bipolar disorder alone group being significantly more likely to be married (p = 0.01). There were also no significant differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning. Conclusion: There were no differences in clinical outcomes over time within the context of an adjunctive randomised controlled trial between those with bipolar disorder alone compared to those with comorbid bipolar disorder and post-traumatic stress disorder. However, differences in psychosocial factors may provide targets for areas of specific support for people with comorbid bipolar disorder and post-traumatic stress disorder.

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

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.

Adjunctive minocycline for major depressive disorder: A sub-study exploring peripheral immune-inflammatory markers and associated treatment response.

Background: Adjunctive minocycline shows promise in treating affective and psychotic disorders; however, the therapeutic mechanism remains unclear. Identifying relevant biomarkers may enhance the efficacy of novel adjunctive treatment candidates. We thus investigated the peripheral immune-inflammatory profile in a randomized controlled trial (RCT) of minocycline in major depressive disorder (MDD). Methods: This sub-study investigated serum samples from a RCT evaluating minocycline (200 mg/day, 12 weeks) in addition to treatment as usual for MDD (ACTRN12612000283875). Of the original sample (N = 71), serum assays were conducted in 47 participants (placebo n = 24; minocycline n = 23) targeting an array of 46 immune-inflammatory analytes including cytokines, chemokines, and acute-phase reactants. General estimating equations (GEE) were used to assess whether analyte concentration at baseline (effect modification) and change in analytes (change association) influenced change in Montgomery-Åsberg Depression Rating Scale (MADRS) score over time. The Benjamini-Hochberg approach was applied when adjusting for false discovery rates (FDR). Results: GEE models revealed several interaction effects. After adjusting for FDR several change association-models survived correction. However, no such models remained significant for effect modification. Three-way group × time × marker interactions were significant for complement C3 (B = -10.46, 95%CI [-16.832, -4.095], q = 0.019) and IL-1Ra (B = -9.008, 95%CI [-15.26, -2.751], q = 0.036). Two-way group × biomarker interactions were significant for ICAM-1/CD54 (B = -0.387, 95%CI [-0.513, -0.26], q < 0.001) and IL-8/CXCL8 (B = -4.586, 95%CI [-7.698, -1.475], q = 0.036) indicating that increases in the serum concentration of these analytes were associated with an improvement in MADRS scores in the minocycline group (compared with placebo). Conclusions: Change in complement C3, IL-1Ra, IL-8/CXCL8, and ICAM-1 may be associated with greater change in depressive scores following adjunctive minocycline treatment in MDD. Further investigations are needed to assess the utility of these biomarkers.

The Impact of Posttraumatic Stress Disorder on Pharmacologic Intervention Outcomes for Adults With Bipolar Disorder: A Systematic Review.

BACKGROUND: The prevalence of posttraumatic stress disorder (PTSD) co-occurring in people with bipolar disorder (BD) is high. People with BD and PTSD may experience different outcomes and quality of life after pharmacologic treatment than those with BD alone. This review systematically explores the impact of PTSD on pharmacologic treatment outcomes for adults with BD. METHODS: We conducted a systematic search up to November 25, 2021, using MEDLINE Complete, Embase, American Psychological Association PsycInfo, and the Cochrane Central Register of Controlled Trials to identify randomized and nonrandomized studies of pharmacologic interventions for adults with BD that assessed for comorbid PTSD. We used the Newcastle-Ottawa Scale and Cochrane Risk of Bias tool to assess the risk of bias. RESULTS: The search identified 5093 articles, and we reviewed 62 full-text articles. Two articles met inclusion criteria (N = 438). One article was an observational study, and the other was a randomized comparative effectiveness trial. The observational study examined lithium response rates and found higher response rates in BD alone compared with BD plus PTSD over 4 years. The randomized trial reported more severe symptoms in the BD plus PTSD group than in those with BD alone following 6 months of quetiapine treatment. There was no significant difference in the lithium treatment group at follow-up. CONCLUSIONS: Comorbid PTSD may affect quetiapine and lithium treatment response in those with BD. Because of the high risk of bias and low quality of evidence, however, these results are preliminary. Specific studies exploring comorbid BD and PTSD are required to inform pharmacotherapy selection and guidelines appropriately. (International Prospective Register of Systematic Reviews ID: CRD42020182540).

Coping with COVID-19: Exploring coping strategies, distress, and post-traumatic growth during the COVID-19 pandemic in Australia.

Objective: This study aimed to explore coping strategies, distress, and post-traumatic growth among Australians with and without a history of a mental health diagnosis during the COVID-19 pandemic. Materials and methods: Australians (N = 381) completed an online survey between 4-August 2020 and 25-October-2020. Coping strategies, distress, and post-traumatic growth were ascertained via the Brief COPE, Depression Anxiety and Stress Scale (DASS-21), and Post-Traumatic Growth Inventory (PTGI), respectively. Linear regression was conducted to examine the relationship between the Brief COPE, DASS-21, and PTGI, adjusting for sociodemographic factors. Models were conducted separately for those with/without a history of a mental health diagnosis. Results: Higher distress was found among those with a history of a mental health diagnosis. Significant differences in the types of coping strategies associated with distress and post-traumatic growth were identified between the groups, however, behavioral disengagement and self-blame consistently predicted depression, anxiety, and stress. For those with a history of a mental health diagnosis, positive reframing decreased anxiety. Self-distraction was associated with post-traumatic growth across both groups. Conclusion: There are important differences in the way people with and without a history of a mental health diagnosis cope with the COVID-19 pandemic.

Exploring interleukin-6, lipopolysaccharide-binding protein and brain-derived neurotrophic factor following 12 weeks of adjunctive minocycline treatment for depression.

This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200 mg/day, added to treatment as usual) for adults (n = 71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06 ± 1.35 pg/ml; minocycline 1.77 ± 0.79 pg/ml; p = 0.317), LBP (week 12; placebo 3.74 ± 0.95 µg/ml; minocycline 3.93 ± 1.33 µg/ml; p = 0.525) or BDNF (week 12; placebo 24.28 ± 6.69 ng/ml; minocycline 26.56 ± 5.45 ng/ml; p = 0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p = 0.021) and quality of life (Q-LES-Q-SF; p = 0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.

Baseline serum amino acid levels predict treatment response to augmentation with N-acetylcysteine (NAC) in a bipolar disorder randomised trial.

N-acetylcysteine (NAC) acts on glutamatergic and redox systems, two systems implicated in the pathophysiology of bipolar disorder (BD). This has led to the investigation of NAC as a potential candidate for the treatment of BD. The aim of this study was to investigate metabolomic markers to identify predictors of NAC response in a cohort of BD participants. This study is a secondary analysis of a 16-week, multi-site, randomized, double-blinded, parallel-group, placebo-controlled trial in BD participants with a current acute depressive episode. This study included trial participants who received either NAC 2000 mg/day, or placebo. Participants (NAC: n = 31, placebo: n = 29) were assessed at baseline and week 16 using the Montgomery Åsberg Depression Rating Scale (MADRS) and were dichotomised into "responders" (MADRS at week 16 < 50% of MADRS at baseline) and "non-responders" (MADRS at week 16 > 50% at baseline). Untargeted gas chromatography-mass spectrometry analysis was performed to analyse baseline levels of 68 serum metabolites. Of the nine metabolites that differentiated placebo and NAC groups, five were amino acids with lower levels in the NAC responder group compared with the NAC non-responders. Further analysis generated a predictive model of MADRS improvement including glycine, norleucine, threonine, proline, phenylalanine, tyrosine, glutamic acid, lysine and leucine (R2 = 0.853; adjusted R2 = 0.733). This prediction model predicted 85% of the variance in MADRS outcome after adjunctive treatment with NAC. BD participants with lower serum levels of free amino acids at baseline may be more likely to respond to adjunctive treatment with NAC.

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.

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.

Minocycline as adjunctive treatment for major depressive disorder: Pooled data from two randomized controlled trials.

BACKGROUND: Randomized controlled clinical trials that have investigated minocycline as an adjunctive treatment for major depressive disorder have proved promising. Data from two studies were pooled to evaluate more definitively whether the addition of minocycline to standard treatment for major depressive disorder leads to an improvement of depressive symptoms when compared with placebo. METHODS: Both studies were multi-site, double-blinded, placebo-controlled trials of minocycline 200 mg/day added to treatment as usual during a 12-week period. The primary outcome measure was change in depressive symptoms (Montgomery-Asberg Depression Rating Scale in Dean et al. and Hamilton Depression Rating Scale in Husain et al.). Secondary outcomes were change in depression severity (Montgomery-Asberg Depression Rating Scale for Dean et al. and 9-item Patient Health Questionnaire in Husain et al.), anxiety severity (Hamilton Anxiety Rating Scale in Dean et al. and Generalized Anxiety Disorder 7-item scale in Husain et al.) and functional status, which were also evaluated as potential mediators on the primary outcome. RESULTS: A total of 112 participants were included in the pooled data (Dean et al., n = 71; Husain et al., n = 41). A significant change from baseline to week 12 was noted in depressive symptoms - differential change (Placebo vs Minocycline): 9.0, 95% confidence interval = [4.2, 13.9], Cohen's D (95% confidence interval): 0.71 [0.29, 1.14], p < 0.001 - anxiety severity - differential change (Placebo vs Minocycline): 0.38, confidence interval = [0.00, 0.75], Cohen's D (95% confidence interval): 0.41 [0.00, 0.82], p = 0.050) and functional status - differential change (Placebo vs Minocycline): 1.0, 95% confidence interval = [0.4, 1.5], Cohen's D (95% confidence interval): 0.76 [0.34, 1.19], p = 0.001). Duration of illness, current use of benzodiazepine and pain medication were identified as moderators, whereas functional status as a mediator/predictor. CONCLUSION: The improvement of depressive symptoms, anxiety severity and functional status is promising and suggests that minocycline has potential as an adjunctive treatment for major depressive disorder. However, further studies are warranted to confirm therapeutic effects of minocycline in major depressive disorder. TRIAL REGISTRATIONS: NCT02263872, registered October 2014, and ACTRN12612000283875, registered March 2012.

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.

Adjunctive Garcinia mangostana Linn. (Mangosteen) Pericarp for Schizophrenia: A 24-Week Double-blind, Randomized, Placebo Controlled Efficacy Trial: Péricarpe d'appoint Garcinia mangostana Linn (mangoustan) pour la schizophrénie : un essai d'efficacité de 24 semaines, à double insu, randomisé et contrôlé par placebo.

OBJECTIVES: Garcinia mangostana Linn. ("mangosteen") pericarp contains bioactive compounds that may target biological pathways implicated in schizophrenia. We conducted a double-blind randomized placebo-controlled trial evaluating the efficacy of adjunctive mangosteen pericarp, compared to placebo, in the treatment of schizophrenia. METHODS: People diagnosed with schizophrenia or schizoaffective disorder (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), recruited across 2 sites (Brisbane and Victoria, Australia), were randomized to receive 24 weeks of adjunctive mangosteen pericarp (1,000 mg/day) or matched placebo. The primary outcome measure was the Positive and Negative Symptom Scale total score. Secondary outcomes included positive and negative symptoms, general psychopathology, clinical global severity and improvement, participant reported overall improvement, depressive symptoms, functioning, quality of life, and safety data at 24 and 28 weeks (4 weeks postdiscontinuation). Data were collected from July 2016 to February 2019. RESULTS: Baseline assessments were conducted on 148 people (mangosteen = 74, placebo = 74); data analyses were conducted on 136 (92%) participants with postbaseline data. The treatment group had significantly higher symptom severity compared to placebo, and both groups significantly improved on all symptom, functioning, and quality of life measures over time. No between-group differences were found for the rate of change between baseline and 24 or 28 weeks. CONCLUSION: Despite promising preclinical and clinical work, our results do not support mangosteen pericarp extract as an adjunctive treatment for schizophrenia or schizoaffective disorder.

Systematic review and meta-analysis of the role of personality disorder in randomised controlled trials of pharmacological interventions for adults with mood disorders.

BACKGROUND: Personality disorder (PD) may affect the efficacy of pharmacological interventions for mood disorders, but the extent to which this occurs is uncertain. We aimed to examine the available published evidence concerning the role of PD in pharmacological treatment outcomes of randomised controlled trials (RCTs) for adults with mood disorders (i.e. depressive and bipolar spectrum disorders). METHODS: A systematic search of Cochrane Central Register of Controlled Clinical Trials, PubMed, EMBASE, PsycINFO, CINAHL Complete, and Google Scholar databases was undertaken to identify studies of interest. Data were independently extracted by two reviewers. The Cochrane Risk of Bias tool was used to assess methodological quality and risk of bias. A random effects model was utilised and statistical heterogeneity was assessed using the I2 statistic. This systematic review was registered with PROSPERO (CRD42018089279) and the protocol is published. RESULTS: The search yielded 11,640 studies. Subsequent to removing duplicates, 9657 studies were screened at title and abstract stage and 1456 were assessed at full-text stage. Eighteen studies met criteria for inclusion in this review. Meta-analysis did not reveal a significant difference between groups for treatment outcome (standardised mean difference 0.22 [-0.09, 0.54]; I2: 69%, p=0.17) and remission (risk ratio 0.84 [0.64, 1.11]; I2: 51%, p=0.22). LIMITATIONS: This review was limited by lack of studies on bipolar disorder. CONCLUSION: PD comorbidity does not appear to affect treatment efficacy of pharmacological interventions for adults with mood disorders.

Prebiotics, probiotics, fermented foods and cognitive outcomes: A meta-analysis of randomized controlled trials.

This systematic review and meta-analysis aimed to evaluate randomized controlled trials that investigated the use of probiotic, prebiotic, and fermented food interventions for cognitive performance. In total, 22 studies (n = 1551) were included that investigated probiotics (11 studies, n = 724), prebiotics (5 studies, n = 355), and fermented foods (6 studies, n = 472). Despite several individual studies (14 of 22) reporting significant improvements in specific cognitive domains, results of the pooled meta-analysis found no significant effect for any intervention for global cognition (Probiotics: g = 0.115, 95 %CI -0.041, 0.270, p = 0.148; Prebiotics: g = 0.077, 95 %CI -0.091, 0.246, p = 0.369; Fermented food: g = 0.164 95 %CI -0.017, 0.345, p = 0.076) or any individual cognitive domain. Most studies (16 of 22) had low risk of bias. These results do not support the use of probiotic, prebiotic, and fermented food interventions for cognitive outcomes. This may be due to the limited number of small and short-term studies as well clinical heterogeneity relating to the population, cognitive tests, and intervention. Therefore, further trials that investigate these interventions in clinical populations using adequately powered samples are warranted. PROSPERO: CRD42019137936.

Personality disorder and functioning in major depressive disorder: a nested study within a randomized controlled trial

Objective: This study aimed to determine if personality disorder (PD) predicted functional outcomes in patients with major depressive disorder (MDD). Methods: Data (n=71) from a double-blind, randomized, placebo-controlled 12-week trial assessing the efficacy of 200 mg/day adjunctive minocycline for MDD were examined. PD was measured using the Standardized Assessment of Personality Abbreviated Scale. Outcome measures included Clinical Global Impression - Improvement (CGI-I), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Social and Occupational Functioning Scale (SOFAS), and Range of Impaired Functioning (RIFT). Analysis of covariance was used to examine the impact of PD (dichotomized factor [≥ 3] or continuous measure) on the outcome measures-treatment group correlation. Results: PD was identified in 69% of the sample. After adjusting for age, sex, and baseline scores for each of the outcome measures, there was no significant difference between participants with and without PD on week 12 scores for any of the outcome measures (all p > 0.14). Conclusion: In this secondary analysis of a primary efficacy study, PD was a common comorbidity among those with MDD, but was not a significant predictor of functional outcomes. This study adds to the limited literature on PD in randomized controlled trials for MDD. Clinical trial registration: ACTRN12612000283875.

Personality disorder and functioning in major depressive disorder: a nested study within a randomized controlled trial.

OBJECTIVE: This study aimed to determine if personality disorder (PD) predicted functional outcomes in patients with major depressive disorder (MDD). METHODS: Data (n=71) from a double-blind, randomized, placebo-controlled 12-week trial assessing the efficacy of 200 mg/day adjunctive minocycline for MDD were examined. PD was measured using the Standardized Assessment of Personality Abbreviated Scale. Outcome measures included Clinical Global Impression - Improvement (CGI-I), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Social and Occupational Functioning Scale (SOFAS), and Range of Impaired Functioning (RIFT). Analysis of covariance was used to examine the impact of PD (dichotomized factor [≥ 3] or continuous measure) on the outcome measures-treatment group correlation. RESULTS: PD was identified in 69% of the sample. After adjusting for age, sex, and baseline scores for each of the outcome measures, there was no significant difference between participants with and without PD on week 12 scores for any of the outcome measures (all p > 0.14). CONCLUSION: In this secondary analysis of a primary efficacy study, PD was a common comorbidity among those with MDD, but was not a significant predictor of functional outcomes. This study adds to the limited literature on PD in randomized controlled trials for MDD. CLINICAL TRIAL REGISTRATION: ACTRN12612000283875.