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ItemNo Preview AvailablePredictors of the placebo response in a nutraceutical randomizedcontrolled trial for depression(ELSEVIER, 2024-01)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.
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ItemNo Preview AvailableLithium use and bone health in women with bipolar disorder: A cross-sectional study(WILEY, 2024-04)INTRODUCTION: Several psychiatric disorders and medications used to treat them appear to be independently associated with skeletal deficits. As there is increasing evidence that lithium possesses skeletal protective properties, we aimed to investigate the association between lithium use and bone health in a group of women with bipolar disorder. METHOD: Women with bipolar disorder (n = 117, 20+ years) were recruited from south-eastern Australia. Bipolar disorder was confirmed using a clinical interview (SCID-I/NP). Bone mineral density (BMD; g/cm2 ) was measured at the spine, hip and total body using dual-energy x-ray absorptiometry and low bone mass determined by BMD T-score of <-1.0. Weight and height were measured, socioeconomic status (SES) determined and information on medication use and lifestyle factors self-reported. Linear and logistic regression were used to test associations between lithium and (i) BMD and (ii) low bone mass, respectively. RESULTS: Thirty-five (29.9%) women reported current lithium use. Lithium users and non-users differed in regard to SES and BMD; otherwise, groups were similar. After adjustments, mean BMD among lithium users was 5.1% greater at the spine (1.275 [95% CI 1.229-1.321] vs. 1.214 [1.183-1.244] g/cm2 , p = 0.03), 4.2% greater at the total hip (0.979 [0.942-1.016] vs. 0.938 [0.910-0.966] g/cm2 , p = 0.03) and 2.2% greater at the total body (1.176 [1.148-1.205] vs. 1.150 [1.129-1.171] g/cm2 , p = 0.08) compared to participants not receiving lithium. Lithium users were also less likely to have low bone mass (22.9% vs. 43.9%, p = 0.031). Associations persisted after adjustment for confounders. CONCLUSION: These data suggest lithium is associated with greater BMD and reduced risk of low bone mass in women with bipolar disorder. Research into the underlying mechanisms is warranted.
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ItemMetergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen(SPRINGER, 2023-12)Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.
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ItemNo Preview AvailableWhat do Australian consumers with lived experience of bipolar disorder want from early intervention services?(SAGE PUBLICATIONS LTD, 2024-03)
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ItemPlasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders(SAGE PUBLICATIONS LTD, 2024-01)OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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ItemEarly interventions for youth at high risk for bipolar disorder(WILEY, 2022-12)
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ItemNo Preview AvailableDoes Post-traumatic Stress Disorder Impact Treatment Outcomes within a Randomised Controlled Trial of Mitochondrial Agents for Bipolar Depression?(KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2023-08)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.
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ItemNo Preview AvailableThe Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder(BMC, 2023-10-24)BACKGROUND: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD). METHODS: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes. DISCUSSION: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 .
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ItemNo Preview AvailableFair funding for mental health research(SAGE PUBLICATIONS LTD, 2023-08)
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ItemNo Preview AvailablePredictors of suicidal ideation severity among treatment-seeking young people with major depressive disorder: The role of state and trait anxiety(SAGE PUBLICATIONS LTD, 2023-08)OBJECTIVE: Depression and suicidal ideation are closely intertwined. Yet, among young people with depression, the specific factors that contribute to changes in suicidal ideation over time are uncertain. Factors other than depressive symptom severity, such as comorbid psychopathology and personality traits, might be important contributors. Our aim was to identify contributors to fluctuations in suicidal ideation severity over a 12-week period in young people with major depressive disorder receiving cognitive behavioural therapy. METHODS: Data were drawn from two 12-week randomised, placebo-controlled treatment trials. Participants (N = 283) were 15-25 years old, with moderate to severe major depressive disorder. The primary outcome measure was the Suicidal Ideation Questionnaire, administered at baseline and weeks 4, 8 and 12. A series of linear mixed models was conducted to examine the relationship between Suicidal Ideation Questionnaire score and demographic characteristics, comorbid psychopathology, personality traits and alcohol use. RESULTS: Depression and anxiety symptom severity, and trait anxiety, independently predicted higher suicidal ideation, after adjusting for the effects of time, demographics, affective instability, non-suicidal self-injury and alcohol use. CONCLUSIONS: Both state and trait anxiety are important longitudinal correlates of suicidal ideation in depressed young people receiving cognitive behavioural therapy, independent of depression severity. Reducing acute psychological distress, through reducing depression and anxiety symptom severity, is important, but interventions aimed at treating trait anxiety could also potentially be an effective intervention approach for suicidal ideation in young people with depression.