Psychiatry - Research Publications
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ItemMixed Methods Thematic Analysis of a Randomised Controlled Trial of Adjunctive Mitochondrial Agents for Bipolar Depression(KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2022-05-01)OBJECTIVE: There is often a shortfall in recovery following treatment for an episode of bipolar disorder (BD). Exploration of participant's experience provides vital information to enhance statistical outcomes for novel therapy trials. This study used mixed-methods to explore participants' experience of a trial testing N -acetyl cysteine (NAC) and mitochondrially active nutraceuticals for BD depression. CASE: report forms from a randomised controlled trial (RCT) of BD depression (n = 148) were analysed using a pragmatic adaption of grounded theory and thematic analysis. RESULTS: Thematic analysis of 148 study participants indicated numerous changes in participant experience over time. For example, perceived environmental stressors reported by participants decreased over the trial in both treatment groups. Quantitative analysis of the themes revealed more positive theme reports in the combination treatment arm compared to the placebo arm and there were more negative themes identified in the placebo arm, compared to the NAC arm. CONCLUSION: This approach revealed additional results not elucidated in the primary quantitative analysis. This emphasises the value of mixed-methods research in capturing participants' experiences in RCTs and detecting possible latent benefits and risks. Such methods can detect latent target signals in novel therapy trials conducted in BD and generate novel hypotheses.
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ItemNo Preview AvailableEffects of aspirin on the long-term management of depression in older people: a double-blind randomised placebo-controlled trial(SPRINGERNATURE, 2021-01-27)Late-life depression is common and often inadequately managed using existing therapies. Depression is also associated with increased markers of inflammation, suggesting a potential role for anti-inflammatory agents. ASPREE-D is a sub-study of ASPREE, a large multi-centre, population-based, double-blind, placebo-controlled trial of aspirin vs placebo in older Australian and American adults (median follow-up: 4.7 years) of whom 1879 were depressed at baseline. Participants were given 100 mg daily dose of aspirin or placebo. Depressive symptoms were assessed annually using the validated, self-rated short version of the Center for Epidemiological Studies Depression scale. There was a significant increase in depressive scores (0.6; 95% CI 0.2 to 0.9; χ2 (1) = 10.37; p = 0.001) and a decreased score in the mental health component of a quality of life scale (-0.7; 95% CI -1.4 to -0.1; χ2 (1) = 4.74; p = 0.029) in the aspirin group compared to the placebo group. These effects were greater in the first year of follow-up and persisted throughout the study, albeit with small to very small effect sizes. This study failed to demonstrate any benefit of aspirin in the long-term course of depression in this community-dwelling sample of older adults over a 5-year period, and identified an adverse effect of aspirin in the course of depression in those with pre-existing depressive symptoms.
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ItemEffect of Glucocorticoid and 11 beta-Hydroxysteroid-Dehydrogenase Type 1 (11 beta-HSD1) in Neurological and Psychiatric Disorders(OXFORD UNIV PRESS, 2022-02-10)11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-HSD1 modulators may be useful pharmacotherapies for clinical improvement in psychiatry and neurology; however, more research is required.
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ItemImpact of irritability: a 2-year observational study of outpatients with bipolar I or schizoaffective disorder(WILEY, 2017-05-01)OBJECTIVES: Many people experience irritability when manic, hypomanic, or depressed, yet its impact on illness severity and quality of life in bipolar and schizoaffective disorders is poorly understood. This study aimed to examine the relationship between irritability and symptom burden, functioning, quality of life, social support, suicidality, and overall illness severity in a naturalistic cohort of people with bipolar I or schizoaffective disorder. METHODS: We used data from 239 adult outpatients with bipolar I or schizoaffective disorder in the Bipolar Comprehensive Outcomes Study (BCOS) - a non-interventional observational study with a 2-year follow-up period. Baseline demographic and clinical characteristics of participants with and without irritability were compared. A mixed-model repeated measures analysis was conducted to examine the longitudinal effect of irritability on clinical and quality-of-life variables over follow-up using significant baseline variables. RESULTS: At baseline, 54% of participants were irritable. Baseline irritability was associated with illness severity, mania, depression, psychotic symptoms, suicidality, poor functioning, and quality of life, but not diagnosis (schizoaffective/bipolar disorder). Participants with irritability were less likely to have a partner and perceived less adequate social support. On average, over follow-up, those with irritability reported more symptoms, functional impairment, and suicidality. Furthermore, the effects of irritability could not be fully explained by illness severity. CONCLUSIONS: Irritability was associated with more negative symptomatic, functional, and quality-of-life outcomes and suicidality. The identification, monitoring, and targeted treatment of irritability may be worth considering, to enhance health and wellbeing outcomes for adults with bipolar and schizoaffective disorders.
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ItemVariations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder(SPRINGER, 2021-09-01)BACKGROUND: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. METHODS: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). RESULTS: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. CONCLUSION: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
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ItemThe Role of Mitochondria in Mood Disorders: From Physiology to Pathophysiology and to Treatment(FRONTIERS MEDIA SA, 2021-07-06)Mitochondria are cellular organelles involved in several biological processes, especially in energy production. Several studies have found a relationship between mitochondrial dysfunction and mood disorders, such as major depressive disorder and bipolar disorder. Impairments in energy production are found in these disorders together with higher levels of oxidative stress. Recently, many agents capable of enhancing antioxidant defenses or mitochondrial functioning have been studied for the treatment of mood disorders as adjuvant therapy to current pharmacological treatments. A better knowledge of mitochondrial physiology and pathophysiology might allow the identification of new therapeutic targets and the development and study of novel effective therapies to treat these specific mitochondrial impairments. This could be especially beneficial for treatment-resistant patients. In this article, we provide a focused narrative review of the currently available evidence supporting the involvement of mitochondrial dysfunction in mood disorders, the effects of current therapies on mitochondrial functions, and novel targeted therapies acting on mitochondrial pathways that might be useful for the treatment of mood disorders.
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ItemPutative neuroprotective pharmacotherapies to target the staged progression of mental illness(WILEY, 2019-10-01)AIM: Neuropsychiatric disorders including depression, bipolar and schizophrenia frequently exhibit a neuroprogressive course from prodrome to chronicity. There are a range of agents exhibiting capacity to attenuate biological mechanisms associated with neuroprogression. This review will update the evidence for putative neuroprotective agents including clinical efficacy, mechanisms of action and limitations in current assessment tools, and identify novel agents with neuroprotective potential. METHOD: Data for this review were sourced from online databases PUBMED, Embase and Web of Science. Only data published since 2012 were included in this review, no data were excluded based on language or publication origin. RESULTS: Each of the agents reviewed inhibit one or multiple pathways of neuroprogression including: inflammatory gene expression and cytokine release, oxidative and nitrosative stress, mitochondrial dysfunction, neurotrophin dysregulation and apoptotic signalling. Some demonstrate clinical efficacy in preventing neural damage or loss, relapse or cognitive/functional decline. Agents include: the psychotropic medications lithium, second generation antipsychotics and antidepressants; other pharmacological agents such as minocycline, aspirin, cyclooxygenase-2 inhibitors, statins, ketamine and alpha-2-delta ligands; and others such as erythropoietin, oestrogen, leptin, N-acetylcysteine, curcumin, melatonin and ebselen. CONCLUSIONS: Signals of evidence of clinical neuroprotection are evident for a number of candidate agents. Adjunctive use of multiple agents may present a viable avenue to clinical realization of neuroprotection. Definitive prospective studies of neuroprotection with multimodal assessment tools are required.
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ItemIncidence and characteristics of the nocebo response from meta-analyses of the placebo arms of clinical trials of olanzapine for bipolar disorder(WILEY, 2019-03-01)OBJECTIVES: In the clinical setting, the nocebo phenomenon is where clinical worsening or adverse events occur as a response to a treatment, in a situation in which conditioning from previous treatment exposure and/or expectations of sickness or symptoms lead to sickness and symptoms in a conditioned or expectant individual. The nocebo response may thus be a confounder in clinical treatment and clinical research. There is a need to know how to predict if an individual is likely to be a nocebo responder, and how significant and commonplace the nocebo effect might be. METHODS: An analysis was conducted on nine placebo-controlled, randomized clinical trials of olanzapine for the treatment of bipolar disorder using data from placebo-treated study participants only. Data were analysed to identify participant or study characteristics associated with a nocebo event, defined as any treatment-emergent adverse event (TEAE) or an increase in score from baseline to endpoint for primary measures of clinical symptoms. RESULTS: A total of 1185 participants were randomized to placebo, of whom 806 (68%) reported a TEAE. Hamilton Depression Rating Scale (HDRS) data were only available for 649 placebo-treated participants, of whom 321 (49.5%) demonstrated worsening. Nocebo events were significantly associated with: not being treatment-naïve, younger age, being located in the USA, being a participant in an earlier study, and being classified as obese compared with normal weight. CONCLUSIONS: A pattern to identify nocebo responders did not emerge, although some prognostic variables were associated with a greater probability of nocebo response. There was some evidence to support the role of expectancy as a cause of nocebo reactions.
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ItemCurrent and Emerging Pharmacotherapies for Cessation of Tobacco Smoking(WILEY, 2018-02-01)Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also considered the most preventable cause of death in developed countries. Since the development of nicotine replacement therapy (NRT) in 1978, treatment options have continued to evolve and expand. Despite this, currently available treatments remain insufficient, with less than 25% of smokers remaining abstinent 1 year after treatment. In this article, we review existing and emerging smoking cessation pharmacotherapies, with a special emphasis on the most promising agents that are currently being investigated. A search of the Cochrane Database of Systematic Reviews and the PubMed, Ovid, and ClinicalTrials.gov databases (August 2 to September 1, 2017) was undertaken for articles on smoking cessation pharmacotherapies, applying no language restrictions. More than 40 pharmacotherapies were reviewed including conventional pharmacotherapies-NRT, bupropion, and varenicline (all approved by the U.S. Food and Drug Administration as first-line treatment of smoking cessation)-and novel therapies: cytisine, N-acetylcysteine, cycloserine, memantine, baclofen, topiramate, galantamine, and bromocriptine. Studies of combination NRT and varenicline showed the greatest smoking cessation rates. Clonidine and nortriptyline are second-line treatments used when first-line treatments fail or are contraindicated, or by patient preference. Some novel therapies, especially acetylcholinesterase inhibitors, cytisine, and N-acetylcysteine, display promising results. Because the results of randomized clinical trials were reported using varied end points and outcome measures, direct comparisons between different pharmacotherapies cannot easily be evaluated. Additional high-quality randomized double-blind placebo-controlled trials with long-term follow-up, using validated sustained abstinence measures, are needed to find more effective smoking cessation aids.
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ItemInternet use by older adults with bipolar disorder: international survey results(SPRINGEROPEN, 2018-09-04)BACKGROUND: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. METHODS: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. RESULTS: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. CONCLUSIONS: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.