Psychiatry - Research Publications

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    A potential role for N-acetylcysteine in the management of methamphetamine dependence
    McKetin, R ; Dean, OM ; Baker, AL ; Carter, G ; Turner, A ; Kelly, PJ ; Berk, M (WILEY, 2017-03-01)
    Methamphetamine dependence is a growing problem in Australia and globally. Currently, there are no approved pharmacotherapy options for the management of methamphetamine dependence. N-acetylcysteine is one potential pharmacotherapy option. It has received growing attention as a therapy for managing addictions because of its capacity to restore homeostasis to brain glutamate systems disrupted in addiction and thereby reduce craving and the risk of relapse. N-acetylcysteine also has antioxidant properties that protect against methamphetamine-induced toxicity and it may therefore assist in the management of the neuropsychiatric and neurocognitive effects of methamphetamine. This commentary overviews the actions of N-acetylcysteine and evidence for its efficacy in treating addiction with a particular focus on its potential utility for methamphetamine dependence. We conclude that the preliminary evidence indicates a need for full-scale trials to definitively establish whether N-acetylcysteine has a therapeutic benefit and the nature of this benefit, for managing methamphetamine dependence. [McKetin R, Dean O, Baker A. L, Carter G, Turner A, Kelly P. J, Berk M. A potential role for N-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev 2017;36:153-159].
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    Measuring cognitive insight in people with problematic substance use: An exploration of the factor validity of the Beck Cognitive Insight Scale
    Raftery, D ; Kelly, PJ ; Deane, FP ; Mcketin, R ; Baker, AL ; Turner, A ; Dean, OM (WILEY, 2019-09-01)
    INTRODUCTION AND AIMS: Insight is a multi-dimensional construct that predicts treatment outcomes of people with mental illness. Research into insight in substance dependent populations is limited and measures of cognitive insight have not been validated for this population. DESIGN AND METHODS: A cross sectional survey was conducted with residents of nine residential substance dependence treatment facilities in Australia. Cognitive insight was assessed using the Beck Cognitive Insight Scale (BCIS). Psychological distress was assessed using the Kessler 6 (K6). RESULTS: Participants (N = 312) were primarily male (68.6%), with an average age of 37.51 years (SD = 9.85). Methamphetamine (45.2%) and alcohol (35.9%) were the primary substances of use. A confirmatory factor analysis confirmed the two-factor model of the BCIS (CMIN/DF = 2.91, CFI = 0.84). Removing two items from the Self-Reflection subscale improved model fit (CMIN/DF = 2.71, CFI = 0.84, Χ 2[22, n = 312] = 76.43, P < 0.02). Internal consistency analyses indicated acceptable internal reliability (Self-Reflection α = 0.73, Self-Certainty α = 0.72, composite α = 0.75). Self-Certainty scores were significantly higher for participants with a self-reported psychotic disorder (M = 14.95 vs. M = 13.04, P = 0.007). Self-Reflection scores were higher for people experiencing psychological distress (M = 17.57 vs. M = 15.95, P = 0.001). DISCUSSION AND CONCLUSIONS: We found that a 12-item version of the BCIS had good psychometric properties in this substance-using population. Further research is needed to explore whether insight can predict treatment outcomes for substance use.
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    Clinical and demographic characteristics of people who smoke versus inject crystalline methamphetamine in Australia: Findings from a pharmacotherapy trial
    McKetin, R ; Quinn, B ; Higgs, P ; Berk, M ; Dean, OM ; Turner, A ; Kelly, PJ ; Lubman, D ; Carter, G ; Baker, AL ; Manning, V ; Thomas, T ; Bathish, R ; Raftery, D ; Saunders, L ; Wrobel, A ; Meehan, A ; Sinclair, B ; Reid, D ; Arunogiri, S ; Hill, H ; Cordaro, F ; Dietze, PM (WILEY, 2021-11-01)
    INTRODUCTION AND AIMS: There has been a rapid increase in smoking crystalline methamphetamine in Australia. We compare the clinical and demographic characteristics of those who smoke versus inject the drug in a cohort of people who use methamphetamine. DESIGN AND METHODS: Participants (N = 151) were dependent on methamphetamine, aged 18-60 years, enrolled in a pharmacotherapy trial for methamphetamine dependence, and reported either injecting (n = 54) or smoking (n = 97) methamphetamine. Measures included the Timeline Followback, Severity of Dependence Scale, Amphetamine Withdrawal Questionnaire, Craving Experience Questionnaire and the Brief Psychiatric Rating Scale (symptoms of depression, hostility, psychosis and suicidality). Simultaneous regression was used to identify independent demographic correlates of smoking methamphetamine and to compare the clinical characteristics of participants who smoked versus injected. RESULTS: Compared to participants who injected methamphetamine, those who smoked methamphetamine were younger and less likely to be unemployed, have a prison history or live alone. Participants who smoked methamphetamine used methamphetamine on more days in the past 4 weeks than participants who injected methamphetamine (26 vs. 19 days, P = 0.001); they did not differ significantly in their severity of methamphetamine dependence, withdrawal, craving or psychiatric symptoms (P > 0.05). After adjustment for demographic differences, participants who smoked had lower craving [b (SE) = -1.1 (0.5), P = 0.021] and were less likely to report psychotic symptoms [b (SE) = -1.8 (0.7), P = 0.013] or antidepressant use [b (SE) = -1.1 (0.5), P = 0.022]. DISCUSSION AND CONCLUSIONS: Smoking crystalline methamphetamine is associated with a younger less marginalised demographic profile than injecting methamphetamine, but a similarly severe clinical profile.
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    Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis A Randomized Clinical Trial
    Scott, JG ; Baker, A ; Lim, CCW ; Foley, S ; Dark, F ; Gordon, A ; Ward, D ; Richardson, D ; Bruxner, G ; Beckmann, KM ; Hatherill, S ; Stathis, S ; Dixon, K ; Ryan, AE ; McWhinney, BC ; Ungerer, JPJ ; Berk, M ; Dean, OM ; Saha, S ; McGrath, J (AMER MEDICAL ASSOC, 2020-11-10)
    Importance: There is evidence that sodium benzoate (BZ) may be an effective adjunctive treatment for schizophrenia. The clinical efficacy of BZ has been investigated in chronic schizophrenia; however, the efficacy of this agent has not been studied in individuals with early psychosis. Objective: To examine the clinical efficacy of the adjunctive use of BZ for symptoms in people with early psychosis. Design, Setting, and Participants: Using a placebo-controlled double-masked parallel-group design, this randomized clinical trial was conducted from August 2015 to July 2018. Participants aged between 15 and 45 years experiencing early psychosis were enrolled from 5 major clinical sites in Queensland, Australia. Data analysis was conducted from October 2018 to February 2020. Interventions: Participants were randomized 1:1 (50 participants in each group) to receive 500 mg of sodium benzoate twice daily or placebo for 12 weeks. Main Outcomes and Measures: The primary efficacy outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks. The key secondary efficacy measures were (1) the Clinical Global Impression score, (2) the Hamilton Depression Rating Scale for depression, (3) functioning as assessed by the clinician-rated Global Assessment of Function, and (4) the Assessment of Quality of Life Scale. The PANSS subscale scores and impact on selected amino acid concentrations were also assessed. Results: The study comprised 100 participants with a mean (SD) age of 21.4 (4.1) years, of whom 73 (73%) were male individuals. The mean (SD) baseline PANSS score was 75.3 (15.4). We found no improvement in total PANSS score in the BZ group compared with the placebo group. The end result of least-squares mean difference (SE) for total PANSS was -1.2 (2.4) (P = .63). There were no differences in any subscales of the PANSS, any secondary measures, nor any amino acid concentrations. The dose of BZ was well tolerated without any clinically significant treatment-emergent adverse event differences between BZ and placebo groups. Conclusions and Relevance: In this randomized clinical trial, there was no evidence that adjunctive use of 500 mg of BZ twice daily is an effective treatment for individuals with early psychosis. Trial Registration: anzctr.org.au Identifier: ACTRN12615000187549.
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    Protocol and Rationale-The Efficacy of Minocycline as an Adjunctive Treatment for Major Depressive Disorder: A Double Blind, Randomised, Placebo Controlled Trial
    Dean, OM ; Maes, M ; Ashton, M ; Berk, L ; Kanchanatawan, B ; Sughondhabirom, A ; Tangwongchai, S ; Ng, C ; Dowling, N ; Malhi, GS ; Berk, M (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2014-12-01)
    While current pharmacotherapies are efficacious, there remain a clear shortfall between symptom remission and functional recovery. With the explosion in our understanding of the biology of these disorders, the time is ripe for the investigation of novel therapies. Recently depression is conceptualized as an immune-inflammatory and nitro-oxidative stress related disorder. Minocycline is a tetracycline antibiotic that has anti-inflammatory, pro-oxidant, glutamatergic, neurotrophic and neuroprotective properties that make it a viable target to explore as a new therapy. This double blind, randomised, placebo controlled adjunctive trial will investigate the benefits of 200 mg/day of minocycline treatment, in addition to any usual treatment, as an adjunctive treatment for moderate-severe major depressive disorder. Sixty adults are being randomised to 12 weeks of treatment (with a 4 week follow-up post-discontinuation). The primary outcome measure for the study is mean change on the Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcomes including the Social and Occupational Functioning Assessment Scale (SOFAS), Clinical Global Impressions (CGI), Hamilton Rating Scale for Anxiety (HAM-A), Patient Global Impression (PGI), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and Range of Impaired Functioning Tool (LIFE-RIFT). Biomarker analyses will also be conducted at baseline and week 12. The study has the potential to provide new treatment targets, both by showing efficacy with a new class of 'antidepressant' but also through the analysis of biomarkers that may further inform our understanding of the pathophysiology of unipolar depression.
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    Future Directions for Pharmacotherapies for Treatment-resistant Bipolar Disorder
    Dodd, S ; Fernandes, BS ; Dean, OM (BENTHAM SCIENCE PUBL LTD, 2015-01-01)
    Current pharmacological treatments for bipolar disorder (BD) are limited and efficacy has historically been discovered through serendipity. There is now scope for new drug development, focused on the underlying biology of BD that is not targeted by current therapies. The need for novel treatments is urgent when considering treatment resistant BD, where current therapies have failed. While established drugs targeting the monoamine systems continue to be worthwhile, new biological targets including inflammatory and oxidative an nitrosative pathways, apoptotic and neurotrophic pathways, mitochondrial pathways, the N-methyl-Daspartate (NMDA)-receptor complex, the purinergic system, neuropeptide system, cholinergic system and melatonin pathways are all being identified as potential anchors for the discovery of new agents. Many agents are experimental and efficacy data is limited, however further investigation may provide a new line for drug discovery, previously stalled by lack of corporate interest.
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    N-Acetyl Cysteine in the Treatment of Obsessive Compulsive and Related Disorders: A Systematic Review
    Oliver, G ; Dean, O ; Camfield, D ; Blair-West, S ; Ng, C ; Berk, M ; Sarris, J (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2015-04-01)
    OBJECTIVE: Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area. METHODS: PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NAC studies were contacted for any unpublished data. RESULTS: Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400-3,000 mg/day of NAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation. CONCLUSIONS: Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research.
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    The efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: study protocol for a randomized controlled trial
    Ryan, A ; Baker, A ; Dark, F ; Foley, S ; Gordon, A ; Hatherill, S ; Stathis, S ; Saha, S ; Bruxner, G ; Beckman, M ; Richardson, D ; Berk, M ; Dean, O ; McGrath, J ; Scott, J (BIOMED CENTRAL LTD, 2017-04-07)
    BACKGROUND: Psychotic disorders affect up to 3% of the population and are often chronic and disabling. Innovation in the pharmacological treatment of psychosis has remained stagnant in recent decades. In order to improve outcomes for those with psychotic disorders, we present a protocol for the trial of a common food preservative, sodium benzoate, as an adjunctive treatment in early psychosis. METHODS: Persons experiencing early psychosis (n = 160) will be recruited through hospitals and community mental health services in Queensland, Australia. Patients will be randomized to receive either 12-week treatment with 1000 mg (500 mg twice daily (BD)) sodium benzoate or placebo. Patients will undergo fortnightly outcome assessments, in addition to weekly ongoing capacity to consent, drug compliance and safety assessments. The primary outcome measure is the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes are Global Assessment of Function (GAF), Assessment of Quality of Life Scale (AQOL), the Activity and Participation Questionnaire (APQ6), International Physical Activity Questionnaires (IPAQ), Simple Physical Activity Questionnaire (SIMPAQ), Physical Activity Questionnaire, Clinical Global Impression (CGI), Hamilton Depression rating Scale-17 items (HDRS), Opiate Treatment Index (OTI) and the Patients' Global Impression of Improvement (PGI-I). As a tertiary objective, changes from baseline to endpoint in to serum markers related to D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate will be investigated. DISCUSSION: Consumers and clinicians are keen to help develop better treatments for those with psychosis. This study, part of the wider Cadence clinical trials platform will examine if a safe and accessible food preservative can help optimize outcomes in those with psychosis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12615000187549 . Registered on 26 February 2015.
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    Mechanisms Underpinning the Polypharmacy Effects of Medications in Psychiatry
    Bortolasci, CC ; Spolding, B ; Callaly, E ; Martin, S ; Panizzutti, B ; Kidnapillai, S ; Connor, T ; Hasebe, K ; Mohebbi, M ; Dean, OM ; McGee, SL ; Dodd, S ; Gray, L ; Berk, M ; Walder, K (OXFORD UNIV PRESS, 2018-06-01)
    Background: Bipolar disorder is a mental health condition with progressive social and cognitive function disturbances. Most patients' treatments are based on polypharmacy, but with no biological basis and little is known of the drugs' interactions. The aim of this study was to analyze the effects of lithium, valproate, quetiapine, and lamotrigine, and the interactions between them, on markers of inflammation, bioenergetics, mitochondrial function, and oxidative stress in neuron-like cells and microglial cells. Methods: Neuron-like cells and lipopolysaccharide-stimulated C8-B4 cells were treated with lithium (2.5 mM), valproate (0.5 mM), quetiapine (0.05 mM), and lamotrigine (0.05 mM) individually and in all possible combinations for 24 h. Twenty cytokines were measured in the media from lipopolysaccharide-stimulated C8-B4 cells. Metabolic flux analysis was used to measure bioenergetics, and real-time PCR was used to measure the expression of mitochondrial function genes in neuron-like cells. The production of superoxide in treated cells was also assessed. Results: The results suggest major inhibitory effects on proinflammatory cytokine release as a therapeutic mechanism of these medications when used in combination. The various combinations of medications also caused overexpression of PGC1α and ATP5A1 in neuron-like cells. Quetiapine appears to have a proinflammatory effect in microglial cells, but this was reversed by the addition of lamotrigine independent of the drug combination. Conclusion: Polypharmacy in bipolar disorder may have antiinflammatory effects on microglial cells as well as effects on mitochondrial biogenesis in neuronal cells.
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    Add-on treatment with N-acetylcysteine for bipolar depression: a 24-week randomized double-blind parallel group placebo-controlled multicentre trial (NACOS-study protocol)
    Ellegaard, PK ; Licht, RW ; Poulsen, HE ; Nielsen, RE ; Berk, M ; Dean, OM ; Mohebbi, M ; Nielsen, CT (SPRINGER, 2018-04-05)
    BACKGROUND: Oxidative stress and inflammation may be involved in the development and progression of mood disorders, including bipolar disorder. Currently, there is a scarcity of useful treatment options for bipolar depressive episodes, especially compared with the efficacy of treatment for acute mania. N-Acetylcysteine (NAC) has been explored for psychiatric disorders for some time given its antioxidant and anti-inflammatory properties. The current trial aims at testing the clinical effects of adjunctive NAC treatment (compared to placebo) for bipolar depression. We will also explore the biological effects of NAC in this context. We hypothesize that adjunctive NAC treatment will reduce symptoms of depression, which will be reflected by changes in selected markers of oxidative stress. METHODS AND ANALYSIS: In the study, we will include adults diagnosed with bipolar disorder, in a currently depressive episode. Participants will undertake a 20-week, adjunctive, randomized, double-blinded, parallel group placebo-controlled trial comparing 3 grams of adjunctive NAC daily with placebo. The primary outcome is the mean change over time from baseline to end of study on the Montgomery-Asberg Depression Rating Scale (MADRS). Among the secondary outcomes are mean changes from baseline to end of study on the Bech-Rafaelsen Melancholia Scale (MES), the Young Mania Rating Scale (YMRS), the WHO-Five Well-being Index (WHO-5), the Global Assessment of Functioning scale (GAF-F), the Global Assessment of Symptoms scale (GAF-S) and the Clinical Global Impression-Severity scale (CGI-S). The potential effects on oxidative stress by NAC treatment will be measured through urine and blood samples. DNA will be examined for potential polymorphisms related to oxidative defences. TRIAL REGISTRATION: Registered at The European Clinical Trials Database, ClinicalTrials.gov: NCT02294591 and The Danish Data Protection Agency: 2008-58-0035.