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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    A study protocol for the N-ICE trial: A randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine ("ice") dependence
    McKetin, R ; Dean, OM ; Turner, A ; Kelly, PJ ; Quinn, B ; Lubman, DI ; Dietze, P ; Carter, G ; Higgs, P ; Baker, AL ; Sinclair, B ; Reid, D ; Manning, V ; te Pas, N ; Liang, W ; Thomas, T ; Bathish, R ; Kent, M ; Raftery, D ; Arunogiri, S ; Cordaro, F ; Hill, H ; Berk, M (BMC, 2019-06-04)
    BACKGROUND: There are currently no approved pharmacotherapies for managing methamphetamine dependence. N-acetylcysteine (NAC) has been found to reduce the craving for methamphetamine and other drugs, but its effect on methamphetamine use and other clinically related endpoints are uncertain. The N-ICE trial is evaluating the safety and efficacy of NAC as a take-home pharmacotherapy for methamphetamine dependence. METHODS/DESIGN: This is a two-arm parallel double-blind placebo-controlled three-site randomised trial (ratio 1:1) using permuted block randomisation, with variable block sizes. It is stratified by site, sex and whether the methamphetamine is injected or not. Participants (N = 180; 60 per site) need to be dependent on methamphetamine, interested in reducing their methamphetamine use and not currently receiving treatment for substance use disorders. The trial is being conducted in outpatient settings in Melbourne, Geelong and Wollongong, Australia. Participants will receive either 2400 mg oral NAC or a matched placebo, delivered as a take-home medication for 12 weeks. Two 600 mg capsules are self-administered in the morning and two more in the evening. Adherence is being monitored using eCAP™ medication bottle lids, which record the date and time of each occasion the bottle is opened. The primary outcome is methamphetamine use during the 12-week trial medication period, measured as (a) days of use, assessed using the timeline followback, and (b) methamphetamine-positive saliva tests, taken weekly. Secondary measures include weekly assessment of methamphetamine craving, severity of methamphetamine dependence, methamphetamine withdrawal symptoms and psychiatric symptoms (depression, suicidality, psychotic symptoms and hostility). Adverse events are monitored at each weekly assessment. Tolerability is assessed using the Treatment Satisfaction Questionnaire for Medication. DISCUSSION: The N-ICE trial is the first clinical trial to assess whether NAC can reduce methamphetamine use. This trial will improve our understanding of the potential utility of NAC in managing methamphetamine dependence and clinically related outcomes. If found to be effective, take-home NAC could be a potentially scalable and affordable pharmacotherapy option for treating methamphetamine dependence. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12618000366257 . Registered on 29 May 2018.
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    Protocol and Rationale: A 24-week Double-blind, Randomized, Placebo Controlled Trial of the Efficacy of Adjunctive Garcinia mangostana Linn. (Mangosteen) Pericarp for Schizophrenia
    Turner, A ; McGrath, JJ ; Dean, OM ; Dodd, S ; Baker, A ; Cotton, SM ; Scott, JG ; Kavanagh, BE ; Ashton, MM ; Walker, AJ ; Brown, E ; Berk, M (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2019-05-01)
    OBJECTIVE: : Garcinia mangostana Linn., commonly known as mangosteen, is a tropical fruit with a thick pericarp rind containing bioactive compounds that may be beneficial as an adjunctive treatment for schizophrenia. The biological underpinnings of schizophrenia are believed to involve altered neurotransmission, inflammation, redox systems, mitochondrial dysfunction, and neurogenesis. Mangosteen pericarp contains xanthones which may target these biological pathways and improve symptoms; this is supported by preclinical evidence. Here we outline the protocol for a double- blind randomized placebo-controlled trial evaluating the efficacy of adjunctive mangosteen pericarp (1,000 mg/day), compared to placebo, in the treatment of schizophrenia. METHODS: : We aim to recruit 150 participants across two sites (Geelong and Brisbane). Participants diagnosed with schizophrenia or schizoaffective disorder will be randomized to receive 24 weeks of either adjunctive 1,000 mg/day of mangosteen pericarp or matched placebo, in addition to their usual treatment. The primary outcome measure is mean change in the Positive and Negative Symptom Scale (total score) over the 24 weeks. Secondary outcomes include positive and negative symptoms, general psychopathology, clinical global severity and improvement, depressive symptoms, life satisfaction, functioning, participants reported overall improvement, substance use, cognition, safety and biological data. A 4-week post treatment interview at week 28 will explore post-discontinuations effects. RESULTS: : Ethical and governance approvals were gained and the trial commenced. CONCLUSION: : A positive finding in this study has the potential to provide a new adjunctive treatment option for people with schizophrenia and schizoaffective disorder. It may also lead to a greater understanding of the pathophysiology of the disorder.
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    Role of personality disorder in randomised controlled trials of pharmacological interventions for adults with mood disorders: a protocol for a systematic review and meta-analysis
    Kavanagh, BE ; Brennan-Olsen, SL ; Turner, A ; Dean, OM ; Berk, M ; Ashton, MM ; Koivumaa-Honkanen, H ; Williams, LJ (BMJ PUBLISHING GROUP, 2019-06-01)
    INTRODUCTION: Remission rates for mood disorders, including depressive and bipolar disorders, remain relatively low despite available treatments, and many patients fail to respond adequately to these interventions. Evidence suggests that personality disorder may play a role in poor outcomes. Although personality disorders are common in patients with mood disorders, it remains unknown whether personality disorder affects treatment outcomes in mood disorders. We aim to review currently available evidence regarding the role of personality disorder on pharmacological interventions in randomised controlled trials for adults with mood disorders. METHODS AND ANALYSIS: A systematic search of Cochrane Central Register of Controlled Clinical Trials (CENTRAL) via cochranelibrary.com, PubMed via PubMed, EMBASE via embase.com, PsycINFO via Ebsco and CINAHL Complete via Ebsco databases will be conducted to identify randomised controlled trials that have investigated pharmacological interventions in participants aged 18 years or older for mood disorders (ie, depressive disorders and bipolar spectrum disorders) and have also included assessment of personality disorder. One reviewer will screen studies against the predetermined eligibility criteria, and a second reviewer will confirm eligible studies. Data will be extracted by two independent reviewers. Methodological quality and risk of bias will be assessed using the Cochrane Risk of Bias tool. A systematic review, and if sufficient evidence is identified, a meta-analysis will be completed. Meta-analysis will be conducted using the standardised mean difference approach and reported with 95% CIs. A random effects model will be employed and statistical heterogeneity will be evaluated using the I2 statistic. Prespecified subgroup analyses will be completed. ETHICS AND DISSEMINATION: As this systematic review will use published data, ethics permission will not be required. The outcomes of this systematic review will be published in a relevant scientific journal and presented at a research conference. TRIAL REGISTRATION NUMBER: CRD42018089279.
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    Efficacy of adjunctive Garcinia mangostana Linn (mangosteen) pericarp for bipolar depression: study protocol for a proof-of-concept trial
    Ashton, MM ; Berk, M ; Ng, CH ; Hopwood, M ; Dodd, S ; Turner, A ; Brown, E ; Jacka, FN ; Cotton, SM ; Khoo, J-P ; Chatterton, ML ; Kavanagh, BE ; Nadjidai, SE ; Lo Monaco, SL ; Harvey, BH ; Sarris, J ; Malhi, GS ; Dowling, NL ; Dean, OM (ASSOC BRASILEIRA PSIQUIATRIA, 2019-05-01)
    OBJECTIVE: Bipolar depression is characterized by neurobiological features including perturbed oxidative biology, reduction in antioxidant levels, and a concomitant rise in oxidative stress markers. Bipolar depression manifests systemic inflammation, mitochondrial dysfunction, and changes in brain growth factors. The depressive phase of the disorder is the most common and responds the least to conventional treatments. Garcinia mangostana Linn, commonly known as mangosteen, is a tropical fruit. The pericarp's properties may reduce oxidative stress and inflammation and improve neurogenesis, making mangosteen pericarp a promising add-on therapy for bipolar depression. METHODS: Participants will receive 24 weeks of either 1,000 mg mangosteen pericarp or placebo per day, in addition to their usual treatment. The primary outcome is change in severity of mood symptoms, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), over the treatment phase. Secondary outcomes include global psychopathology, quality of life, functioning, substance use, cognition, safety, biological data, and cost-effectiveness. A follow-up interview will be conducted 4 weeks post-treatment. CONCLUSION: The findings of this study may have implications for improving treatment outcomes for those with bipolar disorder and may contribute to our understanding of the pathophysiology of bipolar depression. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry, ACTRN12616000028404.
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    Personality disorder and functioning in major depressive disorder: a nested study within a randomized controlled trial
    Kavanagh, BE ; Williams, LJ ; Berk, M ; Turner, A ; Jackson, HJ ; Mohebbi, M ; Kanchanatawan, B ; Ashton, MM ; Ng, CH ; Maes, M ; Berk, L ; Malhi, GS ; Dowling, N ; Singh, AB ; Dean, OM (ASSOC BRASILEIRA PSIQUIATRIA, 2020-01-01)
    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.
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    The Therapeutic Potential of Mangosteen Pericarp as an Adjunctive Therapy for Bipolar Disorder and Schizophrenia
    Ashton, MM ; Dean, OM ; Walker, AJ ; Bortolasci, CC ; Ng, CH ; Hopwood, M ; Harvey, BH ; Moller, M ; McGrath, JJ ; Marx, W ; Turner, A ; Dodd, S ; Scott, JG ; Khoo, J-P ; Walder, K ; Sarris, J ; Berk, M (FRONTIERS MEDIA SA, 2019-03-13)
    New treatments are urgently needed for serious mental illnesses including bipolar disorder and schizophrenia. This review proposes that Garcinia mangostana Linn. (mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders. Research to date demonstrates that neurobiological properties of the mangosteen pericarp are well aligned with the current understanding of the pathophysiology of bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties, with animal studies demonstrating favorable pharmacotherapeutic benefits with respect to these disorders. This review summarizes evidence of its properties and supports the case for future studies to assess the utility of mangosteen pericarp as an adjunctive treatment option for mood and psychotic disorders.
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    A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo
    Berk, M ; Turner, A ; Malhi, GS ; Ng, C ; Cotton, SM ; Dodd, S ; Samuni, Y ; Tanious, M ; McAulay, C ; Dowling, N ; Sarris, J ; Owen, L ; Waterdrinker, A ; Smith, D ; Dean, OM (BMC, 2019-01-25)
    BACKGROUND: A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis. METHODS: A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n = 181) with bipolar disorder and current depressive symptoms were randomised to 2000 mg/day NAC (n = 59), 2000 mg/day NAC with the combination nutraceutical treatment (CT, n = 61), or placebo (n = 61). The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes. RESULTS: One hundred forty-eight participants had post-randomisation data and were analysed (NAC = 52, CT = 47, Placebo = 49). No between-group differences were found for the rate of change between baseline and 16 weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group. CONCLUSIONS: These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction. TRIAL REGISTRATION: ANZCTR ( ACTRN12612000830897 ).