Psychiatry - Research Publications

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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)
    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 Researchers with known involvement in NAC studies were contacted for any unpublished data.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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    Nutritional Deficiencies and Clinical Correlates in First-Episode Psychosis: A Systematic Review and Meta-analysis
    Firth, J ; Carney, R ; Stubbs, B ; Teasdale, SB ; Vancampfort, D ; Ward, PB ; Berk, M ; Sarris, J (OXFORD UNIV PRESS, 2018-11)
    OBJECTIVE: Diet is increasingly recognized as a potentially modifiable factor influencing the onset and outcomes of psychiatric disorders. Whereas, previous research has shown long-term schizophrenia is associated with various nutritional deficiencies, this meta-analysis aimed to determine the prevalence and extent of nutritional deficits in first-episode psychosis (FEP). METHOD: A search of electronic databases conducted in July 2017 identified 28 eligible studies, examining blood levels of 6 vitamins and 10 minerals across 2612 individuals: 1221 individuals with FEP and 1391 control subjects. Meta-analyses compared nutrient levels in FEP to nonpsychiatric controls. Clinical correlates of nutritional status in patient samples were systematically reviewed. RESULTS: Significantly lower blood levels of folate (N = 6, n = 827, g = -0.624, 95% confidence interval [CI] = -1.176 to -0.072, P = .027) and vitamin D (N = 7, n = 906, g = -1.055, 95% CI = -1.99 to -0.119, P = .027) were found in FEP compared to healthy controls. Synthesis of clinical correlates found both folate and vitamin D held significant inverse relationships with psychiatric symptoms in FEP. There was also limited evidence for serum level reductions of vitamin C (N = 2, n = 96, g = -2.207, 95% CI = -3.71 to -0.71, P = .004). No differences were found for other vitamins or minerals. CONCLUSIONS: Deficits in vitamin D and folate previously observed in long-term schizophrenia appear to exist from illness onset, and are associated with worse symptomology. Further research must examine the direction and nature of these relationships (ie, mediator, moderator, or marker) with clinical status in FEP. Future trials assessing efficacy of nutrient supplementation in FEP samples should consider targeting and stratifying for baseline deficiency.
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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)
    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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    Nutraceuticals and nutritional supplements for the treatment of bipolar disorder: protocol for a systematic review
    Ashton, MM ; Berk, M ; Ng, CH ; Hopwood, M ; Kavanagh, B ; Williams, LJ ; Sarris, J ; Dean, OM (BMJ PUBLISHING GROUP, 2019-06)
    INTRODUCTION: First line pharmacological treatments for bipolar disorder (BD) can leave shortfalls in recovery leading to patients seeking alternative and adjunctive treatments such as nutraceuticals. This protocol for a systematic review and proposed meta-analysis aims to answer the research question: in patients with BD, how does use of nutraceutical treatments compare with placebo in reducing depressive and mania symptoms? METHODS AND ANALYSIS: Clinical trials will be identified through database searches using PubMed via PubMed, EMBASE via embase.com, Cochrane Central Register of Controlled Clinical Trials (CENTRAL) via cochranelibrary.com and CINAHL Complete via EBSCO. Search terms for BD and specific nutraceuticals (75 total search terms) will be used. Double-blind, randomised, controlled, clinical trials of adults with BD will be included in the review. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomised trials. ETHICS AND DISSEMINATION: This review will only look at published data (already reviewed for ethical compliance); therefore, ethical approval is not required. We aim to publish the systematic review in a peer-reviewed journal and present at conferences. PROSPERO REGISTRATION NUMBER: CRD42019100745.
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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 ).
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    Lifestyle medicine for depression
    Sarris, J ; O'Neil, A ; Coulson, CE ; Schweitzer, I ; Berk, M (BioMed Central Ltd., 2014)
    The prevalence of depression appears to have increased over the past three decades. While this may be an artefact of diagnostic practices, it is likely that there are factors about modernity that are contributing to this rise. There is now compelling evidence that a range of lifestyle factors are involved in the pathogenesis of depression. Many of these factors can potentially be modified, yet they receive little consideration in the contemporary treatment of depression, where medication and psychological intervention remain the first line treatments. “Lifestyle Medicine” provides a nexus between public health promotion and clinical treatments, involving the application of environmental, behavioural, and psychological principles to enhance physical and mental wellbeing. This may also provide opportunities for general health promotion and potential prevention of depression. In this paper we provide a narrative discussion of the major components of Lifestyle Medicine, consisting of the evidence-based adoption of physical activity or exercise, dietary modification, adequate relaxation/sleep and social interaction, use of mindfulness-based meditation techniques, and the reduction of recreational substances such as nicotine, drugs, and alcohol. We also discuss other potential lifestyle factors that have a more nascent evidence base, such as environmental issues (e.g. urbanisation, and exposure to air, water, noise, and chemical pollution), and the increasing human interface with technology. Clinical considerations are also outlined. While data supports that some of these individual elements are modifiers of overall mental health, and in many cases depression, rigorous research needs to address the long-term application of Lifestyle Medicine for depression prevention and management. Critically, studies exploring lifestyle modification involving multiple lifestyle elements are needed. While the judicious use of medication and psychological techniques are still advocated, due to the complexity of human illness/wellbeing, the emerging evidence encourages a more integrative approach for depression, and an acknowledgment that lifestyle modification should be a routine part of treatment and preventative efforts.
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    N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms
    Rossell, SL ; Francis, PS ; Galletly, C ; Harris, A ; Siskind, D ; Berk, M ; Bozaoglu, K ; Dark, F ; Dean, O ; Liu, D ; Meyer, D ; Neill, E ; Phillipou, A ; Sarris, J ; Castle, DJ (BMC, 2016-09-15)
    BACKGROUND: Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ. METHODS: This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes. DISCUSSION: This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.
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    N-Acetyl Cysteine (NAC) in the Treatment of Obsessive-Compulsive Disorder: A 16-Week, Double-Blind, Randomised, Placebo-Controlled Study
    Sarris, J ; Oliver, G ; Camfield, DA ; Dean, OM ; Dowling, N ; Smith, DJ ; Murphy, J ; Menon, R ; Berk, M ; Blair-West, S ; Ng, CH (ADIS INT LTD, 2015-09)
    BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. Recent preclinical and clinical studies have implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. The amino acid-based nutraceutical N-acetyl cysteine (NAC) is a safe and readily available agent that has been found to modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter. OBJECTIVE: The aim of this study was to assess the efficacy and safety of NAC in treating OCD. METHODS: A 16-week, double-blind, placebo-controlled, randomised trial using 3 g/day of NAC (1.5 g twice daily) in 44 participants (aged 18-70 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)-diagnosed OCD, during 2013-2015. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS), conducted every 4 weeks. RESULTS: Analysis of the full sample (intention-to-treat) with repeated measures mixed linear modelling revealed a nonsignificant time × treatment interaction for the YBOCS scale total score (p = 0.39). A per-protocol analysis removing protocol violators also failed to show a significant time × treatment interaction for YBOCS total score (p = 0.15). However, a significant time × treatment interaction was observed for the YBOCS 'Compulsions' subscale in favour of NAC (p = 0.013), with a significant reduction observed at week 12 (dissipating at week 16). At 16 weeks, only four (20%) participants were considered 'responders' (YBOCS ≥35% reduction at endpoint) versus four (27%) in the placebo group. The NAC was well-tolerated, aside from more cases of heartburn occurring compared with placebo (p = 0.045). CONCLUSION: Further research involving NAC for OCD may require larger samples to detect moderate or small effect sizes, involve dosage or formulation differences, use in concert with exposure therapy, or an additional post-study observational period to mitigate study withdrawal. TRIAL REGISTRATION: ACTRN12613000310763.