Psychiatry - Research Publications

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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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    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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    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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    N-acetylcysteine for cessation of tobacco smoking: rationale and study protocol for a randomised controlled trial
    Arancini, L ; Bortolasci, CC ; Dodd, S ; Dean, OM ; Berk, M (BMC, 2019-09-10)
    BACKGROUND: Tobacco smoking is a highly prevalent, addictive behaviour and a key public health priority. However available cessation therapies have low quit and high relapse rates, indicating an urgent need for more effective treatments. Predicated on promising preclinical and pilot clinical data, this paper presents a rationale and protocol for the trial of N-acetylcysteine (NAC) as a novel anti-craving smoking cessation aid. METHODS: Current smokers (n = 120) of at least 10 cigarettes a day are recruited through online advertisements, print publications and dissemination of flyers. Participants are randomised on a 1:1 ratio to receive either 16-week treatment of 1.8 g/day of NAC or placebo with all participants receiving quit support from the online QuitCoach tool. Participants are attending visits at baseline, 8 and 16 weeks with a 42-week post-discontinuation follow-up. The primary outcome measure is sustained abstinence at six months after treatment based on self-reported rating scales and confirmed by exhaled carbon monoxide and salivary cotinine levels. Secondary outcomes are timing of the first lapse and relapse, between-group cigarette consumption, withdrawal symptoms, general wellbeing and mood/anxiety symptoms. Between-group differences in adverse events and subgroup analyses for variables including gender and Diagnostic Statistics Manual 5 diagnostics will also be investigated. DISCUSSION: The planned trial addresses an issue of major importance to human health and, if an effect is shown, may result in substantial changes to the management of smoking and nicotine addiction with overt public health implications. TRIAL REGISTRATION: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303 . Registered on 19 October 2017.
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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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    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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    Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin
    Berk, M ; Mohebbi, M ; Dean, OM ; Cotton, SM ; Chanen, AM ; Dodd, S ; Ratheesh, A ; Amminger, GP ; Phelan, M ; Weller, A ; Mackinnon, A ; Giorlando, F ; Baird, S ; Incerti, L ; Brodie, RE ; Ferguson, NO ; Rice, S ; Schafer, MR ; Mullen, E ; Hetrick, S ; Kerr, M ; Harrigan, SM ; Quinn, AL ; Mazza, C ; McGorry, P ; Davey, CG (BMC, 2020-01-17)
    BACKGROUND: Inflammation contributes to the pathophysiology of major depressive disorder (MDD), and anti-inflammatory strategies might therefore have therapeutic potential. This trial aimed to determine whether adjunctive aspirin or rosuvastatin, compared with placebo, reduced depressive symptoms in young people (15-25 years). METHODS: YoDA-A, Youth Depression Alleviation with Anti-inflammatory Agents, was a 12-week triple-blind, randomised, controlled trial. Participants were young people (aged 15-25 years) with moderate to severe MDD (MADRS mean at baseline 32.5 ± 6.0; N = 130; age 20.2 ± 2.6; 60% female), recruited between June 2013 and June 2017 across six sites in Victoria, Australia. In addition to treatment as usual, participants were randomised to receive aspirin (n = 40), rosuvastatin (n = 48), or placebo (n = 42), with assessments at baseline and weeks 4, 8, 12, and 26. The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: At the a priori primary endpoint of MADRS differential change from baseline at week 12, there was no significant difference between aspirin and placebo (1.9, 95% CI (- 2.8, 6.6), p = 0.433), or rosuvastatin and placebo (- 4.2, 95% CI (- 9.1, 0.6), p = 0.089). For rosuvastatin, secondary outcomes on self-rated depression and global impression, quality of life, functioning, and mania were not significantly different from placebo. Aspirin was inferior to placebo on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) at week 12. Statins were superior to aspirin on the MADRS, the Clinical Global Impressions Severity Scale (CGI-S), and the Negative Problem Orientation Questionnaire scale (NPOQ) at week 12. CONCLUSIONS: The addition of either aspirin or rosuvastatin did not to confer any beneficial effect over and above routine treatment for depression in young people. Exploratory comparisons of secondary outcomes provide limited support for a potential therapeutic role for adjunctive rosuvastatin, but not for aspirin, in youth depression. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12613000112763. Registered on 30/01/2013.
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    Tobacco Use in Bipolar Disorder
    Thomson, D ; Berk, M ; Dodd, S ; Rapado-Castro, M ; Quirk, SE ; Ellegaard, PK ; Berk, L ; Dean, OM (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2015-04-01)
    Tobacco use in mental health in general and bipolar disorder in particular remains disproportionally common, despite declining smoking rates in the community. Furthermore, interactions between tobacco use and mental health have been shown, indicating the outcomes for those with mental health disorders are impacted by tobacco use. Factors need to be explored and addressed to improve outcomes for those with these disorders and target specific interventions for people with psychiatric illness to cease tobacco smoking. In the context of bipolar disorder, this review explores; the effects of tobacco smoking on symptoms, quality of life, suicidal behavior, the biological interactions between tobacco use and bipolar disorder, the interactions between tobacco smoking and psychiatric medications, rates and factors surrounding tobacco smoking cessation in bipolar disorder and suggests potential directions for research and clinical translation. The importance of this review is to bring together the current understanding of tobacco use in bipolar disorder to highlight the need for specific intervention.
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    Deserves a hearing? A case report of remitting tinnitus with N-acetyl cysteine
    Dean, OM ; Jeavons, S ; Malhi, GS ; Cotton, SM ; Tanious, M ; Kohlmann, K ; Hewitt, K ; Moss, K ; Allwang, C ; Schapkaitz, I ; Robbins, J ; Dodd, S ; Bush, A ; Berk, M (IN HOUSE PUBLICATIONS, 2013-07-01)