Psychiatry - Research Publications
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ItemN-Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms(OXFORD UNIV PRESS, 2022-11-18)BACKGROUND AND HYPOTHESIS: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC). STUDY DESIGN: A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks. STUDY RESULTS: NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26). CONCLUSIONS: NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with "Australian and New Zealand Clinical Trials" on the 30 May, 2016 (Registration Number: ACTRN12615001273572).
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ItemClinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce(TAYLOR & FRANCIS LTD, 2022-07-03)OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.
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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)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 AvailableN-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial.(Elsevier BV, 2022-07-13)OBJECTIVE: Preliminary evidence has suggested that adjunctive N-acetylcysteine (NAC), an antioxidant precursor to glutathione, may reduce symptoms of obsessive-compulsive disorder (OCD). We conducted a 20-week, multi-site, randomized controlled trial to investigate the safety and efficacy of the adjunctive use of NAC in OCD. METHODS: The study was a phase III, 20-week, double-blind, randomized controlled trial across multiple sites in Australia investigating 2 g to 4 g per day of NAC (titrated according to response) in 98 participants with DSM-5 diagnosed OCD. Data were analysed using linear mixed effects models for the 89 participants who attended at least one follow-up visit. RESULTS: A modified intention-to-treat analysis of the primary outcome found no evidence that NAC reduced symptoms of OCD measured on the Yale-Brown Obsessive-Compulsive Scale, relative to placebo (mean difference at week 20 = 0.53, 95% compatibility interval = -2.18, 3.23; p = 0.70; favouring placebo). There was also no evidence that NAC, compared to placebo, improved outcomes on the secondary measures including anxiety, depression, quality of life, functioning, or clinician/participant impression. NAC was well-tolerated with only mild gastrointestinal adverse events associated with the treatment. CONCLUSION: We found no evidence supporting the efficacy of the adjunctive use of NAC in OCD.
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ItemNo Preview AvailableTreatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study(CAMBRIDGE UNIV PRESS, 2022-10-21)BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.
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ItemN-Acetyl Cysteine in the Treatment of Obsessive Compulsive and Related Disorders: A Systematic Review(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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ItemNutritional Deficiencies and Clinical Correlates in First-Episode Psychosis: A Systematic Review and Meta-analysis(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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ItemEfficacy of adjunctive Garcinia mangostana Linn (mangosteen) pericarp for bipolar depression: study protocol for a proof-of-concept trial(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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ItemNutraceuticals and nutritional supplements for the treatment of bipolar disorder: protocol for a systematic review(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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ItemThe Therapeutic Potential of Mangosteen Pericarp as an Adjunctive Therapy for Bipolar Disorder and Schizophrenia(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.