Psychiatry - Research Publications

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    Clinician 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
    Sarris, J ; Ravindran, A ; Yatham, LN ; Marx, W ; Rucklidge, JJ ; McIntyre, RS ; Akhondzadeh, S ; Benedetti, F ; Caneo, C ; Cramer, H ; Cribb, L ; de Manincor, M ; Dean, O ; Deslandes, AC ; Freeman, MP ; Gangadhar, B ; Harvey, BH ; Kasper, S ; Lake, J ; Lopresti, A ; Lu, L ; Metri, N-J ; Mischoulon, D ; Ng, CH ; Nishi, D ; Rahimi, R ; Seedat, S ; Sinclair, J ; Su, K-P ; Zhang, Z-J ; Berk, M (TAYLOR & FRANCIS LTD, 2022-03-16)
    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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    Mixed Methods Thematic Analysis of a Randomised Controlled Trial of Adjunctive Mitochondrial Agents for Bipolar Depression
    Russell, SE ; Wrobel, AL ; Dean, OM ; Berk, M ; Dodd, S ; Ng, CH ; Malhi, GS ; Cotton, SM ; Sarris, J ; Turner, A (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2022-05-01)
    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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    N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial.
    Sarris, J ; Byrne, G ; Castle, D ; Bousman, C ; Oliver, G ; Cribb, L ; Blair-West, S ; Brakoulias, V ; Camfield, D ; Ee, C ; Chamoli, S ; Boschen, M ; Dean, OM ; Dowling, N ; Menon, R ; Murphy, J ; Metri, N-J ; Nguyen, TP ; Wong, A ; Jordan, R ; Karamacoska, D ; Rossell, SL ; Berk, M ; Ng, CH (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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    Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study
    Sarris, J ; Byrne, GJ ; Oliver, G ; Cribb, L ; Blair-West, S ; Castle, D ; Dean, OM ; Camfield, DA ; Brakoulias, V ; Bousman, C ; Dowling, N ; Ee, C ; Murphy, J ; Menon, R ; Berk, M ; Chamoli, S ; Boschen, M ; Ng, CH (CAMBRIDGE UNIV PRESS, 2021-06-21)
    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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    Legalization of Psychedelic Substances
    Downey, LA ; Sarris, J ; Perkins, D (AMER MEDICAL ASSOC, 2021-12-21)
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    Ayahuasca and Childhood Trauma: Potential Therapeutic Applications
    Perkins, D ; Sarris, J ; Caiuby Labate, B ; Cavnar, C (Springer International Publishing, 2021)
    The last 20 years have seen major developments in the understanding of how childhood trauma (negative events that cause distress and overwhelm a person’s ability to cope) can have long-term effects on the health and well-being of adults who have experienced this. Child sexual abuse was first included in global burden of disease and disability estimates in 2004, and there has been a steady accumulation of research and evidence identifying the public health issues and costs associated with various traumatic childhood experiences. Much of this research has used the framework of adverse childhood experiences or ACEs, which encompass emotional, physical, and sexual abuse, as well as various other adverse events, including growing up in a household in which there is domestic violence, alcohol or drug abuse, or a member with mental illness; criminal behavior or incarceration of a family member; caregiver separation or divorce; and neglect, both physical and emotional. Such experiences have been found to be associated with higher rates of physical and mental illness, disability, and premature death in adulthood.
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    Potential biomarkers of major depression diagnosis and chronicity
    de Menezes Galvao, AC ; Almeida, RN ; de Sousa Junior, GM ; Leocadio-Miguel, MA ; Palhano-Fontes, F ; de Araujo, DB ; Lobao-Soares, B ; Maia-de-Oliveira, JP ; Nunes, EA ; Cecilio Hallak, JE ; Sarris, J ; Galvao-Coelho, NL ; Li, Z (PUBLIC LIBRARY SCIENCE, 2021-09-29)
    BACKGROUND: Molecular biomarkers are promising tools to be routinely used in clinical psychiatry. Among psychiatric diseases, major depression disorder (MDD) has gotten attention due to its growing prevalence and morbidity. METHODS: We tested some peripheral molecular parameters such as serum mature Brain-Derived Neurotrophic Factor (mBDNF), plasma C-Reactive Protein (CRP), serum cortisol (SC), and the salivary Cortisol Awakening Response (CAR), as well as the Pittsburgh sleep quality inventory (PSQI), as part of a multibiomarker panel for potential use in MDD diagnosis and evaluation of disease's chronicity using regression models, and ROC curve. RESULTS: For diagnosis model, two groups were analyzed: patients in the first episode of major depression (MD: n = 30) and a healthy control (CG: n = 32). None of those diagnosis models tested had greater power than Hamilton Depression Rating Scale-6. For MDD chronicity, a group of patients with treatment-resistant major depression (TRD: n = 28) was tested across the MD group. The best chronicity model (p < 0.05) that discriminated between MD and TRD included four parameters, namely PSQI, CAR, SC, and mBDNF (AUC ROC = 0.99), with 96% of sensitivity and 93% of specificity. CONCLUSION: These results indicate that changes in specific biomarkers (CAR, SC, mBDNF and PSQI) have potential on the evaluation of MDD chronicity, but not for its diagnosis. Therefore, these findings can contribute for further studies aiming the development of a stronger model to be commercially available and used in psychiatry clinical practice.
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    Effects of a group-based lifestyle medicine for depression: A pilot randomized controlled trial
    Ip, AK-Y ; Ho, FY-Y ; Yeung, W-F ; Chung, K-F ; Ng, CH ; Oliver, G ; Sarris, J ; Abdelbasset, WK (PUBLIC LIBRARY SCIENCE, 2021-10-08)
    Given the growing evidence that a range of lifestyle factors are involved in the etiology of depression, a 'lifestyle medicine' approach can be potentially safe and cost-effective to prevent or treat depression. To examine the effects and acceptability of a group-based, integrative lifestyle medicine intervention as a standalone treatment for managing depressive symptoms, a pilot randomized controlled trial (RCT) was conducted in a Chinese adult population in 2018. Participants (n = 31) with PHQ-9 score above the cut-off of ≥ 10, which was indicative of moderate to severe depression, were recruited from the general community in Hong Kong and randomly assigned to lifestyle medicine group (LM group) or care-as-usual group (CAU group) in a ratio of 1:1. Participants in the LM group received 2-hour group sessions once per week for six consecutive weeks, which covered diet, exercise, mindfulness, psychoeducation, and sleep management. Linear mixed-effects model analyses showed that the LM group had a significant reduction in PHQ-9 scores compared to the CAU group at immediate posttreatment and 12-week posttreatment follow-up (d = 0.69 and 0.73, respectively). Moreover, there were significantly greater improvements in anxiety, stress, and insomnia symptoms (measured by DASS-21 and ISI) at all time points in the LM group (d = 0.42-1.16). The results suggests that our 6-week group-based, integrative lifestyle intervention program is effective in lowering depressive, anxiety, stress, and insomnia symptoms in the Chinese population. Further studies in clinical populations with a larger sample size and longer follow-up are warranted.
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    Effects of cannabis ingestion on endometriosis-associated pelvic pain and related symptoms
    Sinclair, J ; Collett, L ; Abbott, J ; Pate, DW ; Sarris, J ; Armour, M ; Raimondo, D (PUBLIC LIBRARY SCIENCE, 2021-10-26)
    BACKGROUND: The use of cannabis for symptoms of endometriosis was investigated utilising retrospective archival data from Strainprint Technologies Ltd., a Canadian data technology company with a mobile phone application that tracks a range of data including dose, mode of administration, chemovar and their effects on various self-reported outcomes, including pelvic pain. METHODS: A retrospective, electronic record-based cohort study of StrainprintTM users with self-reported endometriosis was conducted. Self-rated cannabis efficacy, defined as a function of initial and final symptom ratings, was investigated across the included symptom clusters of cramps, pelvic pain, gastrointestinal pain, nausea, depression, and low libido. Cannabis dosage form, dose and cannabinoid ratio information was also recorded. RESULTS: A total number of 252 participants identifying as suffering endometriosis recorded 16193 sessions using cannabis between April 2017 and February 2020. The most common method of ingestion was inhalation (n = 10914, 67.4%), with pain as the most common reported symptom being treated by cannabis (n = 9281, 57.3%). Gastrointestinal symptoms, though a less common reason for cannabis usage (15.2%), had the greatest self-reported improvement after use. Inhaled forms had higher efficacy for pain, while oral forms were superior for mood and gastrointestinal symptoms. Dosage varied across ingestion methods, with a median dose of 9 inhalations (IQR 5 to 11) for inhaled dosage forms and 1 mg/mL (IQR 0.5 to 2) for other ingested dosage forms. The ratio of THC to CBD had a statistically significant, yet clinically small, differential effect on efficacy, depending on method of ingestion. CONCLUSIONS: Cannabis appears to be effective for pelvic pain, gastrointestinal issues and mood, with effectiveness differing based on method of ingestion. The greater propensity for use of an inhaled dosage delivery may be due to the rapid onset of pain-relieving effects versus the slower onset of oral products. Oral forms appeared to be superior compared to inhaled forms in the less commonly reported mood or gastrointestinal categories. Clinical trials investigating the tolerability and effectiveness of cannabis for endometriosis pain and associated symptoms are urgently required.
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    GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence
    Savage, K ; Firth, J ; Stough, C ; Sarris, J (WILEY, 2018-01-01)
    Anxiety disorders are chronic and functionally disabling conditions with high psychological stress, characterised by cognitive symptoms of excessive worry and focus difficulties and physiological symptoms such as muscle tension and insomnia. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter within the central nervous system and is a key target of pharmacotherapies in the treatment of anxiety. Although current pharmaceutical treatments are often efficacious, they may cause undesirable side effects including cognitive decrements and withdrawal symptoms. Plant-based "phytomedicines" may provide novel treatment options, to act as an adjunctive or alternative to existing anxiolytic medications. As such, we conducted a systematic review to assess the current body of literature on anxiolytic phytomedicines and/or phytoconstituents. An open-ended search to 5 July 2017 was conducted using MEDLINE (PubMed), Scopus, and Cochrane library online databases and performed in a stepped format from preclinical to clinical investigations. Eligible studies must have had (a) in vitro evidence of GABA-modulating activity, (b) animal studies using anxiety models to test an anxiolytic effect, and (c) human clinical trials. Ten phytomedicines were identified as having preclinical investigations showing interaction with the GABA system, in addition to human clinical trials: kava, valerian, pennywort, hops, chamomile, Ginkgo biloba, passionflower, ashwagandha, skullcap, and lemon balm. Collectively, the literature reveals preclinical and clinical evidence for various phytomedicines modulating GABA-pathways, with comparative anxiolytic effect to the current array of pharmaceuticals, along with good safety and tolerability profiles.