Publications by authors named "Michael Berk"

937 Publications

Inflammation and depression in young people: a systematic review and proposed inflammatory pathways.

Mol Psychiatry 2021 Oct 11. Epub 2021 Oct 11.

Orygen, Parkville, VIC, Australia.

Depression onset peaks during adolescence and young adulthood. Current treatments are only moderately effective, driving the search for novel pathophysiological mechanisms underlying youth depression. Inflammatory dysregulation has been shown in adults with depression, however, less is known about inflammation in youth depression. This systematic review identified 109 studies examining the association between inflammation and youth depression and showed subtle evidence for inflammatory dysregulation in youth depression. Longitudinal studies support the bidirectional association between inflammation and depression in youth. We hypothesise multiple inflammatory pathways contributing to depression. More research is needed on anti-inflammatory treatments, potentially tailored to individual symptom profiles.
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http://dx.doi.org/10.1038/s41380-021-01306-8DOI Listing
October 2021

The influence of childhood trauma on the treatment outcomes of pharmacological and/or psychological interventions for adolescents and adults with bipolar disorder: A systematic review and meta-analysis.

J Affect Disord 2021 Oct 1;296:350-362. Epub 2021 Oct 1.

IMPACT-The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia; School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia. Electronic address:

Objective: The influence of childhood trauma on the treatment outcomes of pharmacological and/or psychological interventions for adolescents and adults with bipolar disorder was systematically reviewed.

Methods: Randomised and non-randomised studies of interventions for bipolar disorder that included an assessment of childhood trauma were eligible. MEDLINE Complete, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were searched. Two independent reviewers completed the screening and extraction process. Two independent reviewers assessed the risk of bias in the included studies using the Cochrane Collaboration's Risk of Bias tool and the Newcastle-Ottawa Scale. Alongside a narrative synthesis, random-effects meta-analyses were performed.

Results: Twelve studies (1175 participants) were included. The narrative review highlighted differential treatment outcomes among individuals with a history of childhood trauma. The meta-analyses suggested that childhood trauma was unrelated to treatment response (five studies, 426 participants; odds ratio 0.58, 95% CI 0.27-1.25, p = .164) but may be associated with greater improvement in global functioning (three studies, 210 participants; Hedge's g 0.65, 95% CI 0.04-1.26, p = .037).

Limitations: The impact of childhood trauma on the effectiveness of specific pharmacological/psychological interventions could not be explored due to the small body of research identified.

Conclusion: The overall quality of the extant evidence is low, which precludes definitive comment on the role of childhood trauma in the treatment of bipolar disorder. Additional research that uses large and representative samples is required to ascertain whether a history of childhood trauma affects the treatment outcomes of interventions for individuals with bipolar disorder.
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http://dx.doi.org/10.1016/j.jad.2021.09.103DOI Listing
October 2021

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations.

Bipolar Disord 2021 Oct 2. Epub 2021 Oct 2.

Department of Psychiatry, George Washington University, Washington, DC, USA.

Objectives: The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address.

Method: Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion.

Results: No agents met threshold for first line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first line, and lithium and olanzapine identified as second line options.

Conclusion: The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.
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http://dx.doi.org/10.1111/bdi.13135DOI Listing
October 2021

Biological Mechanism(s) Underpinning the Association between Antipsychotic Drugs and Weight Gain.

J Clin Med 2021 Sep 10;10(18). Epub 2021 Sep 10.

Institute for Innovation in Physical and Mental Health and Clinical Translation, IMPACT, School of Medicine, Deakin University, Geelong 3220, Australia.

Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs' propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs' propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by and . Furthermore, quetiapine significantly increased the expression of and in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of expression, with evidence of a direct effect of quetiapine on the expression of . The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia.
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http://dx.doi.org/10.3390/jcm10184095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467356PMC
September 2021

Implications of the COVID-19 pandemic for people with bipolar disorders: A scoping review.

J Affect Disord 2021 Sep 4;295:740-751. Epub 2021 Sep 4.

IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. Electronic address:

Introduction: The COVID-19 (coronavirus disease 2019)-related pandemic represents a global source of societal and health burden. Yet, the impact of the pandemic on people with severe mental illness, including bipolar disorder (BD), remains unclear, warranting scoping review on the matter.

Methods: The MEDLINE and EMBASE databases were systematically searched from inception up to April 24, 2021, adopting broad inclusion criteria to assess a variety of clinical and public health themes related to people with a primary diagnosis of BD during the COVID-19 pandemics. The present work complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) registered in the Open Science Framework (OSF) repository (https://osf.io/7evpx/).

Results: Fourteen papers informed the present scoping review. Four major themes were identified: (i) impact of COVID-19-related stressors on BD; (ii) impact of COVID-19 on mental health service utilization among people with BD; (iii) impact of BD on the risk of acquiring SARS-CoV-2 infection; (iv) engagement in preventative behaviors among people with BD. Additional themes warranting further research were nonetheless detected.

Limitations: Further original studies are needed.

Conclusion: The present study confirmed the high-vulnerability hypothesis concerning people with BD versus the general population, reinforcing the need for further research related to the COVID-19 pandemic. Additional information is warranted to compare the impact of the pandemic period among BD people against pre-pandemic records, the general population, and other severe mental illnesses, namely people with schizophrenia or major depressive disorder, to inform the public health and the delivery of patient-tailored interventions.
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http://dx.doi.org/10.1016/j.jad.2021.08.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416293PMC
September 2021

Implications of the COVID-19 pandemic for people with bipolar disorders: A scoping review.

J Affect Disord 2021 Sep 4;295:740-751. Epub 2021 Sep 4.

IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. Electronic address:

Introduction: The COVID-19 (coronavirus disease 2019)-related pandemic represents a global source of societal and health burden. Yet, the impact of the pandemic on people with severe mental illness, including bipolar disorder (BD), remains unclear, warranting scoping review on the matter.

Methods: The MEDLINE and EMBASE databases were systematically searched from inception up to April 24, 2021, adopting broad inclusion criteria to assess a variety of clinical and public health themes related to people with a primary diagnosis of BD during the COVID-19 pandemics. The present work complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) registered in the Open Science Framework (OSF) repository (https://osf.io/7evpx/).

Results: Fourteen papers informed the present scoping review. Four major themes were identified: (i) impact of COVID-19-related stressors on BD; (ii) impact of COVID-19 on mental health service utilization among people with BD; (iii) impact of BD on the risk of acquiring SARS-CoV-2 infection; (iv) engagement in preventative behaviors among people with BD. Additional themes warranting further research were nonetheless detected.

Limitations: Further original studies are needed.

Conclusion: The present study confirmed the high-vulnerability hypothesis concerning people with BD versus the general population, reinforcing the need for further research related to the COVID-19 pandemic. Additional information is warranted to compare the impact of the pandemic period among BD people against pre-pandemic records, the general population, and other severe mental illnesses, namely people with schizophrenia or major depressive disorder, to inform the public health and the delivery of patient-tailored interventions.
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http://dx.doi.org/10.1016/j.jad.2021.08.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416293PMC
September 2021

Anticonvulsant use and fracture: a case-control study.

J Musculoskelet Neuronal Interact 2021 09;21(3):422-428

Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, Geelong, Australia.

Objectives: We aimed to investigate fracture risk associated with anticonvulsant use in a population-based sample of men and women.

Methods: Data from 1,458 participants (51.8% women) with a radiologically confirmed incident fracture (cases) were compared to 1,796 participants (46.5% women) without fracture (controls). Lifestyle factors, medication use and medical history were self-reported. Associations between anticonvulsant use and fracture were explored using binary logistic regression following adjustment for confounders.

Results: In men, fracture cases and controls differed in age, smoking history, education, alcohol use, and gonadal hormone supplementation. In women, fracture cases and controls differed by previous fracture history, alcohol use, physical activity levels and use of anti-fracture agents. After adjustment for age, pooled anticonvulsant use was associated with a 3.4-fold higher risk of fracture in men and a 1.8-fold higher risk in women. Following further adjustments for confounders these patterns persisted; a 2.8-fold higher fracture risk in men and a 1.8-fold higher fracture risk in women.

Conclusions: Anticonvulsant use was associated with increased fracture risk, independent of demographic, lifestyle, medical and medication related factors. While further studies exploring potential underlying mechanisms are warranted, regular monitoring of bone health in anticonvulsant users with risk factors may be useful.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426646PMC
September 2021

Baseline serum amino acid levels predict treatment response to augmentation with N-acetylcysteine (NAC) in a bipolar disorder randomised trial.

J Psychiatr Res 2021 Oct 21;142:376-383. Epub 2021 Aug 21.

IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia. Electronic address:

N-acetylcysteine (NAC) acts on glutamatergic and redox systems, two systems implicated in the pathophysiology of bipolar disorder (BD). This has led to the investigation of NAC as a potential candidate for the treatment of BD. The aim of this study was to investigate metabolomic markers to identify predictors of NAC response in a cohort of BD participants. This study is a secondary analysis of a 16-week, multi-site, randomized, double-blinded, parallel-group, placebo-controlled trial in BD participants with a current acute depressive episode. This study included trial participants who received either NAC 2000 mg/day, or placebo. Participants (NAC: n = 31, placebo: n = 29) were assessed at baseline and week 16 using the Montgomery Åsberg Depression Rating Scale (MADRS) and were dichotomised into "responders" (MADRS at week 16 < 50% of MADRS at baseline) and "non-responders" (MADRS at week 16 > 50% at baseline). Untargeted gas chromatography-mass spectrometry analysis was performed to analyse baseline levels of 68 serum metabolites. Of the nine metabolites that differentiated placebo and NAC groups, five were amino acids with lower levels in the NAC responder group compared with the NAC non-responders. Further analysis generated a predictive model of MADRS improvement including glycine, norleucine, threonine, proline, phenylalanine, tyrosine, glutamic acid, lysine and leucine (R = 0.853; adjusted R = 0.733). This prediction model predicted 85% of the variance in MADRS outcome after adjunctive treatment with NAC. BD participants with lower serum levels of free amino acids at baseline may be more likely to respond to adjunctive treatment with NAC.
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http://dx.doi.org/10.1016/j.jpsychires.2021.08.034DOI Listing
October 2021

A protocol for the first episode psychosis outcome study (FEPOS): ≥15 year follow-up after treatment at the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia.

Early Interv Psychiatry 2021 Aug 20. Epub 2021 Aug 20.

Orygen, Parkville, Victoria, Australia.

Background: Specialist early intervention (SEI) service models are designed to treat symptoms, promote social and vocational recovery, prevent relapse, and resource and up-skill patients and their families. The benefits of SEI over the first few years have been demonstrated. While early recovery can be expected to translate to better long-term outcomes by analogy with other illnesses, there is limited evidence to support this from follow-up studies. The current study involves the long-term follow-up of a sub-set of first episode psychosis (FEP) patients, with a range of diagnoses, who were first treated at Orygen's Early Psychosis Prevention and Intervention Centre (EPPIC) between 1998 and 2000. The aim of this paper is to present the methodology for this follow-up study.

Methods: Between January 1998 and December 2000, 786 patients between the ages of 15-29 years were treated at EPPIC, located in Melbourne, Australia. Our cohort consists of 661 people (82 were transferred/discharged and 43 were not diagnosed with a psychotic disorder at time of discharge). The 18-month treatment characteristics of this cohort have been extensively examined in the First Episode Psychosis Outcome Study (FEPOS). The ≥15 year outcomes of this cohort are being examined in this study, known as FEPOS15.

Results: Participant follow-up is ongoing. In order to extend and assess broader outcomes of the cohort, data linkage with health-related databases will be conducted.

Conclusion: This study will provide a comprehensive evaluation of the long-term trajectory of psychotic disorders after treatment for FEP in a SEI service.
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http://dx.doi.org/10.1111/eip.13204DOI Listing
August 2021

Gender, age at onset, and duration of being ill as predictors for the long-term course and outcome of schizophrenia: an international multicenter study.

CNS Spectr 2021 Aug 9:1-8. Epub 2021 Aug 9.

Department of Psychiatry, National and Kapodistrian University of Athens School of Medicine, Eginition Hospital, Athens, Greece.

Background: The aim of the current study was to explore the effect of gender, age at onset, and duration on the long-term course of schizophrenia.

Methods: Twenty-nine centers from 25 countries representing all continents participated in the study that included 2358 patients aged 37.21 ± 11.87 years with a DSM-IV or DSM-5 diagnosis of schizophrenia; the Positive and Negative Syndrome Scale as well as relevant clinicodemographic data were gathered. Analysis of variance and analysis of covariance were used, and the methodology corrected for the presence of potentially confounding effects.

Results: There was a 3-year later age at onset for females (P < .001) and lower rates of negative symptoms (P < .01) and higher depression/anxiety measures (P < .05) at some stages. The age at onset manifested a distribution with a single peak for both genders with a tendency of patients with younger onset having slower advancement through illness stages (P = .001). No significant effects were found concerning duration of illness.

Discussion: Our results confirmed a later onset and a possibly more benign course and outcome in females. Age at onset manifested a single peak in both genders, and surprisingly, earlier onset was related to a slower progression of the illness. No effect of duration has been detected. These results are partially in accord with the literature, but they also differ as a consequence of the different starting point of our methodology (a novel staging model), which in our opinion precluded the impact of confounding effects. Future research should focus on the therapeutic policy and implications of these results in more representative samples.
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http://dx.doi.org/10.1017/S1092852921000742DOI Listing
August 2021

Mood Regulatory Actions of Active and Sham Nucleus Accumbens Deep Brain Stimulation in Antidepressant Resistant Rats.

Front Hum Neurosci 2021 19;15:644921. Epub 2021 Jul 19.

Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States.

The antidepressant actions of deep brain stimulation (DBS) are associated with progressive neuroadaptations within the mood network, modulated in part, by neurotrophic mechanisms. We investigated the antidepressant-like effects of chronic nucleus accumbens (NAc) DBS and its association with change in glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR) expression in the infralimbic cortex (IL), and the dorsal (dHIP) and ventral (vHIP) subregions of the hippocampus of antidepressant resistant rats. Antidepressant resistance was induced via daily injection of adrenocorticotropic hormone (ACTH; 100 μg/day; 15 days) and confirmed by non-response to tricyclic antidepressant treatment (imipramine, 10 mg/kg). Portable microdevices provided continuous bilateral NAc DBS (130 Hz, 200 μA, 90 μs) for 7 days. A control sham electrode group was included, together with ACTH- and saline-treated control groups. Home cage monitoring, open field, sucrose preference, and, forced swim behavioral tests were performed. Post-mortem levels of GSK3 and mTOR, total and phosphorylated, were determined with Western blot. As previously reported, ACTH treatment blocked the immobility-reducing effects of imipramine in the forced swim test. In contrast, treatment with either active DBS or sham electrode placement in the NAc significantly reduced forced swim immobility time in ACTH-treated animals. This was associated with increased homecage activity in the DBS and sham groups relative to ACTH and saline groups, however, no differences in locomotor activity were observed in the open field test, nor were any group differences seen for sucrose consumption across groups. The antidepressant-like actions of NAc DBS and sham electrode placements were associated with an increase in levels of IL and vHIP phospho-GSK3β and phospho-mTOR, however, no differences in these protein levels were observed in the dHIP region. These data suggest that early response to electrode placement in the NAc, irrespective of whether active DBS or sham, has antidepressant-like effects in the ACTH-model of antidepressant resistance associated with distal upregulation of phospho-GSK3β and phospho-mTOR in the IL and vHIP regions of the mood network.
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http://dx.doi.org/10.3389/fnhum.2021.644921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326323PMC
July 2021

Diabetes and mood disorders: shared mechanisms and therapeutic opportunities.

Int J Psychiatry Clin Pract 2021 Aug 4:1-13. Epub 2021 Aug 4.

Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX, USA.

Objective: The objective of this manuscript is to provide a comprehensive and critical overview of the current evidence on the association between Diabetes mellitus (DM) and mood disorders [i.e., Major depressive disorder (MDD) and bipolar disorder (BD)], and therapeutic opportunities.

Methods: We searched in MEDLINE (via Ovid) for placebo-controlled clinical trials published in the last 20 years that assessed drug repurposing approaches for the treatment of DM or mood disorders.

Results: We found seven studies that aimed to verify the effects of antidepressants in patients diagnosed with DM, and eight studies that tested the effect of antidiabetic drugs in patients diagnosed with MDD or BD. Most studies published in the last two decades did not report a positive effect of antidepressants on glycemic control in patients with DM. On the other hand, antidiabetic drugs seem to have a positive effect on the treatment of MDD and BD.

Conclusions: While effect of antidepressants on glycemic control in patients with DM is still controversial, the use of antidiabetic drugs may be a promising strategy for patients with MDD or BD. Prospective studies are still needed.Key pointsMood disorders in patients with DM affect glycemic control, potentially increasing mortality risk.The effect of antidepressants on glycemic control in patients with DM is still controversial. The coexistence of complicated DM and a mood disorders would require a careful, individualised, and comprehensive evaluation.Insulin resistance may increase the risk of depressive symptoms and is associated with worse outcomes in BD.The use antidiabetic drugs may be a promising strategy for patients with MDD or BD. However, prospective trials are needed to prove a potential antidepressant activity of antidiabetic drugs.
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http://dx.doi.org/10.1080/13651501.2021.1957117DOI Listing
August 2021

Peripheral levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability.

Brain Behav Immun 2021 10 28;97:193-203. Epub 2021 Jul 28.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, 75 Pigdon's Road, Waurn Ponds, Geelong, VIC 3216, Australia. Electronic address:

Importance: It is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls.

Objective: To run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity.

Data Sources: Systematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.

Study Selection: Case-control studies reporting inflammatory mediators' levels in BD and controls.

Data Extraction And Synthesis: Summary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge's g).

Main Outcomes And Measures: Co-primary outcomes were inflammatory mediators' levels (Hedge's g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls.

Results: Out of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31-1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46-1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19-0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI -0.68-0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.

Conclusions And Relevance: Peripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.
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http://dx.doi.org/10.1016/j.bbi.2021.07.014DOI Listing
October 2021

Not in education, employment and training status in the early stages of bipolar I disorder with psychotic features.

Early Interv Psychiatry 2021 Jul 27. Epub 2021 Jul 27.

Treatment and Early Intervention in Psychosis Program (TIPP), Departement de Psychiatrie CHUV, Université de Lausanne, Prilly, Switzerland.

Objective: There is a lack of existing research regarding young people with bipolar I disorder (BD-I) and psychotic features, who are not in education, employment, and training (NEET). Thus, the aims of the study were to: (a) establish rates of NEET at service entry to a specialist early intervention service; (b) delineate premorbid and current variables associated with NEET status at service entry and (c) examine correlates of NEET status at discharge.

Method: Medical file audit methodology was utilized to collect information on 118 patients with first episode psychotic mania treated at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. NEET status was determined using the modified vocation status index (MVCI). Bivariate and multivariable logistic variables were used to examine relationships between premorbid, service entry and treatment variables, and NEET status at service entry and discharge.

Results: The NEET rate was 33.9% at service entry, and 39.2% at discharge. Variables associated with NEET status at service entry were premorbid functioning and polysubstance use. NEET status at service entry was the only significant correlate of NEET status at discharge. When service entry NEET was taken out of the model, substance use during treatment was predictive of NEET status at discharge.

Conclusions: NEET status at service entry was related to a history of premorbid decline, and risk factors such as substance use and forensic issues. NEET status can decline during treatment, and utility of vocational intervention programs specifically for BD, in addition to specialist early intervention, needs to be examined.
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http://dx.doi.org/10.1111/eip.13203DOI Listing
July 2021

N-acetylcysteine (NAC) for methamphetamine dependence: A randomised controlled trial.

EClinicalMedicine 2021 Aug 13;38:101005. Epub 2021 Jul 13.

Deakin University, School of Medicine, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Geelong, Australia.

Background: Methamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence.

Methods: A parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400 mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were  < 0.025 for primary outcomes and  < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257.

Results: Participants ( = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo ( = 77) or NAC ( = 76). Both groups had a median (IQR) of 24 (15-28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean [SE] reduction of 7.3 [1.2]) days for placebo, 6.8 [1.2] for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4-4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6-7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or psychotic symptoms relative to placebo. Adverse events did not differ significantly between placebo and NAC groups.

Interpretation: These findings suggest that take-home oral NAC has no significant effect on methamphetamine use or most clinically related outcomes amongst people who are dependent on the drug.
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http://dx.doi.org/10.1016/j.eclinm.2021.101005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283342PMC
August 2021

Why do medications with little or no efficacy continue to be prescribed in the management of patients with bipolar disorder?

Bipolar Disord 2021 Sep 23;23(6):541-543. Epub 2021 Jul 23.

Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada.

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http://dx.doi.org/10.1111/bdi.13114DOI Listing
September 2021

The Role of Mitochondria in Mood Disorders: From Physiology to Pathophysiology and to Treatment.

Front Psychiatry 2021 6;12:546801. Epub 2021 Jul 6.

School of Medicine, The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Barwon Health, Geelong, VIC, Australia.

Mitochondria are cellular organelles involved in several biological processes, especially in energy production. Several studies have found a relationship between mitochondrial dysfunction and mood disorders, such as major depressive disorder and bipolar disorder. Impairments in energy production are found in these disorders together with higher levels of oxidative stress. Recently, many agents capable of enhancing antioxidant defenses or mitochondrial functioning have been studied for the treatment of mood disorders as adjuvant therapy to current pharmacological treatments. A better knowledge of mitochondrial physiology and pathophysiology might allow the identification of new therapeutic targets and the development and study of novel effective therapies to treat these specific mitochondrial impairments. This could be especially beneficial for treatment-resistant patients. In this article, we provide a focused narrative review of the currently available evidence supporting the involvement of mitochondrial dysfunction in mood disorders, the effects of current therapies on mitochondrial functions, and novel targeted therapies acting on mitochondrial pathways that might be useful for the treatment of mood disorders.
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http://dx.doi.org/10.3389/fpsyt.2021.546801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291901PMC
July 2021

Cocaine-Induced Changes in Tonic Dopamine Concentrations Measured Using Multiple-Cyclic Square Wave Voltammetry .

Front Pharmacol 2021 6;12:705254. Epub 2021 Jul 6.

Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States.

For over 40 years, microdialysis techniques have been at the forefront in measuring the effects of illicit substances on brain tonic extracellular levels of dopamine that underlie many aspects of drug addiction. However, the size of microdialysis probes and sampling rate may limit this technique's ability to provide an accurate assessment of drug effects in microneural environments. A novel electrochemical method known as multiple-cyclic square wave voltammetry (M-CSWV), was recently developed to measure second-to-second changes in tonic dopamine levels at microelectrodes, providing spatiotemporal resolution superior to microdialysis. Here, we utilized M-CSWV and fast-scan cyclic voltammetry (FSCV) to measure changes in tonic or phasic dopamine release in the nucleus accumbens core (NAcc) after acute cocaine administration. Carbon-fiber microelectrodes (CFM) and stimulating electrodes were implanted into the NAcc and medial forebrain bundle (MFB) of urethane anesthetized (1.5 g/kg i.p.) Sprague-Dawley rats, respectively. Using FSCV, depths of each electrode were optimized by determining maximal MFB electrical stimulation-evoked phasic dopamine release. Changes in phasic responses were measured after a single dose of intravenous saline or cocaine hydrochloride (3 mg/kg; = 4). In a separate group, changes in tonic dopamine levels were measured using M-CSWV after intravenous saline and after cocaine hydrochloride (3 mg/kg; = 5). Both the phasic and tonic dopamine responses in the NAcc were augmented by the injection of cocaine compared to saline control. The phasic and tonic levels changed by approximately x2.4 and x1.9, respectively. These increases were largely consistent with previous studies using FSCV and microdialysis. However, the minimal disruption/disturbance of neuronal tissue by the CFM may explain why the baseline tonic dopamine values (134 ± 32 nM) measured by M-CSWV were found to be 10-fold higher when compared to conventional microdialysis. In this study, we demonstrated phasic dopamine dynamics in the NAcc with acute cocaine administration. M-CSWV was able to record rapid changes in tonic levels of dopamine, which cannot be achieved with other current voltammetric techniques. Taken together, M-CSWV has the potential to provide an unprecedented level of physiologic insight into dopamine signaling, both and , which will significantly enhance our understanding of neurochemical mechanisms underlying psychiatric conditions.
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http://dx.doi.org/10.3389/fphar.2021.705254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290896PMC
July 2021

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia.

Int J Mol Sci 2021 Jul 2;22(13). Epub 2021 Jul 2.

Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, IMPACT, Geelong 3220, Australia.

Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.
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http://dx.doi.org/10.3390/ijms22137164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268913PMC
July 2021

Lithium therapy and weight change in people with bipolar disorder: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2021 Jul 13. Epub 2021 Jul 13.

Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel St, 12-0, 08036, Barcelona, Spain.

Lithium remains the gold standard maintenance treatment for Bipolar Disorder (BD). However, weight gain is a side effect of increasing relevance due to its metabolic implications. We conducted a systematic review and meta-analysis aimed at summarizing evidence on the use of lithium and weight change in BD. We followed the PRISMA methodology, searching Pubmed, Scopus and Web of Science. From 1003 screened references, 20 studies were included in the systematic review and 9 included in the meta-analysis. In line with the studies included in the systematic review, the meta-analysis revealed that weight gain with lithium was not significant, noting a weight increase of 0.462 Kg (p = 0158). A shorter duration of treatment was significantly associated with more weight gain. Compared to placebo, there were no significant differences in weight gain. Weight gain was significantly lower with lithium than with active comparators. This work reveals a low impact of lithium on weight change, especially compared to some of the most widely used active comparators. Our results could impact clinical decisions.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.011DOI Listing
July 2021

Statins: Neurobiological underpinnings and mechanisms in mood disorders.

Neurosci Biobehav Rev 2021 09 13;128:693-708. Epub 2021 Jul 13.

Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, VIC, Australia; Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia; Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia. Electronic address:

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.012DOI Listing
September 2021

A proof-of-concept study of maternal immune activation mediated induction of Toll-like receptor (TLR) and inflammasome pathways leading to neuroprogressive changes and schizophrenia-like behaviours in offspring.

Eur Neuropsychopharmacol 2021 Jul 11;52:48-61. Epub 2021 Jul 11.

Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India. Electronic address:

Infection, particularly prenatal infection, leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes that drive prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviours through activation of TLR and inflammasome pathways in the brain of offspring. Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-6, TNF-α and IL-17A assessed after 24 hours were observed in both the poly (I:C) and LPS-treated rats, while IL-1β was only elevated in LPS-treated rats, indicating MIA. The offspring of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviours, deficits in social behaviours and prepulse inhibition. The hippocampus of offspring rats showed increased expression of Tlr3, Tlr4, Nlrp3, Il1b, and Il18 of poly (I:C) and Tlr4, Nlrp3, Cas1, Il1b, and Il18 of LPS-treated dams. Furthermore, Tlr and inflammasome genes were associated with social deficits and impaired prepulse inhibition in offspring rats. The results suggest that MIA due to prenatal infection can trigger TLR and inflammasome pathways and enhances the risk of schizophrenia-like behaviours in the later stages of life of the offspring.
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http://dx.doi.org/10.1016/j.euroneuro.2021.06.009DOI Listing
July 2021

Cognitive Profile and Relationship with Quality of Life and Psychosocial Functioning in Mood Disorders.

Arch Clin Neuropsychol 2021 Jul 13. Epub 2021 Jul 13.

Londrina State University, Health Sciences Graduate Program, Londrina, Brazil.

Background: Comparisons between healthy controls (HCs) and individuals with mood disorders have shown more cognitive dysfunction among the latter group, in particular in bipolar disorder (BD). This study aimed to characterize the pattern of cognitive function of BD and major depressive disorder (MDD) and compare them to HC using the (CogState Research Battery) CSRB™.

Method: Participants were tested, comprising the following domains: processing speed, attention, working memory, visual memory, executive functions, and verbal memory. Quality of life and functionality were also assessed. Multiple linear regression models were performed to examine the effect of demographic characteristics and functionality on cognitive outcomes separately for BD and MDD.

Results: Ninety individuals participated in the study, of which 32 had BD, 30 had MDD, and 28 were HC. Differences were found between both BD and MDD and HC for the composite cognitive score, with significant differences between BD and HC (Diff = -5.5, 95% CI = [-9.5, -1.5], p = 0.005), and MDD and HC (Diff = -4.6, 95% CI = [-8.6, -0.5], p = 0.025). There were overall significant differences in five cognitive domains: processing speed (p = 0.001 and p = 0.004), attention (p = 0.002), working memory (p = 0.02), visual memory (p = 0.021), and verbal memory (p = 0.007). BD also presented worse performance than both MDD and HC, and MDD presented better performance than BD but worse than HC in quality of life and functionality. Multiple linear regression models were significative for education (p < 0.001) and age (p = 0.004) for BD and education (p < 0.001) for MDD.

Conclusion: In general, cognition is more affected in BD than MDD, which could be associated with functional and quality of life impairment.
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http://dx.doi.org/10.1093/arclin/acab054DOI Listing
July 2021

Social isolation, social support and loneliness as independent concepts, and their relationship with health-related quality of life among older women.

Aging Ment Health 2021 Jul 5:1-10. Epub 2021 Jul 5.

Research Centre for Generational Health and Ageing, University of Newcastle, Newcastle, Australia.

To assess whether social isolation, social support, and loneliness are independently associated with health-related quality of life (HRQoL). Retrospective analysis including 10,517 women aged 70-75 years from the Australian Longitudinal Study on Women's Health (ALSWH). Social isolation, social support (Duke Social Support Index), and loneliness (single item) were investigated for their association with standardised HRQoL (physical [PCS] and mental [MCS] components of the SF-36® questionnaire). Analyses were adjusted for sociodemographic variables and number of medical conditions. Only 3% reported being socially isolated, having low social support and being lonely, and 34% reported being not socially isolated, high social support and not being lonely. Each construct was independently associated with HRQoL, with loneliness having the strongest inverse association (PCS: isolation -0.98, low support -2.01, loneliness -2.03; MCS: isolation -1.97, low support -4.79, loneliness -10.20; p-value < 0.001 for each). Women who were not isolated or lonely and with high social support had the greatest HRQoL (compared to isolated, low social support and lonely; MCS: 17 to 18 points higher, PCS: 5 to 8 points higher). Other combinations of social isolation, social support and loneliness varied in their associations with HRQoL. Ageing populations face the challenge of supporting older people to maintain longer, healthy, meaningful and community-dwelling lives. Among older women, social isolation, low social support and loneliness are distinct, partially overlapping yet interconnected concepts that coexist and are each adversely associated with HRQoL. Findings should be replicated in other cohorts to ensure generalisability across other age groups and men.
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http://dx.doi.org/10.1080/13607863.2021.1940097DOI Listing
July 2021

The Effect of Adjunctive Mangosteen Pericarp on Cognition in People With Schizophrenia: Secondary Analysis of a Randomized Controlled Trial.

Front Psychiatry 2021 15;12:626486. Epub 2021 Jun 15.

Deakin University, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Geelong, VIC, Australia.

Cognitive impairment is prevalent and often highly burdensome in people with schizophrenia. The aim of this study was to investigate if mangosteen ( Linn.) pericarp extract may be an effective intervention to improve cognitive performance in this population. This was a secondary analysis of a larger randomized placebo-controlled trial that investigated a 24-weeks intervention of mangosteen pericarp extract supplementation in people diagnosed with schizophrenia. A subset of = 114 participants with completed cognitive outcomes at follow up were included in this analysis. Using the Cogstate Brief Battery, the following cognitive outcomes were assessed: psychomotor function, attention, visual learning and memory (visual and working). Subgroup analyses investigated whether baseline clinical parameters (baseline cognitive functioning, illness severity and duration, depressive symptoms) moderated the relationship between mangosteen pericarp extract intervention and change in cognitive outcomes. There were no significant between-group changes in any cognitive outcomes assessed. Subgroup analysis based on baseline cognition and clinical characteristics did not reveal any significant between-group difference in change. Mangosteen pericarp extract did not affect cognitive outcomes in people with schizophrenia. Further investigation regarding optimal dosing strategies for mangosteen interventions and the testing of additional cognitive domains may be warranted. ANZCTR.org.au identifier: ACTRN12616000859482, registered 30 June 3 2016.
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http://dx.doi.org/10.3389/fpsyt.2021.626486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239132PMC
June 2021

Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

Bipolar Disord 2021 Jun 26. Epub 2021 Jun 26.

St. Joseph's Healthcare Hamilton McMaster University, Hamilton, ON, Canada.

Objectives: Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking.

Methods: Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders.

Results: Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed.

Conclusion: The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.
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http://dx.doi.org/10.1111/bdi.13105DOI Listing
June 2021

Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study.

CNS Spectr 2021 Jun 21:1-10. Epub 2021 Jun 21.

The Melbourne Clinic, Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia.

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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http://dx.doi.org/10.1017/S1092852921000638DOI Listing
June 2021

The endocannabinoidome in neuropsychiatry: Opportunities and potential risks.

Pharmacol Res 2021 08 11;170:105729. Epub 2021 Jun 11.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia. Electronic address:

The endocannabinoid system (ECS) comprises two cognate endocannabinoid receptors referred to as CB1R and CB2R ECS dysregulation is apparent in neurodegenerative/neuro-psychiatric disorders including but not limited to schizophrenia, major depressive disorder and potentially bipolar disorder. The aim of this paper is to review mechanisms whereby both receptors may interact with neuro-immune and neuro-oxidative pathways, which play a pathophysiological role in these disorders. CB1R is located in the presynaptic terminals of GABAergic, glutamatergic, cholinergic, noradrenergic and serotonergic neurons where it regulates the retrograde suppression of neurotransmission. CB1R plays a key role in long-term depression, and, to a lesser extent, long-term potentiation, thereby modulating synaptic transmission and mediating learning and memory. Optimal CB1R activity plays an essential neuroprotective role by providing a defense against the development of glutamate-mediated excitotoxicity, which is achieved, at least in part, by impeding AMPA-mediated increase in intracellular calcium overload and oxidative stress. Moreover, CB1R activity enables optimal neuron-glial communication and the function of the neurovascular unit. CB2R receptors are detected in peripheral immune cells and also in central nervous system regions including the striatum, basal ganglia, frontal cortex, hippocampus, amygdala as well as the ventral tegmental area. CB2R upregulation inhibits the presynaptic release of glutamate in several brain regions. CB2R activation also decreases neuroinflammation partly by mediating the transition from a predominantly neurotoxic "M1" microglial phenotype to a more neuroprotective "M2" phenotype. CB1R and CB2R are thus novel drug targets for the treatment of neuro-immune and neuro-oxidative disorders including schizophrenia and affective disorders.
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http://dx.doi.org/10.1016/j.phrs.2021.105729DOI Listing
August 2021

The lipid paradox in neuroprogressive disorders: Causes and consequences.

Neurosci Biobehav Rev 2021 09 9;128:35-57. Epub 2021 Jun 9.

C.A.R., Cambridge, UK. Electronic address:

Chronic systemic inflammation is associated with an increased risk of cardiovascular disease in an environment of low low-density lipoprotein (LDL) and low total cholesterol and with the pathophysiology of neuroprogressive disorders. The causes and consequences of this lipid paradox are explored. Circulating activated neutrophils can release inflammatory molecules such as myeloperoxidase and the pro-inflammatory cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. Since activated neutrophils are associated with atherosclerosis and cardiovascular disease and with major depressive disorder, bipolar disorder and schizophrenia, it seems reasonable to hypothesise that the inflammatory molecules released by them may act as mediators of the link between systemic inflammation and the development of atherosclerosis in neuroprogressive disorders. This hypothesis is tested by considering the association at a molecular level of systemic inflammation with increased LDL oxidation; increased small dense LDL levels; increased lipoprotein (a) concentration; secretory phospholipase A activation; cytosolic phospholipase A activation; increased platelet activation; decreased apolipoprotein A1 levels and function; decreased paroxonase-1 activity; hyperhomocysteinaemia; and metabolic endotoxaemia. These molecular mechanisms suggest potential therapeutic targets.
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http://dx.doi.org/10.1016/j.neubiorev.2021.06.017DOI Listing
September 2021

Hospital-in-the-Home as a Model for Mental Health Care Delivery: A Narrative Review.

Psychiatr Serv 2021 Jun 9:appips202000763. Epub 2021 Jun 9.

Barwon Health, Geelong, Victoria, Australia.

Objective: Hospital-in-the-home (HITH) is a service model widely adopted in medical specialties to help alleviate pressure on the availability of inpatient beds and allow patients to receive acute care in familiar surroundings. To date, such models are not widely utilized in mental health care. The authors review existing HITH-type mental health services, focusing on the domains of design, implementation, and outcomes.

Methods: An electronic database search was conducted of MEDLINE, PsycINFO, CINAHL, Embase, Scopus, Web of Science, and Google Scholar. Fifty-six studies were eligible for inclusion in this review. Because of heterogeneous methods and outcome reporting in the available research, a narrative approach was used to highlight key themes in the literature.

Results: Mental health HITH services exist under a wide range of names with differing theoretical origins and governance structures. Common characteristics and functions are summarized. The authors found moderate evidence for a reduced number and length of hospital admissions as a result of mental health HITH programs. HITH is likely to be cost-effective because of these effects. Limited evidence exists for clinical measures, consumer satisfaction, and effects on caregivers and staff.

Conclusions: Mental health HITH services are an effective alternative to inpatient admission for certain consumers. The authors propose a definition of HITH as any service intended to provide inpatient-comparable mental health care in the home instead of the hospital. Standardized studies are needed for systematic analysis of key HITH outcomes.
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http://dx.doi.org/10.1176/appi.ps.202000763DOI Listing
June 2021
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