Publications by authors named "Andre F Carvalho"

399 Publications

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
September 2021

Risk and protective factors for mental disorders beyond genetics: an evidence-based atlas.

World Psychiatry 2021 Oct;20(3):417-436

Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer-tain. We conducted a "meta-umbrella" systematic synthesis of umbrella reviews, which are systematic reviews of meta-analyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on non-purely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convincing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of meta-analyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 meta-analyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social contacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For non-organic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or four-five (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention-deficit/hyperactivity disorder (ADHD), they were maternal pre-pregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer's disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class I-III risk/protective factors were mostly involved in the early neurodevelopmental period. The evidence-based atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expanding early intervention and preventive strategies for mental disorders.
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http://dx.doi.org/10.1002/wps.20894DOI Listing
October 2021

The growing field of digital psychiatry: current evidence and the future of apps, social media, chatbots, and virtual reality.

World Psychiatry 2021 Oct;20(3):318-335

Division of Psychology and Mental Health, University of Manchester, Manchester, UK.

As the COVID-19 pandemic has largely increased the utilization of telehealth, mobile mental health technologies - such as smartphone apps, vir-tual reality, chatbots, and social media - have also gained attention. These digital health technologies offer the potential of accessible and scalable interventions that can augment traditional care. In this paper, we provide a comprehensive update on the overall field of digital psychiatry, covering three areas. First, we outline the relevance of recent technological advances to mental health research and care, by detailing how smartphones, social media, artificial intelligence and virtual reality present new opportunities for "digital phenotyping" and remote intervention. Second, we review the current evidence for the use of these new technological approaches across different mental health contexts, covering their emerging efficacy in self-management of psychological well-being and early intervention, along with more nascent research supporting their use in clinical management of long-term psychiatric conditions - including major depression; anxiety, bipolar and psychotic disorders; and eating and substance use disorders - as well as in child and adolescent mental health care. Third, we discuss the most pressing challenges and opportunities towards real-world implementation, using the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework to explain how the innovations themselves, the recipients of these innovations, and the context surrounding innovations all must be considered to facilitate their adoption and use in mental health care systems. We conclude that the new technological capabilities of smartphones, artificial intelligence, social media and virtual reality are already changing mental health care in unforeseen and exciting ways, each accompanied by an early but promising evidence base. We point out that further efforts towards strengthening implementation are needed, and detail the key issues at the patient, provider and policy levels which must now be addressed for digital health technologies to truly improve mental health research and treatment in the future.
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http://dx.doi.org/10.1002/wps.20883DOI Listing
October 2021

Association of pharmacological prophylaxis with the risk of pediatric emergence delirium after sevoflurane anesthesia: An updated network meta-analysis.

J Clin Anesth 2021 Sep 1;75:110488. Epub 2021 Sep 1.

Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan. Electronic address:

Study Objective: This updated network meta-analysis aims at exploring whether the concurrent use of midazolam or antiemetics may enhance the efficacy of other pharmacological regimens for delirium prophylaxis in pediatric population after general anesthesia (GA).

Design: Network meta-analysis (PROSPERO registration: CRD42020179483).

Setting: Postoperative recovery area.

Patients: Pediatric patients undergoing GA with sevoflurane.

Interventions: Pharmacological interventions applied during GA with sevoflurane.

Measurements: This network meta-analysis of randomized controlled trials (RCTs) was conducted with a frequentist model. PubMed, Embase, ProQuest, ScienceDirect, Cochrane CENTRAL, ClinicalKey, Web of Science, and ClinicalTrials.gov were searched from their inception dates to April 12, 2020, for RCTs of either placebo-controlled or active-controlled design containing information on the incidence of emergence delirium in pediatric patients undergoing sevoflurane anesthesia.

Main Results: Seventy studies comprising 6904 participants were included for the analysis of 30 pharmacological interventions. Based on surface under the cumulative ranking curve (SUCRA) analysis, midazolam was ranked the lowest in therapeutic effect (SUCRA: 20%), while antiemetics as a monotherapy had no effect on delirium prophylaxis. However, there was a trend that most combination therapies with midazolam or antiemetics were superior to monotherapies for delirium prophylaxis. Subgroup analyses based on age (i.e., ≤7 years) and a validated scoring system (i.e., the Pediatric Anesthesia Emergence Delirium scale) for delirium also suggested a better efficacy of combination therapies than monotherapies. Overall, combination therapies with midazolam or antiemetics did not have a negative impact on the incidence of postoperative nausea and vomiting, length of stay in the postanesthesia care unit, or time to extubation. The dexmedetomidine-midazolam-antiemetic combination was the most effective strategy for the prevention of emergence delirium.

Conclusions: This network meta-analysis suggested that the incorporation of midazolam or antiemetics as adjuncts for combination therapies may have synergistic effects against pediatric postoperative emergence delirium. Future large-scale placebo-controlled RCTs are warranted to validate our findings.
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http://dx.doi.org/10.1016/j.jclinane.2021.110488DOI Listing
September 2021

The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics.

Braz J Psychiatry 2021 Aug 30. Epub 2021 Aug 30.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Social anxiety disorder (SAD) is a highly prevalent psychiatric disorder that presents with an early age of onset, chronic disease course, and increased risk of psychiatric comorbidity. Current treatment options for SAD are associated with low response rates, suboptimal efficacy, and possible risk of adverse effects. Investigation of new neurobiological mechanisms may aid in the identification of more specific therapeutic targets for the treatment of this disorder. Emerging evidence suggests that the endogenous cannabinoid system, also referred to as the endocannabinoid system (ECS), could play a potential role in the pathophysiology of SAD. This review discusses the known pathophysiological mechanisms of SAD, the potential role of the ECS in this disorder, current drugs targeting the ECS, and the potential of these novel compounds to enhance the therapeutic armamentarium for SAD. Further investigational efforts, specifically in human populations, are warranted to improve our knowledge of the ECS in SAD.
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http://dx.doi.org/10.1590/1516-4446-2021-1926DOI Listing
August 2021

Efficacy of non-invasive brain stimulation interventions in reducing smoking frequency in patients with nicotine dependence: a systematic review and network meta-analysis of randomized controlled trials.

Addiction 2021 Aug 4. Epub 2021 Aug 4.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.

Background And Aims: Nicotine is a highly addictive substance in tobacco products that dysregulates several neurotransmitters in the brain and impairs executive function. Non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are promising treatments for nicotine dependence. We investigated the efficacy and acceptability of NIBS in managing smoking cessation through a systematic review and network meta-analysis (NMA).

Methods: We conducted a systematic review to identify randomized controlled trials (RCTs) that investigated the efficacy of NIBS for smoking cessation. All pairwise meta-analyses and NMA procedures were conducted using random-effects and frequentist models. The co-primary outcomes were (1) the change in number of cigarettes smoked per day (change in frequency of smoking) in patients with nicotine dependence after NIBS and (2) acceptability (the dropout rate). The effect sizes for co-primary outcomes of change in frequency of smoking and acceptability were assessed according to standardized mean difference (SMD) and odds ratio, respectively.

Results: Twelve RCTs with 710 participants (mean age: 44.2 years, 31.2% female) were included. Compared with the sham control, 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) was associated with the largest changes in smoking frequency [SMD = -1.22, 95% confidence interval (95% CI) = -1.77 to -0.66]. The 2-mA bifrontal tDCS (SMD = -0.97, 95% CI = -1.32 to -0.62) and 10-Hz deep rTMS over the bilateral DLPFC with cue provocation (SMD = -0.77, 95% CI = -1.20 to -0.34) were associated with a significantly larger decrease in smoking frequency versus the sham. None of the investigated NIBSs was associated with dropout rates significantly different from those of the sham control groups.

Conclusion: Prefrontal non-invasive brain stimulation interventions appear to reduce the number of cigarettes smoked with good acceptability.
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http://dx.doi.org/10.1111/add.15624DOI 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 Jul 28. 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
July 2021

Duration of untreated illness and bipolar disorder: time for a new definition? Results from a cross-sectional study.

J Affect Disord 2021 Nov 22;294:513-520. Epub 2021 Jul 22.

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

Background: We primarily aimed to explore the associations between duration of untreated illness (DUI), treatment response, and functioning in a cohort of patients with bipolar disorder (BD).

Methods: 261 participants with BD were recruited. DUI was defined as months from the first affective episode to the start of a mood-stabilizer. The functioning assessment short test (FAST) scores and treatment response scores for lithium, valproate, or lamotrigine according to the Alda Scale Total Score (TS) were compared between patients with short (<24 months) or long DUI. Differences in FAST scores among good (GR; TS≥7), poor (PR; TS=2-6), or non-responders (NR; TS<2) to each mood-stabilizer were analyzed. Linear regression was computed using the FAST global score as the dependent variable.

Results: DUI and FAST scores showed no statistically significant correlation. Patients with a longer DUI showed poorer response to lithium (Z=-3.196; p<0.001), but not to valproate or lamotrigine. Response to lithium (β=-1.814; p<0.001), number of hospitalizations (β=0.237; p<0.001), and illness duration (β=0.160; p=0.028) were associated with FAST total scores. GR to lithium was associated with better global functioning compared to PR or NR [H=27.631; p<0.001].

Limitations: The retrospective design could expose our data to a recall bias. Also, only few patients were on valproate or lamotrigine treatment.

Conclusions: Poor functioning in BD could be the result of multiple affective relapses, rather than a direct effect of DUI. A timely diagnosis with subsequent effective prophylactic treatment, such as lithium, may prevent poor functional outcomes in real-world patients with BD.
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http://dx.doi.org/10.1016/j.jad.2021.07.062DOI Listing
November 2021

Transition to psychosis in randomized clinical trials of individuals at clinical high risk of psychosis compared to observational cohorts: a systematic review and meta-analysis.

Eur Psychiatry 2021 Jul 28;64(1):e51. Epub 2021 Jul 28.

Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: Individuals at clinical high risk of psychosis (CHR-P) recruited in randomized clinical trials (RCTs) and observational cohorts may display a different enrichment and hence risk of transition to psychosis. No meta-analysis has ever addressed this issue.

Methods: "Preferred Reporting Items for Systematic reviews and Meta-Analyses" (PRISMA) and "Meta-analysis Of Observational Studies in Epidemiology" (MOOSE)-compliant meta-analysis. PubMed and Web of Science were searched until November 2020 (PROSPERO:CRD42021229223). We included nonoverlapping longitudinal studies (RCTs-control condition and observational cohorts) reporting the transition to psychosis in CHR-P individuals. The primary effect size measure was the cumulative risk of transition at 0.5, 1, and 2 years follow-up in RCTs compared to observational cohorts. Random effects meta-analyses, heterogeneity assessment, quality assessment, and meta-regressions were conducted.

Results: Ninety-four independent studies (24 RCTs, 70 observational cohorts) and 9,243 individuals (mean age = 20.1 ± 3.0 years; 43.7% females) were included. The meta-analytical risk of transitioning to psychosis from a CHR-P stage was 0.091 (95% confidence intervals [CI] = 0.068-0.121) at 0.5 years, 0.140 (95% CI = 0.101-0.191) at 1 year and 0.165 (95% CI = 0.097-0.267) at 2 years follow-up in RCTs, and 0.081 (95% CI = 0.067-0.099) at 0.5 years, 0.138 (95% CI = 0.114-0.167) at 1 year, and 0.174 (95% CI = 0.156-0.193) at 2 years follow-up in observational cohorts. There were no between-group differences in transition risks (p > 0.05). The proportion of CHR-P individuals with substance use disorders (excluding alcohol and cannabis) was higher in observational cohorts (16.8, 95% CI = 13.3-21.0%) than in RCTs (3.4, 95% CI = 0.8-12.7%; p = 0.018).

Conclusions: There is no meta-analytic evidence supporting sampling biases in RCTs of CHR-P individuals. Further RCTs are needed to detect effective interventions to prevent psychosis in this at-risk group.
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http://dx.doi.org/10.1192/j.eurpsy.2021.2222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390336PMC
July 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

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

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 Systematic Review of Depression and Anxiety in Adults with Pyoderma Gangrenosum.

Adv Skin Wound Care 2021 Aug;34(8):432-436

Meghan L. McPhie, PhD, is Medical Student, Queen's University, School of Medicine, Kingston, Ontario, Canada. At the University of Toronto, Ontario, Joshua Fletcher, MD, is Family Medicine Resident, Division of Dermatology; Myrela O. Machado, MD, is Clinical Fellow, Division of Dermatology; Andre F. Carvalho, MD, PhD, is Associate Professor of Psychiatry, Department of Psychiatry; and Vincent Piguet, MD, PhD, is Director, Division of Dermatology. Afsaneh Alavi, MD, MSc, is Associate Professor, Department of Dermatology, Mayo Clinic, Rochester, Minnesota. Acknowledgments: Dr Alavi has been consultant for AbbVie, BI, Janssen, InflaRx, Novartis, UCB, and an investigator for BI and Castle Creek. The authors have disclosed no financial relationships related to this article. Submitted August 13, 2020; accepted in revised form October 28, 2020.

Objective: To synthesize the available evidence on the prevalence and odds for anxiety and depression in adults with pyoderma gangrenosum (PG).

Data Sources: Observational studies examining anxiety and depression in adults with PG were systematically searched using the MEDLINE, EMBASE, PsycINFO, and CINAHL databases from the inception of each database to March 11, 2020.

Study Selection: Two authors independently screened references based on predetermined eligibility criteria.

Data Extraction: Of the 244 articles identified, three met the eligibility criteria. Relevant data were extracted from included studies, and methodological quality was evaluated independently by two authors using the modified Newcastle-Ottawa Scale.

Data Synthesis: Three observational studies comprising 183 participants with PG met the inclusion criteria. Estimated rates of depression in adults with PG ranged from 10% to 23%. None of the studies measured rates of anxiety.

Conclusions: The current systematic review suggests that depression is a common psychological comorbidity in adults with PG. Additional research is required to further assess the psychological comorbidities in this population.
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http://dx.doi.org/10.1097/01.ASW.0000755920.76330.21DOI Listing
August 2021

Disparities in Screening and Treatment of Cardiovascular Diseases in Patients With Mental Disorders Across the World: Systematic Review and Meta-Analysis of 47 Observational Studies.

Am J Psychiatry 2021 09 14;178(9):793-803. Epub 2021 Jul 14.

Neurosciences Department (Solmi, Miola), Padua Neuroscience Center (Solmi), Department of General Psychology (Poddighe), and Department of Philosophy, Sociology, Education, and Applied Psychology (Delogu), University of Padua, Italy; Early Psychosis: Interventions and Clinical Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Solmi, Fusar-Poli); Psychiatry Department, University of Ottawa, Ottawa (Fiedorowicz); Department of Clinical Medicine, Faculty of Health Sciences, UiT-Arctic University of Norway, Tromsø (Høye); Division of Mental Health and Substance Abuse, University Hospital of North Norway, Tromsø (Høye); Center for Clinical Documentation and Evaluation (SKDE), Tromsø (Høye, Heiberg); Physiotherapy Department, South London and Maudsley NHS Foundation Trust, and Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Stubbs); Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, U.K. (Smith); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, and School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark, and Department of Clinical Sciences, Lund University, Lund, Sweden (Attar); Department of Psychiatry, Aalborg University Hospital, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark (Nielsen); Centre for Innovation in Mental Health-Developmental Lab, School of Psychology, University of Southampton, and NHS Trust, Southampton, U.K. (Cortese); Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York (Cortese); Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, U.K. (Cortese); Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea (Shin); National Institute for Health Research, Maudsley Biomedical Research Centre, and OASIS Service, South London and Maudsley NHS Foundation Trust, London (Fusar-Poli); Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy (Fusar-Poli); Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, U.K. (Firth); NICM Health Research Institute, Western Sydney University, Westmead, Australia (Firth); Department of Psychiatry, University of British Columbia, Vancouver (Yatham); Department of Psychiatry, University of Toronto, and Centre for Addiction and Mental Health, Toronto (Castle, Seeman); IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia (Carvalho); Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Charité University Medicine Berlin, Berlin (Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y. (Correll); and Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. (Correll).

Objective: This study used meta-analysis to assess disparities in cardiovascular disease (CVD) screening and treatment in people with mental disorders, a group that has elevated CVD incidence and mortality.

Methods: The authors searched PubMed and PsycInfo through July 31, 2020, and conducted a random-effect meta-analysis of observational studies comparing CVD screening and treatment in people with and without mental disorders. The primary outcome was odds ratios for CVD screening and treatment. Sensitivity analyses on screening and treatment separately and on specific procedures, subgroup analyses by country, and by controlling for confounding by indication, as well as meta-regressions, were also run, and publication bias and quality were assessed.

Results: Forty-seven studies (N=24,400,452 patients, of whom 1,283,602 had mental disorders) from North America (k=26), Europe (k=16), Asia (k=4), and Australia (k=1) were meta-analyzed. Lower rates of screening or treatment in patients with mental disorders emerged for any CVD (k=47, odds ratio=0.773, 95% CI=0.742, 0.804), coronary artery disease (k=34, odds ratio=0.734, 95% CI=0.690, 0.781), cerebrovascular disease (k=8, odds ratio=0.810, 95% CI=0.779, 0.842), and other mixed CVDs (k=11, odds ratio=0.839, 95% CI=0.761, 0.924). Significant disparities emerged for any screening, any intervention, catheterization or revascularization in coronary artery disease, intravenous thrombolysis for stroke, and treatment with any and with specific medications for CVD across all mental disorders (except for CVD medications in mood disorders). Disparities were largest for schizophrenia, and they differed across countries. Median study quality was high (Newcastle-Ottawa Scale score, 8); higher-quality studies found larger disparities, and publication bias did not affect results.

Conclusions: People with mental disorders, and those with schizophrenia in particular, receive less screening and lower-quality treatment for CVD. It is of paramount importance to address underprescribing of CVD medications and underutilization of diagnostic and therapeutic procedures across all mental disorders.
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http://dx.doi.org/10.1176/appi.ajp.2021.21010031DOI Listing
September 2021

Treatment Efficacy and Acceptabilityof Pharmacotherapies for Dementia with Lewy Bodies: A Systematic Review and Network Meta-Analysis.

Arch Gerontol Geriatr 2021 Sep-Oct;96:104474. Epub 2021 Jul 2.

Institute of Psychiatry, King's College London, UK; Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan. Electronic address:

Introduction: We investigated the efficacy and acceptability of pharmacotherapy for dementia with Lewy bodies (DLB) while simultaneously considering the neuropsychiatric symptoms (NPS), cognitive function, motor symptoms, and acceptability.

Methods: Electronic databases were searched from inception through June 5, 2019, for randomized controlled trials (RCTs) and open-label trials (OLTs) in patients with DLB. We performed a pairwise conventional meta-analysis (PWMA) and network meta-analysis (NMA) within a frequentist framework. The main outcomes were mean change scores in NPS, general cognition, motor symptoms and acceptability. The effect sizes and odds ratios with 95% confidence intervals (CIs) were calculated. This study was registered with PROSPERO (CRD42018096996).

Results: In total, we included 29 studies (9 RCTs and 20 OLTs). In the NMA with 9 RCTs, both high- (mean difference [MD] 2.00, 95% CIs, 0.69 to 3.31) and low-dose (1.86, 0.58 to 3.15) donepezil were associated with a greater cognitive improvement than placebo. High-dose zonisamide was associated with greater motor symptom improvement ( -4.10, -7.03 to -1.17]). No medications reached statistical significance regarding improving neuropsychiatric symptoms or developing intolerable adverse effects as compared to placebo. In the second NMA, with 29 studies as an exploratory analysis, aripiprazole and yokukansan may be effective for neuropsychiatric symptoms, while levodopa may be associated with cognitive impairment.

Conclusions: We report the most comprehensive evidence for the selection of pharmacotherapy for treating different clusters of DLB-related symptoms. Due to the limited availability of RCTs on DLB, more well-conducted RCTs are needed for MMA to warrant clinical efficacy in the future.
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http://dx.doi.org/10.1016/j.archger.2021.104474DOI Listing
September 2021

Lithium concentration and recurrence risk during maintenance treatment of bipolar disorder: Multicenter cohort and meta-analysis.

Acta Psychiatr Scand 2021 Oct 16;144(4):368-378. Epub 2021 Jul 16.

Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan.

Objective: To compare differences in efficacy during maintenance treatment for bipolar disorder (BD) according to lithium serum levels. A multicenter retrospective cohort study and a dose-response meta-analysis were conducted.

Methods: The cohort study was conducted in Taiwan from 2001 to 2019 to identify patients with euthymic BD according to different serum levels (<0.4, 0.4-0.8, and 0.8-1.2 mmol/L). We adopted adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for time to the recurrence of mood episodes having the <0.4 mmol/L group as the reference group. Moreover, we systematically searched for related articles in major databases before January 31, 2021 (PROSPERO: CRD42021235812). We used random-effects modeling to estimate the dose-response relationships between lithium serum levels and recurrence of mood episodes, which were depicted as odds ratios (ORs) with 95% CIs.

Results: A total of 1406 participants (cohort: 466; meta-analysis: 940) were included. In the cohort study, the 0.4-0.8 mmol/L group was associated with a significantly lower risk of recurrences (aHR: 0.75), while the 0.8-1.2 mmol/L group had a lower risk without statistical significance (aHR: 0.77). The dose-response meta-analysis showed that with the increase in lithium serum levels, the risk decreased (linear model OR: 0.85, for every 0.1 mmol/L increase; non-linear model OR: 1.00 at 0.0 mmol/L, 0.42 at 0.4 mmol/L, and 0.27 at 0.8 mmol/L).

Conclusion: Although confounding by indication cannot be excluded, the combined results suggest a significant preventative effect on the recurrence of major affective episodes among those with serum levels of 0.4-0.8 mmol/L.
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http://dx.doi.org/10.1111/acps.13346DOI Listing
October 2021

The endocannabinoidome in neuropsychiatry: Opportunities and potential risks.

Pharmacol Res 2021 Aug 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

Route map for machine learning in psychiatry: Absence of bias, reproducibility, and utility.

Eur Neuropsychopharmacol 2021 Sep 8;50:115-117. Epub 2021 Jun 8.

IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.

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http://dx.doi.org/10.1016/j.euroneuro.2021.05.006DOI Listing
September 2021

Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies.

Mol Psychiatry 2021 Jun 2. Epub 2021 Jun 2.

Department of Psychosis Studies, Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11-34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7-16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9-25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14-29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15-23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17-48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20-41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20-34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20-33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21-46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.
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http://dx.doi.org/10.1038/s41380-021-01161-7DOI Listing
June 2021

The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all?

Cytokine 2021 08 26;144:155593. Epub 2021 May 26.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria. Electronic address:

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1β, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.
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http://dx.doi.org/10.1016/j.cyto.2021.155593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149193PMC
August 2021

Polyphenols as adjunctive treatments in psychiatric and neurodegenerative disorders: Efficacy, mechanisms of action, and factors influencing inter-individual response.

Free Radic Biol Med 2021 08 29;172:101-122. Epub 2021 May 29.

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

The pathophysiology of psychiatric and neurodegenerative disorders is complex and multifactorial. Polyphenols possess a range of potentially beneficial mechanisms of action that relate to the implicated pathways in psychiatric and neurodegenerative disorders. The aim of this review is to highlight the emerging clinical trial and preclinical efficacy data regarding the role of polyphenols in mental and brain health, elucidate novel mechanisms of action including the gut microbiome and gene expression, and discuss the factors that may be responsible for the mixed clinical results; namely, the role of interindividual differences in treatment response and the potentially pro-oxidant effects of some polyphenols. Further clarification as part of larger, well conducted randomized controlled trials that incorporate precision medicine methods are required to inform clinical efficacy and optimal dosing regimens.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.036DOI Listing
August 2021

Cortical gray matter reduction precedes transition to psychosis in individuals at clinical high-risk for psychosis: A voxel-based meta-analysis.

Schizophr Res 2021 06 22;232:98-106. Epub 2021 May 22.

Department of Child and Adolescent Psychiatry and Psychology, 2017SGR881, Institute of Neuroscience, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; Fundació Clínic per a la Recerca Biomèdica (FCRB), Esther Koplowitz Centre, Rosselló 153, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain. Electronic address:

Gray matter and cortical thickness reductions have been documented in individuals at clinical high-risk for psychosis and may be more pronounced in those who transition to psychosis. However, these findings rely on small samples and are inconsistent across studies. In this review and meta-analysis we aimed to investigate neuroanatomical correlates of clinical high-risk for psychosis and potential predictors of transition, using a novel meta-analytic method (Seed-based d Mapping with Permutation of Subject Images) and cortical mask, combining data from surface-based and voxel-based morphometry studies. Individuals at clinical high-risk for psychosis who later transitioned to psychosis were compared to those who did not and to controls, and included three statistical maps. Overall, individuals at clinical high-risk for psychosis did not differ from controls, however, within the clinical high-risk for psychosis group, transition to psychosis was associated with less cortical gray matter in the right temporal lobe (Hedges' g = -0.377), anterior cingulate and paracingulate (Hedges' g = -0.391). These findings have the potential to help refine prognostic and etiopathological research in early psychosis.
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http://dx.doi.org/10.1016/j.schres.2021.05.008DOI Listing
June 2021

Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review.

World Psychiatry 2021 Jun;20(2):244-275

Neurosciences Department, University of Padua, Padua, Italy.

Top-tier evidence on the safety/tolerability of 80 medications in children/adolescents with mental disorders has recently been reviewed in this jour-nal. To guide clinical practice, such data must be combined with evidence on efficacy and acceptability. Besides medications, psychosocial inter-ventions and brain stimulation techniques are treatment options for children/adolescents with mental disorders. For this umbrella review, we systematically searched network meta-analyses (NMAs) and meta-analyses (MAs) of randomized controlled trials (RCTs) evaluating 48 medications, 20 psychosocial interventions, and four brain stimulation techniques in children/adolescents with 52 different mental disorders or groups of mental disorders, reporting on 20 different efficacy/acceptability outcomes. Co-primary outcomes were disease-specific symptom reduction and all-cause discontinuation ("acceptability"). We included 14 NMAs and 90 MAs, reporting on 15 mental disorders or groups of mental disorders. Overall, 21 medications outperformed placebo regarding the co-primary outcomes, and three psychosocial interventions did so (while seven outperformed waiting list/no treatment). Based on the meta-analytic evidence, the most convincing efficacy profile emerged for amphetamines, methylphenidate and, to a smaller extent, behavioral therapy in attention-deficit/hyperactivity disorder; aripiprazole, risperidone and several psychosocial interventions in autism; risperidone and behavioral interventions in disruptive behavior disorders; several antipsychotics in schizophrenia spectrum disorders; fluoxetine, the combination of fluoxetine and cognitive behavioral therapy (CBT), and interpersonal therapy in depression; aripiprazole in mania; fluoxetine and group CBT in anxiety disorders; fluoxetine/selective serotonin reuptake inhibitors, CBT, and behavioral therapy with exposure and response prevention in obsessive-compulsive disorder; CBT in post-traumatic stress disorder; imipramine and alarm behavioral intervention in enuresis; behavioral therapy in encopresis; and family therapy in anorexia nervosa. Results from this umbrella review of interventions for mental disorders in children/adolescents provide evidence-based information for clinical decision making.
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http://dx.doi.org/10.1002/wps.20881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129843PMC
June 2021

Efficacy and acceptability of noninvasive brain stimulation interventions for weight reduction in obesity: a pilot network meta-analysis.

Int J Obes (Lond) 2021 08 10;45(8):1705-1716. Epub 2021 May 10.

Division of Community & Rehabilitation Psychiatry, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.

Background/objectives: Obesity has recently been recognized as a neurocognitive disorder involving circuits associated with the reward system and the dorsolateral prefrontal cortex (DLPFC). Noninvasive brain stimulation (NIBS) has been proposed as a strategy for the management of obesity. However, the results have been inconclusive. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and acceptability of different NIBS modalities for weight reduction in participants with obesity.

Methods: Randomized controlled trials (RCTs) examining NIBS interventions in patients with obesity were analyzed using the frequentist model of NMA. The coprimary outcome was change in body mass index (BMI) and acceptability, which was calculated using the dropout rate.

Results: Overall, the current NMA, consisting of eight RCTs, revealed that the high-frequency repetitive transcranial magnetic stimulation (TMS) over the left DLPFC was ranked to be associated with the second-largest decrease in BMI and the largest decrease in total energy intake and craving severity, whereas the high-frequency deep TMS over bilateral DLPFC and the insula was ranked to be associated with the largest decrease in BMI.

Conclusion: This pilot study provided a "signal" for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on weight reduction in participants with obesity by different NIBS interventions.
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http://dx.doi.org/10.1038/s41366-021-00833-2DOI Listing
August 2021

The Impact of COVID-19 on Psychiatric Emergency and Inpatient Services in the First Month of the Pandemic in a Large Urban Mental Health Hospital in Ontario, Canada.

Front Psychiatry 2021 23;12:563906. Epub 2021 Apr 23.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

The World Health Organization characterized COVID-19 (coronavirus disease 2019) as a pandemic on March 11, 2020 (WHO). Within a couple of days, all Canadian provinces announced the implementation of social distancing measures. We evaluated the immediate effect of COVID-19 on psychiatric emergency and inpatient services in Canada's largest psychiatric hospital in the first month of the pandemic. We extracted data from the electronic medical records of the Center for Addiction and Mental Health in Toronto, Canada. We compared emergency department visits, inpatient occupancy rates, and length of stay in March 2019 and March 2020, and during the first and second half of March 2020. There was a decrease in the number of emergency department visits and inpatient occupancy rates in March 2020 compared to March 2019. There was also a significant decrease in the number of emergency department visits and inpatient occupancy rates in the second half of March 2020 compared to the first half. Our findings suggest that the pandemic was followed by a rapid decrease in the usage of psychiatric emergency and inpatient services in a large mental health hospital. Future studies will need to assess whether this decrease will be followed by a return to baseline or an increase in need for these services.
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http://dx.doi.org/10.3389/fpsyt.2021.563906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102788PMC
April 2021

Pharmacologic and hormonal treatments for menopausal sleep disturbances: A network meta-analysis of 43 randomized controlled trials and 32,271 menopausal women.

Sleep Med Rev 2021 Jun 11;57:101469. Epub 2021 Mar 11.

Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. Electronic address:

This network meta-analysis aimed at investigating efficacy/tolerability of pharmacologic/hormonal interventions for menopausal sleep disturbances. Major databases were searched for randomized controlled trials (RCTs) examining pharmacologic or hormonal interventions with either placebo or active controlled designs. Primary outcomes were improvements in sleep disturbance severity/tolerability (i.e., overall dropout rates), whereas secondary outcome was adverse event-related discontinuation rates. Analysis of 43 RCTs with 25 treatment arms involving 32,271 women during/after menopausal transition (age: 61.24 ± 4.23, duration: 90.83 ± 66.29 wks) showed therapeutic effect of melatonin-fluoxetine [SMD = -2.47 (95% CI:-4.19-0.74)] against sleep disturbances compared to placebo. Subgroup analysis of 15 RCTs on vasomotor symptoms demonstrated superior benefits of gabapentin [SMD = -1.04 (95% CI:-1.90-0.18)], oral combined hormone therapy [SMD = -0.62 (95% CI:-1.06-0.18)], and bazedoxifene-conjugated estrogens [SMD = -0.50 (95% CI:-0.96-0.04)] to placebo/control. Despite benefits of raloxifene-only [SMD = -1.86 (95% CI:-3.09-0.63)] and raloxifene-oral estrogen [SMD = -2.64 (95% CI:-4.64-0.63)], patient selection may be a confounder. Dropout rates were comparable between interventions and placebo/control. Eszopiclone [RR = 3.84 (95% CI: 1.14-12.87)] and oral combined hormone therapy [RR = 2.51 (95% CI: 1.04-6.07)] were associated with higher rates of adverse event-related discontinuation. The results support combined estrogen-progesterone therapy for menopausal sleep disturbances associated with vasomotor symptoms but showed no significant effects of hypnotics in this clinical setting.
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http://dx.doi.org/10.1016/j.smrv.2021.101469DOI Listing
June 2021

Risk of cancer in bipolar disorder and the potential role of lithium: International collaborative systematic review and meta-analyses.

Neurosci Biobehav Rev 2021 07 5;126:529-541. Epub 2021 Apr 5.

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

We examined bipolar disorder (BD) as a risk factor for developing cancer and the role of lithium on cancer incidence. We conducted two systematic review and meta-analyses of population-based studies providing data on these associations. We screened articles indexed in MEDLINE, Scopus, Embase, and PsycINFO up to August 2020. The first random-effects meta-analysis, based on 4,910,661 individuals from nine studies estimated an increased risk of cancer of any kind [RR = 1.24 (1.05-1.46); p < 0.01], especially breast cancer [RR = 1.33 (1.15-1.55); p < 0.01] in BD. The second random-effects meta-analysis, based on 2,606,187 individuals from five studies did not show increased risk of cancer in people with BD using lithium, and even suggested a small protective effect both in overall [RR = 0.94 (0.72-1.22); p = 0.66] and urinary cancer [RR = 0.93 (0.75-1.14); p = 0.48] although these findings did not reach statistical significance. The current evidence highlights that cancer risk is increased in individuals with BD, particularly breast cancer in women. Lithium may have a potential protective effect on cancer, including urinary cancer. The role of lithium as a mainstay of treatment for BD is reinforced by this study.
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http://dx.doi.org/10.1016/j.neubiorev.2021.03.034DOI Listing
July 2021

Risk and protective factors for cannabis, cocaine, and opioid use disorders: An umbrella review of meta-analyses of observational studies.

Neurosci Biobehav Rev 2021 07 15;126:243-251. Epub 2021 Mar 15.

Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, London, UK; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Outreach and Support in South London (OASIS) Service, South London and Maudsley NHS Foundation Trust, London, UK.

Several meta-analyses of observational studies have addressed the association between risk and protective factors and cannabis/cocaine/opioid use disorders, but results are conflicting. No umbrella review has ever graded the credibility of this evidence (not significant/weak/suggestive/highly suggestive/convincing). We searched Pubmed-MEDLINE/PsycInfo, last search September 21, 2020. We assessed the quality of meta-analyses with the AMSTAR-2 tool. Out of 3,072 initial references, five were included, providing 19 associations between 12 putative risk/protective factors and cannabis/cocaine/opioid use disorders (cases: 4539; N = 1,118,872,721). While 84 % of the associations were statistically significant, none was convincing. One risk factor (smoking) had highly suggestive evidence for association with nonmedical use of prescription opioid medicines (OR = 3.07, 95 %CI:2.27 to 4.14). Convincing evidence emerged in sensitivity analyses on antisocial behavior and cannabis use disoder (OR 3.34, 95 %CI 2.53-4.41). Remaining associations had weak evidence. The quality of meta-analyses was rated as moderate in two (40 %), low in one (20 %), and critically low in two (40 %). Future research is needed to better profile risk/protective factors for cannabis/cocaine/opioid use disorders disorders informing preventive approaches.
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http://dx.doi.org/10.1016/j.neubiorev.2021.03.014DOI Listing
July 2021

Efficacy and acceptability of different interventions for acrophobia: A network meta-analysis of randomised controlled trials.

J Affect Disord 2021 03 30;282:786-794. Epub 2020 Dec 30.

Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital; College of Medicine, China Medical University, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan. Electronic address:

Background: Currently, different psychological interventions have shown significant efficacy in the treatment of acrophobia. However, the superiority of these individual treatments remains unclear. This network meta-analysis (NMA) aimed to investigate the efficacy, acceptability, and superiority of different existing interventions for acrophobia.

Methods: We conducted a NMA of randomised controlled trials (RCTs) and compared the efficacy, acceptability, and superiority of different existing interventions for acrophobia.

Results: In total, 17 RCTs (946 participants) were included in this study. The NMA demonstrated that virtual reality (VR) coach-delivered psychotherapy (standardised mean difference [SMD]=-2.08, 95% confidence interval [CI]: -3.22 to -0.93), in vivo exposure augmented with oppositional action (SMD=-1.66, 95% CI: -2.81 to -0.51), VR exposure therapy with 20 mg cortisol administration (SMD=-1.61, 95% CI: -3.14 to -0.09), VR based cognitive behavioural therapy (VRbasedCBT; SMD=-1.14, 95% CI: -2.22 to -0.05), and in vivo exposure (SMD=-1.02, 95% CI: -1.81 to -0.23) were significantly superior than the placebo/control interventions in improving the symptoms of patients with acrophobia. The NMA further indicated that VR coach-delivered psychotherapy was associated with the best improvement among all the 19 treatments for acrophobia. Furthermore, only VRbasedCBT (odds ratio=2.55, 95% CI: 1.09 to 5.96) was associated with higher dropout rate than the control/placebo.

Limitations: Sample heterogeneity, non-standardised assessment tools, and limited RCTs in some of the treatment arms.

Conclusions: VR coach-delivered psychotherapy could be considered as a first-line intervention for treating acrophobia. However, because of the study limitations, the overall evidence was not sufficiently strong, which warrants future studies.
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http://dx.doi.org/10.1016/j.jad.2020.12.172DOI Listing
March 2021
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