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ImportancePersistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.ObjectiveTo determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.Design, Setting, and ParticipantsThis case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.Main Outcomes and MeasuresThe TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.ResultsThe study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, −0.53; 95% CI, −0.79 to −0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).Conclusions and RelevanceIn this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

Background Long-term clinical monitoring in bipolar disorder (BD) is an important therapeutic tool. The availability of smartphones and wearables has sparked the development of automated applications to remotely monitor patients. This systematic review focus on the current state of electronic (e-) monitoring for episode prediction in BD. Methods We systematically reviewed the literature on e-monitoring for episode prediction in adult BD patients. The systematic review was done according to the guidelines for reporting of systematic reviews and meta-analyses (PRISMA) and was registered in PROSPERO on April 29, 2020 (CRD42020155795). We conducted a search of Web of Science, MEDLINE, EMBASE, and PsycINFO (all 2000–2020) databases. We identified and extracted data from 17 published reports on 15 relevant studies. Results Studies were heterogeneous and most had substantial methodological and technical limitations. Models varied widely in their performance. Published metrics were too heterogeneous to lend themselves to a meta-analysis. Four studies reported sensitivity (range: 0.21 - 0.95); and two reported specificity for prediction of mood episodes (range: 0.36 - 0.99). Two studies reported accuracy (range: 0.64 - 0.88) and four reported area under the curve (AUC; range: 0.52-0.95). Overall, models were better in predicting manic or hypomanic episodes, but their performance depended on feature type. Limitations Our conclusions are tempered by the lack of appropriate information impeding our ability to synthesize the available evidence. Conclusions Given the clinical variability in BD, predicting mood episodes remains a challenging task. Emerging e-monitoring technology for episode prediction in BD requires more development before it can be adopted clinically.

Background: Clinical use of psychedelics has gained considerable attention, with promising benefits across a range of mental disorders. Current pharmacological and psychotherapeutic treatments for body dysmorphic disorder (BDD) and eating disorders (EDs) have limited efficacy. As such, other treatment options such as psychedelic-assisted therapies are being explored in these clinical groups. Aims: This systematic review evaluates evidence related to the therapeutic potential of psychedelics in individuals diagnosed with BDD and EDs. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic review of all study designs published to the end of February 2022 that identified changes in ED/BDD symptom severity from psychedelics using validated measures to assess symptom changes. Results: Our search detected a total of 372 studies, of which five met inclusion criteria (two exploratory studies, two case reports, and one prospective study). These were included in the data evaluation. Effects of psychedelics on BDD and various ED symptoms were identified mostly through thematic analyses and self-reports. Conclusions: Our findings highlight that more research is needed to determine the safety and efficacy of psychedelics in BDD and EDs and we suggest avenues for future exploration.

There has been resurgence of interest in the therapeutic use of serotonergic ("classic") psychedelics in major depressive disorder (MDD) and end-of-life distress. This commentary offers a critical appraisal of current evidence for antidepressant effects of classic psychedelics from contemporary clinical trials and highlights pitfalls that should be addressed before clinical translation.A narrative review was conducted to identify clinical trials of serotonergic psychedelics for the treatment of MDD and end-of-life distress. Trials published between January 1990 and May 2022 were identified on PubMed using combinations of search terms.Psilocybin, lysergic acid diethylamide, and ayahuasca have clinical trials to evaluate antidepressant effects. Two studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression. Similar results were seen in lysergic acid diethylamide for end-of-life distress. Small randomized clinical trials (RCTs) of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator in MDD, with additional RCTs showing efficacy in end-of-life distress. Adverse events associated with psychedelics were reported as mild and transient. Small homogenous samples, expectancy bias, functional unblinding, and lack of consensus and standardization of psychotherapy are major limitations of all studies.Given the methodological limitations of published RCTs, the evidence supporting the efficacy and safety of serotonergic psychedelics for depression is currently of low level. Future research should assess the role of expectancy and psychedelic effects in moderating and mediating treatment response. Innovative trial designs are needed to overcome functional unblinding. For now, psychedelics should remain experimental interventions used within clinical trials.

OBJECTIVES Depression has long been considered a significant feature of schizophrenia and is associated with more frequent psychotic episodes, increased service utilisation, substance misuse, poor quality of life and completed suicide. However, there is a distinct lack of literature on this comorbidity from low- and middle-income countries or non-western cultural backgrounds. METHODS This is a cross-sectional analysis of baseline data from a large randomised controlled trial, examining the prevalence of depression and suicidal ideation in patients with schizophrenia spectrum disorder. A total of 298 participants were recruited from inpatient and outpatient psychiatric units in Karachi, Pakistan. Participants completed the Calgary Depression Scale for Schizophrenia (CDSS), Positive and Negative Syndrome Scale (PANSS), Euro Qol (EQ-5D) and Social Functioning Scale (SFS). RESULTS Data indicate that 36% of participants in the study were depressed and 18% endorsed suicidal ideation. Depression was associated with higher positive symptom scores and reduced quality of life, but no significant difference in negative symptoms and social functioning. CONCLUSIONS Depression and suicidal ideation are prevalent in Pakistani patients diagnosed with schizophrenia spectrum disorder. Evaluation of depressive symptoms in this group may help identify individuals at higher risk of completed suicide, allowing for targeted interventions to improve outcomes.Key pointsTo our knowledge, this is the first study describing the prevalence of depression and suicidal ideation in individuals with schizophrenia from Pakistan.Our data indicate that 36% of individuals with schizophrenia in our sample were depressed and 18% endorsed suicidal ideation.Depression in schizophrenia was associated with poorer quality of life and higher positive symptom burden.This study adds to the scarce literature from low- and middle-income countries where the burden of mental illness is great and where the majority of suicide deaths occur.Addressing social inequality, food insecurity, high rates of unemployment and low levels of literacy in these settings may have a profound effect on population mental health and suicide risk.

Objective Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. Methods A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. Results Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. Conclusions There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

Bipolar Disorders (BDs) are chronic mental health disorders that often result in functional impairment and contribute significantly to the disability-adjusted life years (DALY). BDs are historically under-researched compared to other mental health disorders, especially in Sub-Saharan Africa and Nigeria.We adopted a mixed-methods design. Study 1 examined the public knowledge of BDs in relation to sociodemographic outcomes using quantitative data whilst Study 2 qualitatively assessed the lived experiences of patients with BDs, clinicians, and family caregivers.In Study 1, a non-clinical sample of n = 575 participants responded to a compact questionnaire that examined their knowledge of BDs and how they relate to certain sociodemographic variables. One-way ANOVA was used to analyse quantitative data. Study 2 interviewed N = 15 participants (n = 5 patients with BDs; n = 7 clinicians; n = 3 family caregivers). These semi-structured interviews were audio-recorded, transcribed, and thematically analysed.In Study 1, findings showed no statistically significant differences, suggesting low awareness of BDs, especially among vulnerable populations such as young people and older adults. However, there was a trajectory in increased knowledge of BDs among participants between the ages of 25-44 years and part-time workers compared to other ages and employment statuses. In Study 2, qualitative findings showed that BDs are perceived to be genetically and psycho-socially induced by specific lived experiences of patients and their family caregivers. Although psychotropic medications and psychotherapy are available treatment options in Nigeria, cultural and religious beliefs were significant barriers to treatment uptake.This study provides insight into knowledge and beliefs about BDs, including the lived experiences of patients with BDs, their caregivers and clinicians in Nigeria. It highlights the need for further studies assessing Nigeria's feasibility and acceptability of culturally adapted psychosocial interventions for patients with BDs.

The COVID-19 pandemic resulted in drastic disruptions to lives and possible pernicious impacts on mental health, including suicidality. Understanding these relations, as well as impacts on at-risk populations, is essential. The present study examined changes in daily behaviors and cognitions after the implementation of physical/social distancing mandates in individuals with symptoms of suicide crisis syndrome (SCS) and/or suicidal ideation. Adults ( N = 5,528) across 10 countries completed online self-report measures. There were significant main effects of time and various configurations of interactions between time, SCS, and suicidal ideation in predicting behaviors (outdoor and social engagements) and cognitions (thoughts about health, finances, and living situation). Cross-culturally, individuals with more severe SCS symptoms generally had the largest changes in behaviors and cognitions, though this effect was not replicated across all countries. Overall, these findings highlight the implications of the potentially mutually exacerbating influences of routine disruptions and suicide risk and the importance of examining associations cross-culturally.

The transition to virtual care (telehealth) during the COVID-19 pandemic has led to both challenges and opportunities in delivering effective mental health care that meets the needs of patients and families. The negative mental and physical health effects of isolation and loneliness associated with the pandemic present a challenge for community mental and behavioral health care. However, the advantages that virtual care provides for the delivery of mental health services, particularly the potential for improved access, also benefit both providers and patients. Ongoing barriers to wider adoption and utilization of virtual mental health care need to be addressed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BackgroundRelatively few studies have assessed the prevalence, correlates, and independent impact on quality of life (QoL) of trichotillomania (TTM) in large samples.MethodsConsecutive participants (N = 7639) were recruited from a cross-sectional web-based study. Sociodemographic data were collected and several validated self-reported mental health measures were completed (Minnesota Impulsive Disorders Interview, Hypomania checklist, Fagerström Test for Nicotine Dependence, Alcohol Use Disorders Identification Test, Early Trauma Inventory Self Report–Short Form, and the Symptom Checklist-90–Revised Inventory). Health-related QoL was assessed with the World Health Organization QoL abbreviated scale (WHOQOL-Bref). Multivariable models adjusted associations to potential confounders.ResultsThe sample was predominantly composed of young females (71.3%; mean age: 27.2 ± 7.9 years). The prevalence of probable TTM was 1.4% (95% confidence intervals [CI]: 1.2-1.7), and was more common among females. Participants with probable TTM had a greater likelihood of having co-occurring probable depression (adjusted odds ratio [ORadj] = 1.744; 95% CI: 1.187-2.560), tobacco (ORadj = 2.250; 95% CI: 1.191-4.250), and alcohol (ORadj = 1.751; 95% CI: 1.169-2.621) use disorders. Probable TTM was also independently associated with suicidal ideation (ORadj = 1.917; 95% CI: 1.224-3.003) and exposure to childhood sexual abuse (ORadj = 1.221; 95% CI: 1.098-1.358). In addition, a positive screen for TTM had more impaired physical and mental QoL.ConclusionsTTM was associated with a positive screen for several psychiatric comorbidities as well as impaired physical and psychological QoL. Efforts towards the recognition and treatment of TTM across psycho-dermatology services are warranted.

ImportanceImmune-metabolic disturbances have been implicated in the pathophysiology of major depressive disorder and may be more prominent in individuals with treatment-resistant depression (TRD). Preliminary trials suggest that lipid-lowering agents, including statins, may be useful adjunctive treatments for major depressive disorder. However, no adequately powered clinical trials have assessed the antidepressant efficacy of these agents in TRD.ObjectiveTo assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD.Design, Setting, and ParticipantsThis 12-week, double-blind, placebo-controlled randomized clinical trial was conducted in 5 centers in Pakistan. The study involved adults (aged 18-75 years) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) major depressive episode that had failed to respond to at least 2 adequate trials of antidepressants. Participants were enrolled between March 1, 2019, and February 28, 2021; statistical analysis was performed from February 1 to June 15, 2022, using mixed models.InterventionParticipants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo.Main Outcomes and MeasuresThe primary outcome was the difference between the 2 groups in change in Montgomery-Åsberg Depression Rating Scale total scores at week 12. Secondary outcomes included changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, and the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. C-reactive protein and plasma lipids were measured at baseline and week 12.ResultsA total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n = 73; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-Åsberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, −0.61; 95% CI, −3.69 to 2.46; P = .70). Similarly, there were no significant group differences in any of the secondary outcomes or evidence for differences in adverse effects between groups. A planned secondary analysis indicated that changes in plasma C-reactive protein and lipids from baseline to end point did not mediate response to simvastatin.Conclusions and RelevanceIn this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care.Trial RegistrationClinicalTrials.gov Identifier: NCT03435744

Key Points Question What is the placebo effect magnitude in different treatment modalities used for management of patients with treatment-resistant depression? Findings In this systematic review and meta-analysis of 3228 patients with treatment-resistant depression in 50 randomized clinical trials, the placebo effect size was large and consistent across treatment modalities. Response and remission rates associated with placebo effect were comparable across modalities. Meaning The findings of this study suggest a placebo effect size benchmark may be used to interpret the findings of past and future clinical trials., Importance The placebo effect in depression clinical trials is a substantial factor associated with failure to establish efficacy of novel and repurposed treatments. However, the magnitude of the placebo effect and whether it differs across treatment modalities in treatment-resistant depression (TRD) is unclear. Objective To examine the magnitude of the placebo effect in patients with TRD across different treatment modalities and its possible moderators. Data Sources Searches were conducted on MEDLINE, Web of Science, and PsychInfo from inception to June 21, 2021. Study Selection Randomized clinical trials (RCTs) were included if they recruited patients with TRD and randomized them to a placebo or sham arm and a pharmacotherapy, brain stimulation, or psychotherapy arm. Data Extraction and Synthesis Independent reviewers used standard forms for data extraction and quality assessment. Random-effects analyses and standard pairwise meta-analyses were performed. Main Outcomes and Measures The primary outcome was the Hedges g value for the reported depression scales. Secondary outcomes included moderators assessed via meta-regression and response and remission rates. Heterogeneity was assessed with the I2 test, and publication bias was evaluated using the Egger test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks. Results Fifty RCTs were included involving various types of placebo or sham interventions with a total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooled placebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in RCTs of specific treatment modalities did not significantly differ. Similarly, response and remission rates associated with placebo were comparable across modalities. Heterogeneity was large. Three variables were associated with a larger placebo effect size: open-label prospective treatment before double-blind placebo randomization (β = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (β = 0.34; 95% CI, 0.09 to 0.58; P = .007). The number of failed interventions was associated with the probability a smaller placebo effect size (β = −0.12; 95% CI, −0.23 to −0.01, P = .03). The Egger test result was not significant for small studies’ effects. Conclusions and Relevance This analysis may provide a benchmark for past and future clinical RCTs that recruit patients with TRD standardizing an expected placebo effect size., This systematic review and meta-analysis examines the placebo effect shown in randomized clinical trials of patients with treatment-resistant depression.

Introduction: Physical activity has been shown to have a multitude of mental health benefits. However, there is limited evidence on the specific mental health benefits of boxing. We conducted a scoping review of academic and grey literature to map research of boxing exercises as an intervention in mental health and to identify gaps in knowledge. Methods: The authors utilized the PRISMA-ScR methodological approach and guidelines from the Joanna Briggs Institute and a structured search was completed from inception until August 08, 2022. Results: We identified 16 documents that used non-contact boxing as an exercise intervention that improved various mental health difficulties. Non-contact boxing exercises, usually in a high-intensity-interval training group setting, provided significant reduction in symptoms of anxiety, depression, PTSD and negative symptoms of schizophrenia. Non-contact boxing provided a cathartic release of anger and stress, with evidence of improved mood, self-esteem, confidence, concentration, metabolic burden, strength and coordination. Conclusions: Preliminary evidence indicates that non-contact boxing exercises are a promising intervention to improve mental health burden. Further well designed randomized controlled trials using group, non-contact boxing exercises as an intervention for common mental disorders are warranted to confirm its benefits for mental health.

Background : Metabolic dysfunction is prevalent in bipolar disorder (BD) and associated with illness severity and treatment outcomes. There is little research exploring this relationship in low and middle-income countries (LMICs) and little is known about the moderating effect of metabolic health on treatment response to anti-inflammatory drugs in BD. Methods : MINDCARE, a randomized-controlled-trial conducted in Pakistan, investigated the efficacy of minocycline and celecoxib in 266 adults with bipolar depression. This secondary analysis evaluated the association between depression severity at baseline and treatment outcome with metabolic parameters including body mass index (BMI), waist circumference (WC), heart rate (HR), systolic blood pressure (s-BP), and diastolic blood pressure (d-BP). Depression severity was measured using the Hamilton Depression Rating Scale-17. The exploratory aim was to assess whether treatment impacted change in metabolic variables. Associations were evaluated using linear regression. Results : Higher BMI (B=-0.38, 95%CI: -0.55 to -0.21) and WC (B=-0.68, 95%CI: -0.97 to -0.39) were associated with lower baseline depression severity in both the unadjusted and the adjusted models. Baseline metabolic parameters were not associated with treatment response to minocycline or celecoxib nor did treatment significantly impact metabolic variables. Limitations : Our sample represents patients in an RCT and may not be fully representative of the overall BD population in Pakistan. Conclusions : Our findings indicate a potential association of poor metabolic health and lower severity of bipolar depression but not treatment outcomes. Future work should evaluate potential relationships of metabolic parameters and BD in diverse populations to increase the transferability of this line of work.

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.

Major Depressive Disorder (MDD) is a chronic, relapsing, and remitting disorder affecting over 250 million persons each year worldwide. More than 50% of the patients do not respond to their initial antidepressant treatment and may benefit from sequential pharmacotherapy for the acute treatment of their MDD. Although guidelines outline options for next-step treatments, there is a paucity of evidence to select specific second- or third-step treatments.This scoping review synthesizes and discusses available evidence for sequential pharmacotherapy for MDD. MEDLINE was searched from inception to 7 July 2020; 4490 studies were identified. We selected meta-analyses and reports on clinical trials that were judged to inform the sequential selection of pharmacotherapy for MDD.Most relevant published trials are focused on, and support, the use of augmentation pharmacotherapy. There is also some support for other strategies such as combining or switching antidepressants. In the future, more studies need to directly compare these sequential options. To provide more personalized treatment within the framework of precision psychiatry, these studies should include an assessment of moderators and mediators ('mechanism') of antidepressant response.

IntroductionThe high placebo response in depression treatment trials is a major contributing factor for randomised control trial failure to establish efficacy of novel or repurposed treatments in treatment-resistant depression (TRD) and major depressive disorder in general. Though there have been a number of meta-analyses and primary research studies evaluating the placebo response in non-TRD, placebo response in TRD is poorly understood. It is important to understand the placebo response of TRD as treatments are only moderately effective and up to 1/3 of patients will experience TRD.Methods and analysisWe will conduct a search of electronic databases (MEDLINE and PsychINFO) from inception to 24th January 2020 including randomised, placebo-controlled trials of pharmacological, somatic and psychological interventions for adults with TRD. TRD will be defined as a failure to respond to at least two interventions of adequate dose or duration. We will also search reference lists from review articles. We will perform several meta-analyses to quantify the placebo response for each treatment modality. Regression analysis will explore potential contributing demographic and clinical variables to the placebo response. We will use Cochrane risk of bias tool.Ethics and disseminationThere is no research ethics board approval required. The dissemination plan is to publish results in a peer-reviewed academic journal.PROSPERO registration number190 465.

Background Canadians of South Asian (SA) origin comprise the largest racialized group in Canada, representing 25.6% of what Statistics Canada terms “visible minority populations”. South Asian Canadians are disproportionately impacted by the social determinants of health, and this can result in high rates of mood and anxiety disorders. These factors can negatively impact mental health and decrease access to care, thereby increasing mental health inequities. Cognitive Behavioural Therapy (CBT) in its current form is not suitable for persons from the non-western cultural backgrounds. Culturally adapted Cognitive Behavioural Therapy (CaCBT) is an evidence-based practice. CaCBT is more effective than standard CBT and can reduce dropouts from therapy compared with standard CBT. Thus, CaCBT can increase access to mental health services and improve outcomes for immigrant, refugee and ethno-cultural and racialized populations. Adapting CBT for growing SA populations in Canada will ensure equitable access to effective and culturally appropriate interventions. Methods The primary aim of the study is to develop and evaluate CaCBT for Canadian South Asian persons with depression and anxiety and to gather data from stakeholders to develop guidelines to culturally adapt CBT. This mixed methods study will use three phases: (1) cultural adaptation of CBT, (2) pilot feasibility of CaCBT and (3) implementation and evaluation of CaCBT. Phase 1 will use purposive sampling to recruit individuals from four different groups: (1) SA patients with depression and anxiety, (b) caregivers and family members of individuals affected by anxiety and depression, (c) mental health professionals and (d) SA community opinion leaders. Semi-structured interviews will be conducted virtually and analysis of interviews will be informed by an ethnographic approach. Phase 2 will pilot test the newly developed CaCBT for feasibility, acceptability and effectiveness via quantitative methodology and a randomized controlled trial, including an economic analysis. Phase 3 will recruit therapists to train and evaluate them in the new CaCBT. Discussion The outcome of this trial will benefit health services in Canada, in terms of helping to reduce the burden of depression and anxiety and provide better care for South Asians. We expect the results to help guide the development of better services and tailor existing services to the needs of other vulnerable groups. Trial registration ClinicalTrials.gov NCT04010890. Registered on July 8, 2019

Online cognitive behaviour therapy (CBT), self-help and guided self-help (GSH) interventions have been found to be efficacious and cost-effective for treatment of anxiety and depression, but there are limited data from low- and middle-income countries on culturally adapted digital interventions for these common mental disorders. The aim of this study was to investigate the feasibility and acceptability of an online culturally adapted CBT-based guided self-help (CaCBT-GSH) for patients with anxiety and depression in Pakistan. This randomized controlled trial recruited 39 participants from primary care in Karachi, Pakistan and randomized them to two groups. The intervention group received seven modules of CaCBT-GSH plus treatment as usual (TAU) over 12 weeks. The control group was a waitlist control plus TAU. The primary outcomes were feasibility and acceptability. Clinical outcomes included results from the Hospital Anxiety and Depression Scale (HADS) and the WHO Disability Assessment Schedule 2 (WHODAS 2). Assessments were carried out at baseline and at 12 weeks. All 39 individuals who met eligibility criteria for the study agreed to participate. Adherence to the intervention was excellent, with 85% (17/20) completing more than five modules. Statistically significant improvements were found in all clinical outcomes in the intervention group. This was the first trial of an online CaCBT-GSH intervention, which was found to be feasible and acceptable to Pakistani patients with anxiety and depression. CaCBT-GSH may help improve symptoms, depression, anxiety and overall functioning in this population. The results provide rationale for a larger, confirmatory randomized controlled trial of digital CaCBT-GSH. Key learning aims (1) Leveraging digital and virtual platforms to deliver psychosocial interventions may contribute to addressing the significant treatment gap in low-resource settings. (2) CBT-informed guided self-help is feasible and acceptable in the treatment of common mental disorders in Pakistan. (3) The results of this study merit a larger, appropriately powered confirmatory randomized controlled trial to determine clinical and cost effectiveness.

Background Bipolar disorder (BD) is associated with premature death and ischemic heart disease is the main cause of excess mortality. Heart rate variability (HRV) predicts mortality in patients with or without cardiovascular disease. While several studies have analyzed the association between HRV and BD, none has analyzed the association of HRV with illness burden in BD. Methods 53 participants with BD I and II used a wearable device to assess the association between HRV and factors characterizing illness burden, including illness duration, number and type of previous episode(s), duration of the most severe episode, history of suicide attempts or psychotic symptoms during episodes, and co-morbid psychiatric disorders. We ran unadjusted models and models controlling statistically for age, sex, pharmacotherapy, baseline functional cardiovascular capacity, BMI, years of education, and marital status. We also explored the association between HRV and an overall illness burden index (IBI) integrating all these factors using a weighted geometric mean. Results Adjusted and unadjusted models had similar results. Longer illness duration, higher number of depressive episodes, longer duration of most severe manic/hypomanic episode, co-morbid anxiety disorders, and family history of suicide were associated with reduced HRV, as was bipolar depression severity in the participants experiencing a depressive episode. Finally, a higher IBI score was associated with lower HRV. Conclusions High illness burden is associated with reduced HRV in BD. While the IBI needs to be validated in a larger sample, it may provide an overall measure that captures illness burden in BD.

Background:Cognitive behaviour therapy (CBT), self-help and guided self-help interventions have been found to be efficacious and cost effective for victims of trauma, but there are limited data from low- and middle-income countries on culturally adapted interventions for trauma.Aims:To investigate the feasibility and acceptability of culturally adapted trauma-focused CBT-based guided self-help (CatCBT GSH) for female victims of domestic violence in Pakistan.Method:This randomized controlled trial (RCT) recruited 50 participants from shelter homes in Karachi and randomized them to two equal groups. The intervention group received GSH in nine sessions over 12 weeks. The control group was a waitlist control. The primary outcomes were feasibility and acceptability. Secondary outcomes included Impact of Event Scale-Revised (IES-R), Hospital Anxiety and Depression Scale (HADS) and the WHO Disability Assessment Schedule 2 (WHO DAS 2). Assessments were carried out at baseline and at 12 weeks.Results:Out of 60 clients who metDSM-5criteria for post-traumatic stress disorder (PTSD), 56 (93.3%) agreed to participate in the study. Retention to the intervention group was excellent, with 92% (23/25) attending more than six sessions. Statistically significant differences were noted post-intervention in secondary outcomes in favour of the intervention.Conclusions:A trial of CatCBT GSH was feasible and the intervention was acceptable to Pakistani women who had experienced domestic violence. Furthermore, it may be helpful in improving symptoms of PTSD, depression, anxiety and overall functioning in this population. The results provide a rationale for a larger, confirmatory RCT of CatCBT GSH.

Objectives: Cannabis use is proposed as a risk factor for psychosis and is associated with depressive disorders. However, the relationship between recreational cannabis use and its longitudinal implications on anxiety conditions is less studied. The aim of this investigation is to systematically evaluate published literature and perform a meta-analysis of the data. Methods: A systematic search was performed of MEDLINE, Embase, and PsychINFO from inception to May 31, 2020, in addition to a hand search. Longitudinal studies that evaluated the relationship of cannabis use and development of anxiety were included. Where applicable, adjusted odds ratios ( ORs) were extracted, pooled, and evaluated using random-effects meta-analysis. Results: After screening of unique abstracts ( n = 6835), the final evaluation included 24 studies, of which 10 reported ORs that were analyzed quantitatively. Cannabis use was significantly associated with increased odds of developing any anxiety conditions ( OR = 1.25; 95% CI, 1.01 to 1.54). Cannabis use was not significantly associated with developing generalized anxiety disorder, panic disorder, or social anxiety disorder. Review of studies not reporting OR revealed mixed results but are suggestive of a link between cannabis use and increased rates/severity of anxiety. Conclusions: Published evidence suggests that cannabis use is likely associated with increased risk of anxiety in the long term but variability of study designs precludes declaration of a causal relationship. Awareness of this association is of relevance for both clinical practice and mental health policy implementation.

The COVID-19 pandemic has posed significant challenges to health care globally, and individuals with bipolar disorder are likely disproportionally affected. Based on review of literature and collective clinical experience, we discuss that without special intervention, individuals with bipolar disorder will experience poorer physical and mental health outcomes due to interplay of patient, provider and societal factors. Some risk factors associated with bipolar disorder, including irregular social rhythms, risk-taking behaviours, substantial medical comorbidities, and prevalent substance use, may be compounded by lockdowns, social isolation and decrease in preventive and maintenance care. We further discuss implications for clinical research of bipolar disorders during the pandemic. Finally, we propose mitigation strategies on working with individuals with bipolar disorder in a clinical and research context, focusing on digital medicine strategies to improve quality of and accessibility to service.

Background Mood disorders, i.e. major depressive disorder (MDD) and bipolar disorders, are leading sources of disability worldwide. Currently available treatments do not yield remission in approximately a third of patients with a mood disorder. This is in part because these treatments do not target a specific core pathology underlying these heterogeneous disorders. In recent years, abnormal inflammatory processes have been identified as putative pathophysiological mechanisms and treatment targets in mood disorders, particularly among individuals with treatment-resistant conditions. Aims In this selective review, we aimed to summarise recent advances in the field of immunopsychiatry, including emerging pathophysiological models and findings from treatment ttrials of immunomodulatory agents for both MDD and bipolar disorders. Method We performed a literature review by searching Medline for clinical trials of immunomodulating agents as monotherapy or adjunctive treatments in MDD and bipolar disorders. Included studies are randomised controlled trials (RCTs), cluster RCTs or cross-over trials of immunomodulating agents that had an active comparator or a placebo-arm. Results Current evidence shows an association between inflammation and mood symptoms. However, there is conflicting evidence on whether this link is causal. Conclusions Future studies should focus on identifying specific neurobiological underpinnings for the putative causal association between an activated inflammatory response and mood disorders. Results of these studies are needed before further treatment trials of immunomodulatory agents can be justified.

AimsThe placebo response in depression clinical trials is a major contributing factor for failure to establish the efficacy of novel and repurposed treatments. However, it is not clear as to what the placebo response in treatment-resistant depression (TRD) patients is or whether it differs across treatment modalities. Our objective was to conduct a systematic review and meta-analysis of the magnitude of the placebo response in TRD patients across different treatment modalities and its possible moderators.MethodSearches were conducted on MEDLINE and PsychInfo from inception to January 24, 2020. Only studies that recruited TRD patients and randomization to a placebo (or sham) arm in a pharmacotherapy, brain stimulation, or psychotherapy study were included (PROSPERO 2020 CRD42020190465). The primary outcome was the Hedges’ g for the reported depression scale using a random-effects model. Secondary outcomes included moderators assessed via meta-regression and response and remission rate. Heterogeneity was evaluated using the Egger's Test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks.Result46 studies met our inclusion criteria involving a total of 3083 participants (mean (SD) age: 45.7 (6.2); female: 52.4%). The pooled placebo effect for all modalities was large (N = 3083, g = 1.08 ,95% CI [0.95-1.20)I 2 = 0.1). The placebo effect in studies of specific treatment modalities did not significantly differ: oral medications g = 1.14 (95%CI:0.99-1.29); parenteral medications g = 1.32 (95%CI:0.59-2.04); ayahuasca g = 0.47 (95%CI:-0.28-1.17); rTMS g = 0.93 (95%CI:0.63-1.23); tDCS g = 1.32 (95%CI:0.52-2.11); invasive brain stimulation g = 1.06 (95%CI:0.64-1.47). There were no psychotherapy trials that met our eligibility criteria. Similarly, response and remission rates were comparable across modalities. Heterogeneity was large. Two variables predicted a lager placebo effect: open-label prospective design (B:0.32, 95%CI: 0.05-0.58; p:0.02) and sponsoring by a pharmaceutical or medical device company (B:0.39, 95%CI:0.13-0.65, p:0.004)). No risk of publication bias was found.ConclusionThe overall placebo effect in TRD studies was large (g = 1.08) and did not differ among treatment modalities. A better understanding of the placebo response in TRD will require: standardizing the definition of TRD, head-to-head comparisons of treatment modalities, an assessment of patient expectations and experiences, and standardized reporting of outcomes.

OBJECTIVES: The aim of the current study was to assess the associations between dynapenia and the onset and persistence of depression and anxiety among older adults. METHODS: This prospective cohort study enrolled community-living older adults (N = 5271; 51.1% females) aged = 50 years (mean age = 63.2, standard deviation = 9.0) from The Irish Longitudinal Study on Aging (TILDA), Ireland. At baseline, participants completed a handgrip assessment. Depression was defined by a score = 16 in the Center of Epidemiology Studies Depression (CES-D) tool and anxiety was considered when participants scored = 8 on the anxiety section of the Hospital Anxiety and Depression Scale (HADS). Outcomes were incident and persistent depression and anxiety at two years follow-up. Multivariable logistic regression models were built for each outcome. RESULTS: After controlling for age, sex, education, marital status, employment status, smoking, body mass index, number of chronic conditions, physical activity, and cognitive function, low handgrip strength indicative of dyapenia (< 30 Kg for men and < 20 Kg for women) was associated with a greater likelihood for incident depressive (OR = 1.44; 95%CI: 1.08-1.92) as well as for persistent depressive (OR = 1.61; 95% CI: 1.01-2.58) and anxiety (OR = 1.61; 95% CI: 1.20-2.14) symptoms. CONCLUSIONS: Dynapenia was associated with a higher odds of developing depressive symptoms as well as a greater likelihood to persistent depressive and anxiety symptoms among older adults. Our data suggest that interventions targeting muscle strength may prevent the onset of late-life depression and also may hold promise as novel therapeutic opportunities for depression and anxiety in later life.