Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II

BACKGROUND: Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Electroconvulsive therapy and pharmacotherapy are each efficacious in the treatment of PD. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the acute pharmacologic treatment of PD. However, little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical importance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder. METHODS/DESIGN: The primary goal of this multicenter randomized placebo-controlled trial is to assess the risks and benefits of continuing antipsychotic medication in persons with PD once the episode of depression has responded to treatment with an antidepressant and an antipsychotic. Secondary goals are to examine age and genetic polymorphisms as predictors or moderators of treatment variability, potentially leading to more personalized treatment of PD. Individuals aged 18-85 years with unipolar psychotic depression receive up to 12 weeks of open-label treatment with sertraline and olanzapine. Participants who achieve remission of psychosis and remission/near-remission of depressive symptoms continue with 8 weeks of open-label treatment to ensure stability of remission. Participants with stability of remission are then randomized to 36 weeks of double-blind treatment with either sertraline and olanzapine or sertraline and placebo. Relapse is the primary outcome. Metabolic changes are a secondary outcome. DISCUSSION: This trial will provide clinicians with much-needed evidence to guide the continuation and maintenance treatment of one of the most disabling and lethal of psychiatric disorders. TRIAL REGISTRATION AND URL: NCT: NCT01427608

Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD study

BACKGROUND: There is paucity of neurobiological knowledge about major depressive disorder with psychotic features ( psychotic depression ). This study addresses this knowledge gap by using resting state functional magnetic resonance imaging (R-fMRI) to compare functional connectivity in patients with psychotic depression and healthy controls. METHODS: We scanned patients who participated in a randomized controlled trial as well as healthy controls. All patients achieved remission from depressive and psychotic symptoms with sertraline and olanzapine. We employed Independent Component Analysis in independent samples to isolate the default mode network (DMN) and compared patients and controls. FINDINGS: The Toronto sample included 28 patients (mean [SD], age 56.2 [13.7]) and 39 controls (age 55.1 [13.5]). The Replication sample included 29 patients (age 56.1 [17.7]) and 36 controls (age 48.3 [17.9]). Patients in the Toronto sample demonstrated decreased between-network functional connectivity between the DMN and bilateral insular, somatosensory/motor, and auditory cortices with peak activity in the right planum polare (t=4.831; p=0.001, Family Wise Error (FWE) corrected). A similar pattern of between-network functional connectivity was present in our Replication sample with peak activity in the right precentral gyrus (t=4.144; p=0.003, FWE corrected). INTERPRETATION: Remission from psychotic depression is consistently associated with an absence of increased DMN-related functional connectivity and presence of decreased between-network functional connectivity. Future research will evaluate this abnormal DMN-related functional connectivity as a potential biomarker for treatment trajectories. FUNDING: National Institute of Mental Health

Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial

Importance: Psychotic depression is a severely disabling and potentially lethal disorder. Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with psychotic depression in remission. Objective: To determine the clinical effects of continuing antipsychotic medication once an episode of psychotic depression has responded to combination treatment with an antidepressant and antipsychotic agent. Design, Setting, and Participants: Thirty-six week randomized clinical trial conducted at 4 academic medical centers. Patients aged 18 years or older had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks and met criteria for remission of psychosis and remission or near-remission of depressive symptoms for 8 weeks before entering the clinical trial. The study was conducted from November 2011 to June 2017, and the final date of follow-up was June 13, 2017. Interventions: Participants were randomized either to continue olanzapine (n = 64) or switch from olanzapine to placebo (n = 62). All participants continued sertraline. Main Outcomes and Measures: The primary outcome was risk of relapse. Main secondary outcomes were change in weight, waist circumference, lipids, serum glucose, and hemoglobin A1c (HbA1c). Results: Among 126 participants who were randomized (mean [SD] age, 55.3 years [14.9 years]; 78 women [61.9%]), 114 (90.5%) completed the trial. At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range [IQR], 150-200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10-20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P \u3c .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb; 95% CI, 0.11 to 0.15), waist circumference (0.009 inches; 95% CI, 0.004 to 0.014), and total cholesterol (0.29 mg/dL; 95% CI, 0.13 to 0.45) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, -0.01 to 0.10), high-density lipoprotein cholesterol (-0.01 mg/dL; 95% CI, -0.03 to 0.01), triglyceride (-0.153 mg/dL; 95% CI, -0.306 to 0.004), glucose (-0.02 mg/dL; 95% CI, -0.12 to 0.08), or HbA1c levels (-0.0002 mg/dL; 95% CI, -0.0021 to 0.0016). Conclusions and Relevance: Among patients with psychotic depression in remission, continuing sertraline plus olanzapine compared with sertraline plus placebo reduced the risk of relapse over 36 weeks. This benefit needs to be balanced against potential adverse effects of olanzapine, including weight gain. Trial Registration: ClinicalTrials.gov Identifier: NCT01427608

Prevalence, causes, and consequences of moral distress in healthcare providers caring for people living with dementia in long-term care during a pandemic

Healthcare providers caring for people living with dementia may experience moral distress when faced with ethically challenging situations, such as the inability to provide care that is consistent with their values. The COVID-19 pandemic produced conditions in long-term care homes (LTCHs) that could potentially contribute to moral distress. We conducted an online survey to examine changes in moral distress during the pandemic, its contributing factors and correlates, and its impact on the well-being of LTCH staff. Survey participants (n=227) working in LTCHs across Ontario, Canada were recruited through provincial LTCH organizations. Using a Bayesian approach, we examined the association between moral distress and staff demographics and roles, and characteristics of the LTCH. We performed a qualitative analysis of the survey's free-text responses. More than 80% of LTCH healthcare providers working with people with dementia reported an increase in moral distress since the start of the pandemic. There was no difference in the severity of distress by age, sex, role, or years of experience. The most common factors associated with moral distress were lack of activities and family visits, insufficient staffing and high turnover, and having to follow policies and procedures that were perceived to harm residents with dementia. At least two-thirds of respondents reported feelings of physical exhaustion, sadness/anxiety, frustration, powerlessness, and guilt due to the moral distress experienced during the pandemic. Respondents working in not-for-profit or municipal homes reported less sadness/anxiety and feelings of not wanting to go to work than those in for-profit homes. Front-line staff were more likely to report not wanting to work than those in management or administrative positions. Overall, we found that increases in moral distress during the pandemic negatively affected the well-being of healthcare providers in LTCHs, with preliminary evidence suggesting that individual and systemic factors may intensify the negative effect

HD-PTP Is a Catalytically Inactive Tyrosine Phosphatase Due to a Conserved Divergence in Its Phosphatase Domain

The HD-PTP protein has been described as a tumor suppressor candidate and based on its amino acid sequence, categorized as a classical non-transmembrane protein tyrosine phosphatase (PTP). To date, no HD-PTP phosphorylated substrate has been identified and controversial results concerning its catalytic activity have been recently reported

Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal rTMS in major depression

Background Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain’s emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. Methods Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. Results Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. Conclusions The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection

Resting state cortico-thalamic-striatal connectivity predicts pesponse to dorsomedial prefrontal rTMS in major depressive disorder

Despite its high toll on society, there has been little recent improvement in treatment efficacy for Major Depressive Disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting state functional connectivity predicted response to treatment with rapid transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased sgACC-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work

Sustaining remission of psychotic depression: Rationale, design and methodology of STOP-PD II

Background: Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Electroconvulsive therapy and pharmacotherapy are each efficacious in the treatment of PD. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the acute pharmacologic treatment of PD. However, little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical importance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder.Methods/design: The primary goal of this multicenter randomized placebo-controlled trial is to assess the risks and benefits of continuing antipsychotic medication in persons with PD once the episode of depression has responded to treatment with an antidepressant and an antipsychotic. Secondary goals are to examine age and genetic polymorphisms as predictors or moderators of treatment variability, potentially leading to more personalized treatment of PD. Individuals aged 18-85 years with unipolar psychotic depression receive up to 12 weeks of open-label treatment with sertraline and olanzapine. Participants who achieve remission of psychosis and remission/near-remission of depressive symptoms continue with 8 weeks of open-label treatment to ensure stability of remission. Participants with stability of remission are then randomized to 36 weeks of double-blind treatment with either sertraline and olanzapine or sertraline and placebo. Relapse is the primary outcome. Metabolic changes are a secondary outcome.Discussion: This trial will provide clinicians with much-needed evidence to guide the continuation and maintenance treatment of one of the most disabling and lethal of psychiatric disorders.Trial registration and URL: NCT: NCT01427608. © 2013 Flint et al; licensee BioMed Central Ltd

Depression prevalence using the HADS-D compared to SCID major depression classification:An individual participant data meta-analysis

Objectives: Validated diagnostic interviews are required to classify depression status and estimate prevalence of disorder, but screening tools are often used instead. We used individual participant data meta-analysis to compare prevalence based on standard Hospital Anxiety and Depression Scale – depression subscale (HADS-D) cutoffs of ≥8 and ≥11 versus Structured Clinical Interview for DSM (SCID) major depression and determined if an alternative HADS-D cutoff could more accurately estimate prevalence. Methods: We searched Medline, Medline In-Process & Other Non-Indexed Citations via Ovid, PsycINFO, and Web of Science (inception-July 11, 2016) for studies comparing HADS-D scores to SCID major depression status. Pooled prevalence and pooled differences in prevalence for HADS-D cutoffs versus SCID major depression were estimated. Results: 6005 participants (689 SCID major depression cases) from 41 primary studies were included. Pooled prevalence was 24.5% (95% Confidence Interval (CI): 20.5%, 29.0%) for HADS-D ≥8, 10.7% (95% CI: 8.3%, 13.8%) for HADS-D ≥11, and 11.6% (95% CI: 9.2%, 14.6%) for SCID major depression. HADS-D ≥11 was closest to SCID major depression prevalence, but the 95% prediction interval for the difference that could be expected for HADS-D ≥11 versus SCID in a new study was −21.1% to 19.5%. Conclusions: HADS-D ≥8 substantially overestimates depression prevalence. Of all possible cutoff thresholds, HADS-D ≥11 was closest to the SCID, but there was substantial heterogeneity in the difference between HADS-D ≥11 and SCID-based estimates. HADS-D should not be used as a substitute for a validated diagnostic interview.This study was funded by the Canadian Institutes of Health Research (CIHR, KRS-144045 & PCG 155468). Ms. Neupane was supported by a G.R. Caverhill Fellowship from the Faculty of Medicine, McGill University. Drs. Levis and Wu were supported by Fonds de recherche du Québec - Santé (FRQS) Postdoctoral Training Fellowships. Mr. Bhandari was supported by a studentship from the Research Institute of the McGill University Health Centre. Ms. Rice was supported by a Vanier Canada Graduate Scholarship. Dr. Patten was supported by a Senior Health Scholar award from Alberta Innovates, Health Solutions. The primary study by Scott et al. was supported by the Cumming School of Medicine and Alberta Health Services through the Calgary Health Trust, and funding from the Hotchkiss Brain Institute. The primary study by Amoozegar et al. was supported by the Alberta Health Services, the University of Calgary Faculty of Medicine, and the Hotchkiss Brain Institute. The primary study by Cheung et al. was supported by the Waikato Clinical School, University of Auckland, the Waikato Medical Research Foundation and the Waikato Respiratory Research Fund. The primary study by Cukor et al. was supported in part by a Promoting Psychological Research and Training on Health-Disparities Issues at Ethnic Minority Serving Institutions Grants (ProDIGs) awarded to Dr. Cukor from the American Psychological Association. The primary study by De Souza et al. was supported by Birmingham and Solihull Mental Health Foundation Trust. The primary study by Honarmand et al. was supported by a grant from the Multiple Sclerosis Society of Canada. The primary study by Fischer et al. was supported as part of the RECODEHF study by the German Federal Ministry of Education and Research (01GY1150). The primary study by Gagnon et al. was supported by the Drummond Foundation and the Department of Psychiatry, University Health Network. The primary study by Akechi et al. was supported in part by a Grant-in-Aid for Cancer Research (11−2) from the Japanese Ministry of Health, Labour and Welfare and a Grant-in-Aid for Young Scientists (B) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. The primary study by Kugaya et al. was supported in part by a Grant-in-Aid for Cancer Research (9–31) and the Second-Term Comprehensive 10-year Strategy for Cancer Control from the Japanese Ministry of Health, Labour and Welfare. The primary study Ryan et al. was supported by the Irish Cancer Society (Grant CRP08GAL). The primary study by Keller et al. was supported by the Medical Faculty of the University of Heidelberg (grant no. 175/2000). The primary study by Love et al. (2004) was supported by the Kathleen Cuningham Foundation (National Breast Cancer Foundation), the Cancer Council of Victoria and the National Health and Medical Research Council. The primary study by Love et al. (2002) was supported by a grant from the Bethlehem Griffiths Research Foundation. The primary study by Löwe et al. was supported by the medical faculty of the University of Heidelberg, Germany (Project 121/2000). The primary study by Navines et al. was supported in part by the Spanish grants from the Fondo de Investigación en Salud, Instituto de Salud Carlos III (EO PI08/90869 and PSIGEN-VHC Study: FIS-E08/00268) and the support of FEDER (one way to make Europe). The primary study by O'Rourke et al. was supported by the Scottish Home and Health Department, Stroke Association, and Medical Research Council. The primary study by Sanchez-Gistau et al. was supported by a grant from the Ministry of Health of Spain (PI040418) and in part by Catalonia Government, DURSI 2009SGR1119. The primary study by Gould et al. was supported by the Transport Accident Commission Grant. The primary study by Rooney et al. was supported by the NHS Lothian Neuro-Oncology Endowment Fund. The primary study by Schwarzbold et al. was supported by PRONEX Program (NENASC Project) and PPSUS Program of Fundaçao de Amparo a esquisa e Inovacao do Estado de Santa Catarina (FAPESC) and the National Science and Technology Institute for Translational Medicine (INCT-TM). The primary study by Simard et al. was supported by IDEA grants from the Canadian Prostate Cancer Research Initiative and the Canadian Breast Cancer Research Alliance, as well as a studentship from the Canadian Institutes of Health Research. The primary study by Singer et al. (2009) was supported by a grant from the German Federal Ministry for Education and Research (no. 01ZZ0106). The primary study by Singer et al. (2008) was supported by grants from the German Federal Ministry for Education and Research (# 7DZAIQTX) and of the University of Leipzig (# formel. 1–57). The primary study by Meyer et al. was supported by the Federal Ministry of Education and Research (BMBF). The primary study by Stone et al. was supported by the Medical Research Council, UK and Chest Heart and Stroke, Scotland. The primary study by Turner et al. was supported by a bequest from Jennie Thomas through Hunter Medical Research Institute. The primary study by Walterfang et al. was supported by Melbourne Health. Drs. Benedetti and Thombs were supported by FRQS researcher salary awards. No other authors reported funding for primary studies or for their work on this study. No funder had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead