Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

BACKGROUND: The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. METHODS: Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. RESULTS: Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. CONCLUSIONS: Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

Trajectories of remitted psychotic depression: identification of predictors of worsening by machine learning.

BACKGROUND: Remitted psychotic depression (MDDPsy) has heterogeneity of outcome. The study's aims were to identify subgroups of persons with remitted MDDPsy with distinct trajectories of depression severity during continuation treatment and to detect predictors of membership to the worsening trajectory. METHOD: One hundred and twenty-six persons aged 18-85 years participated in a 36-week randomized placebo-controlled trial (RCT) that examined the clinical effects of continuing olanzapine once an episode of MDDPsy had remitted with sertraline plus olanzapine. Latent class mixed modeling was used to identify subgroups of participants with distinct trajectories of depression severity during the RCT. Machine learning was used to predict membership to the trajectories based on participant pre-trajectory characteristics. RESULTS: Seventy-one (56.3%) participants belonged to a subgroup with a stable trajectory of depression scores and 55 (43.7%) belonged to a subgroup with a worsening trajectory. A random forest model with high prediction accuracy (AUC of 0.812) found that the strongest predictors of membership to the worsening subgroup were residual depression symptoms at onset of remission, followed by anxiety score at RCT baseline and age of onset of the first lifetime depressive episode. In a logistic regression model that examined depression score at onset of remission as the only predictor variable, the AUC (0.778) was close to that of the machine learning model. CONCLUSIONS: Residual depression at onset of remission has high accuracy in predicting membership to worsening outcome of remitted MDDPsy. Research is needed to determine how best to optimize the outcome of psychotic MDDPsy with residual symptoms.

Cancer screening in China: a steep road from evidence to implementation.

Cancer screening has the potential to decrease mortality from several common cancer types. The first cancer screening programme in China was initiated in 1958 and the Cancer High Incidence Fields established in the 1970s have provided an extensive source of information for national cancer screening programmes. From 2012 onwards, four ongoing national cancer screening programmes have targeted eight cancer types: cervical, breast, colorectal, lung, oesophageal, stomach, liver, and nasopharyngeal cancers. By synthesising evidence from pilot screening programmes and population-based studies for various screening tests, China has developed a series of cancer screening guidelines. Nevertheless, challenges remain for the implementation of a fully successful population-based programme. The aim of this Review is to highlight the key milestones and the current status of cancer screening in China, describe what has been achieved to date, and identify the barriers in transitioning from evidence to implementation. We also make a set of implementation recommendations on the basis of the Chinese experience, which might be useful in the establishment of cancer screening programmes in other countries.

Effects of antipsychotic medication on functional connectivity in major depressive disorder with psychotic features.

The effect of antipsychotic medication on resting state functional connectivity in major depressive disorder (MDD) is currently unknown. To address this gap, we examined patients with MDD with psychotic features (MDDPsy) participating in the Study of the Pharmacotherapy of Psychotic Depression II. All participants were treated with sertraline plus olanzapine and were subsequently randomized to continue sertraline plus olanzapine or be switched to sertraline plus placebo. Participants completed an MRI at randomization and at study endpoint (study completion at Week 36, relapse, or early termination). The primary outcome was change in functional connectivity measured within and between specified networks and the rest of the brain. The secondary outcome was change in network topology measured by graph metrics. Eighty-eight participants completed a baseline scan; 73 completed a follow-up scan, of which 58 were usable for analyses. There was a significant treatment X time interaction for functional connectivity between the secondary visual network and rest of the brain (t = -3.684; p = 0.0004; pFDR = 0.0111). There was no significant treatment X time interaction for graph metrics. Overall, functional connectivity between the secondary visual network and the rest of the brain did not change in participants who stayed on olanzapine but decreased in those switched to placebo. There were no differences in changes in network topology measures when patients stayed on olanzapine or switched to placebo. This suggests that olanzapine may stabilize functional connectivity, particularly between the secondary visual network and the rest of the brain.

The relationship of white matter microstructure with psychomotor disturbance and relapse in remitted psychotic depression.

BACKGROUND: Psychomotor disturbance is common in psychotic depression and is associated with relapse. In this analysis, we examined whether white matter microstructure is associated with relapse probability in psychotic depression and, if so, whether white matter microstructure accounts for the association between psychomotor disturbance and relapse. METHODS: We used tractography to characterize diffusion-weighted MRI data in 80 participants enrolled in a randomized clinical trial that compared efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo in the continuation treatment of remitted psychotic depression. Cox proportional hazard models tested the relationships between psychomotor disturbance (processing speed and CORE score) at baseline, white matter microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) in 15 selected tracts at baseline, and relapse probability. RESULTS: CORE was significantly associated with relapse. Higher mean MD was significantly associated with relapse in the each of the following tracts: corpus callosum, left striato-frontal, left thalamo-frontal, and right thalamo-frontal. CORE and MD were each associated with relapse in the final models. LIMITATIONS: As a secondary analysis with a small sample size, this study was not powered for its aims, and is vulnerable to types I and II statistical errors. Further, the sample size was not sufficient to test the interaction of the independent variables and randomized treatment group with relapse probability. CONCLUSIONS: While both psychomotor disturbance and MD were associated with psychotic depression relapse, MD did not account for the relationship between psychomotor disturbance and relapse. The mechanism by which of psychomotor disturbance increases the risk of relapse requires further investigation. CLINICAL TRIAL REGISTRATION: Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II); NCT01427608. URL: https://clinicaltrials.gov/ct2/show/NCT01427608.

Genomic Investigation of Remission and Relapse of Psychotic Depression Treated with Sertraline plus Olanzapine: The STOP-PD II Study.

INTRODUCTION: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. METHODS: Genomic analyses were performed in 171 men and women aged 18-85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. RESULTS: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer's disease had a significantly decreased likelihood of relapse. CONCLUSION: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.

Residual or re-emergent impaired insight into delusions following remission is unrelated to later relapse during a randomized clinical trial of continuation pharmacotherapy for psychotic depression - The STOP-PD II Study.

BACKGROUND: Impaired insight into delusions is associated with a lower probability of remission of psychotic depression, independent of illness severity. The relationship between participant characteristics and impaired insight into delusions in remitted psychotic depression, and whether impaired insight is associated with risk of relapse of psychotic depression during continuation pharmacotherapy were examined. METHODS: Data were analyzed from 126 participants in the STOP-PD II study who experienced sustained remission of psychotic depression during 8-week stabilization treatment with sertraline plus olanzapine and were then randomized to 36 weeks of continuation treatment with sertraline plus either olanzapine or placebo. Insight into delusions was assessed with the Resolution of Delusions Scale (RODS). Linear regression analyses examined the associations between participant characteristics and insight into delusions. Cox proportional-hazards models examined whether i) change in RODS during stabilization treatment; or ii) RODS at the end of stabilization treatment predicted risk of relapse during 36 weeks of continuation treatment. RESULTS: Severity of psychosis before initiation of treatment was the only participant characteristic associated with the change in insight during stabilization treatment. Neither change in insight during stabilization treatment nor insight at the end of stabilization treatment was associated with risk of relapse. LIMITATIONS: Insufficient statistical power and the lack of variability in RODS scores at the time of randomization may have contributed to the absence of a relationship between RODS and risk of relapse. CONCLUSION: Residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression in a randomized placebo-controlled trial.

Predictors of relapse of psychotic depression: Findings from the STOP-PD II randomized clinical trial.

Psychotic depression has a high rate of relapse. The study aims were to identify a prediction model of risk of relapse of psychotic depression and examine whether predictors moderated the effect of treatment on relapse. One hundred and twenty-six men and women aged 18-85 years, who experienced sustained remission or near-remission of psychotic depression with sertraline plus olanzapine, participated in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse (NCT01427608). Cox regression analyses were performed to identify significant predictors of relapse and to model the combined role of significant predictors. Concordance statistic was calculated to determine the accuracy of the best fit multivariable models in predicting relapse. Finally, interaction terms were tested for each significant predictor to examine whether they moderated the effect of treatment on risk of relapse. Lifetime number of depressive episodes, severity of residual depressive symptoms at the time of randomization, and psychomotor disturbance both at acute enrollment when participants were depressed and at the time of randomization predicted risk of relapse. Multivariable models had 69-70% accuracy in predicting relapse. Psychomotor disturbance was associated with increased risk of relapse in the sertraline plus olanzapine group compared with sertraline plus placebo, whereas the other predictors did not moderate the effect of treatment on relapse. Future research is needed to determine whether a combination of clinical and biological variables can further increase the accuracy of prediction of relapse of psychotic depression.

Cancer overdiagnosis: a challenge in the era of screening.

"Screening" is a search for preclinical, asymptomatic disease, including cancer. Widespread cancer screening has led to large increases in early-stage cancers and pre-cancers. Ubiquitous public messages emphasize the potential benefits to screening for these lesions based on the underlying assumption that treating cancer at early stages before spread to other organs should make it easier to treat and cure, using more tolerable interventions. The intuition is so strong that public campaigns are sometimes launched without conducting definitive trials directly comparing screening to usual care. An effective cancer screening test should not only increase the incidence of early-stage preclinical disease but should also decrease the incidence of advanced and metastatic cancer, as well as a subsequent decrease in cancer-related mortality. Otherwise, screening efforts may be uncovering a reservoir of non-progressive and very slowly progressive lesions that were not destined to cause symptoms or suffering during the person's remaining natural lifespan: a phenomenon known as "overdiagnosis." We provide here a qualitative review of cancer overdiagnosis and discuss specific examples due to extensive population-based screening, including neuroblastoma, prostate cancer, thyroid cancer, lung cancer, melanoma, and breast cancer. The harms of unnecessary diagnosis and cancer therapy call for a balanced presentation to people considering undergoing screening, even with a test of accepted benefit, with a goal of informed decision-making. We also discuss proposed strategies to mitigate the adverse sequelae of overdiagnosis.

Factor analysis of the CORE measure of psychomotor disturbance in psychotic depression: Findings from the STOP-PD II study.

The CORE instrument is commonly used to measure psychomotor disturbance. We examined the factor structure of the CORE in 266 adults with an acute episode psychotic depression, a disorder with a high rate of psychomotor disturbance. Exploratory factor analysis identified a two-factor solution: Factor 1 corresponded to the CORE's retardation and non-interactiveness items and Factor 2 corresponded to its agitation items. Internal consistency was excellent for Factor 1 but questionable for Factor 2. These findings suggest that the CORE's retardation and non-interactiveness items should be combined in one subscale when assessing patients with an acute episode of psychotic depression.

Examining the Dynamic Nature of Anterior Cruciate Ligament Injury Risk Factors in Women's Collegiate Soccer.

CONTEXT: Anterior cruciate ligament (ACL) injuries are a common and devastating injury in women's soccer. Several risk factors for ACL injury have been identified, but have not yet been examined as potentially dynamic risk factors, which may change throughout a collegiate soccer season. DESIGN: Prospective cohort study. METHODS: Nine common clinical screening assessments for ACL injury risk, consisting of range of motion, movement quality, and power, were assessed in 29 Division I collegiate women's soccer players. Preseason and midseason values were compared for significant differences. Change scores for each risk factor were also correlated with cumulative training loads during the first 10 weeks of a competitive soccer season. RESULTS: Hip external rotation range of motion and power had statistically significant and meaningful differences at midseason compared with preseason, indicating they are dynamic risk factors. There were no significant associations between the observed risk factor changes and cumulative training load. CONCLUSIONS: Hip external rotation range of motion and power are dynamic risk factors for ACL injury in women's collegiate soccer athletes. Serial screening of these risk factors may elucidate stronger associations with injury risk and improve prognostic accuracy of screening tools.

Regional Differences in Gamma-Aminobutyric Acid and Glutamate Concentrations in the Healthy Newborn Brain.

BACKGROUND AND PURPOSE: Gamma-aminobutyric acid and glutamate system disruptions may underlie neonatal brain injury. However, in vivo investigations are challenged by the need for special 1H-MR spectroscopy sequences for the reliable measurement of the neurotransmitters in this population. We used J-edited 1H-MR spectroscopy (Mescher-Garwood point-resolved spectroscopy) to quantify regional in vivo gamma-aminobutyric acid and glutamate concentrations during the early postnatal period in healthy neonates. MATERIALS AND METHODS: We prospectively enrolled healthy neonates and acquired Mescher-Garwood point-resolved spectroscopy spectra on a 3T MR imaging scanner from voxels located in the cerebellum, the right basal ganglia, and the right frontal lobe. CSF-corrected metabolite concentrations were compared for regional variations and cross-sectional temporal trends with advancing age. RESULTS: Fifty-eight neonates with acceptable spectra acquired at postmenstrual age of 39.1 (SD, 1.3) weeks were included for analysis. Gamma-aminobutyric acid (+ macromolecule) (2.56 [SD, 0.1]) i.u., glutamate (3.80 [SD, 0.2]), Cho, and mIns concentrations were highest in the cerebellum, whereas NAA (6.72 [SD, 0.2]), NAA/Cho, Cr/Cho, and Glx/Cho were highest in the basal ganglia. Frontal gamma-aminobutyric acid (1.63 [SD, 0.1]), Glx (4.33 [SD, 0.3]), Cr (3.64 [SD, 0.2]), and Cho concentrations were the lowest among the ROIs. Glx, NAA, and Cr demonstrated a significant adjusted increase with postmenstrual age (ß = 0.2-0.35), whereas gamma-aminobutyric acid and Cho did not. CONCLUSIONS: We report normative regional variations and temporal trends of in vivo gamma-aminobutyric acid and glutamate concentrations reflecting the functional and maturational status of 3 distinct brain regions of the neonate. These measures will serve as important normative values to allow early detection of subtle neurometabolic alterations in high-risk neonates.

Delivery of Financial Navigation Services Within National Cancer Institute-Designated Cancer Centers.

Background: Cancer centers have a responsibility to help patients manage the costs of their cancer treatment. This article describes the availability of financial navigation services within the National Cancer Institute (NCI)-designated cancer centers. Methods: Data were obtained from the NCI Survey of Financial Navigation Services and Research, an online survey administered to NCI-designated cancer centers from July to September 2019. Of the 62 eligible centers, 57 completed all or most of the survey, for a response rate of 90.5%. Results: Nearly all cancer centers reported providing help with applications for pharmaceutical assistance programs and medical discounts (96.5%), health insurance coverage (91.2%), assistance with nonmedical costs (96.5%), and help understanding medical bills and out-of-pocket costs (85.9%). Although other services were common, in some cases they were only available to certain patients. These services included direct financial assistance with medical and nonmedical costs and referrals to outside organizations for financial assistance. The least common services included medical debt management (63.2%), detailed discussions about the cost of treatment (54.4%), and guidance about legal protections (50.1%). Providing treatment cost transparency to patients was reported as a common challenge: 71.9% of centers agreed or strongly agreed that it is difficult to determine how much a cancer patient's treatment will cost, and 70.2% of oncologists are reluctant to discuss financial issues with patients. Conclusions: Cancer centers provide many financial services and resources. However, there remains a need to build additional capacity to deliver comprehensive financial navigation services and to understand the extent to which patients are referred and helped by these services.

DeImplementing Ineffective and Low-Value Clinical Practices: Research and Practice Opportunities in Community Oncology Settings.

Patients, practitioners, and policy makers are increasingly concerned about the delivery of ineffective or low-value clinical practices in cancer care settings. Research is needed on how to effectively deimplement these types of practices from cancer care. In this commentary, we spotlight the National Cancer Institute Community Oncology Research Program (NCORP), a national network of community oncology practices, and elaborate on how it is an ideal infrastructure for conducting rigorous, real-world research on deimplementation. We describe key multilevel issues that affect deimplementation and also serve as a guidepost for developing strategies to drive deimplementation. We describe optimal study designs for testing deimplementation strategies and elaborate on how and why the NCORP network is uniquely positioned to conduct rigorous and impactful deimplementation trials. The number and diversity of affiliated community oncology care sites, coupled with the overall objective of improving cancer care delivery, make the NCORP an opportune infrastructure for advancing deimplementation research while simultaneously improving the care of millions of cancer patients nationwide.

Association between psychomotor disturbance and treatment outcome in psychotic depression: a STOP-PD II report.

BACKGROUND: Little is known about the relationship between psychomotor disturbance (PMD) and treatment outcome of psychotic depression. This study examined the association between PMD and subsequent remission and relapse of treated psychotic depression. METHODS: Two hundred and sixty-nine men and women aged 18-85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission or near-remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine (n = 64) with sertraline plus placebo (n = 62). PMD was measured with the psychiatrist-rated sign-based CORE at acute phase baseline and at RCT baseline. Spearman's correlations and logistic regression analyses were used to analyze the association between CORE total score at acute phase baseline and remission/near-remission and CORE total score at RCT baseline and relapse. RESULTS: Higher CORE total score at acute phase baseline was associated with lower frequency of remission/near-remission. Higher CORE total score at RCT baseline was associated with higher frequency of relapse, in the RCT sample as a whole, as well as in each of the two randomized groups. CONCLUSIONS: PMD is associated with poorer outcome of psychotic depression treated with sertraline plus olanzapine. Future research needs to examine the neurobiology of PMD in psychotic depression in relation to treatment outcome.

Pharmacotherapy Prescriptions for Relapse Prevention of Psychotic Depression After Electroconvulsive Therapy.

PURPOSE/BACKGROUND: Electroconvulsive therapy (ECT) is effective in the treatment of acute episodes of psychotic depression. However, no adequately powered studies have directly investigated the efficacy of antipsychotic pharmacotherapy in relapse prevention of psychotic depression after ECT. In the absence of such literature, we reviewed the clinical practice of 4 academic medical centers that have made research contributions in the treatment of psychotic depression over the past 20 years. METHODS/PROCEDURES: We reviewed medical records of patients with a diagnosis of psychotic depression who received 1 or more acute courses of ECT over the span of 3 years. Chi-square tests were used to compare pharmacotherapy prescribed at the time of completion of ECT. FINDINGS/RESULTS: A total of 163 patients received 176 courses of ECT for separate episodes of psychotic depression. The combination of an antidepressant plus an antipsychotic was the most common regimen, ranging from 61.9% to 85.5% of all prescriptions. One center added lithium in 45.5% of cases treated with the combination of an antidepressant plus an antipsychotic. An antipsychotic alone was prescribed in less than 10% of cases. An antidepressant alone or other drug combinations were rare. IMPLICATIONS/CONCLUSIONS: The combination of an antidepressant plus an antipsychotic was the most commonly prescribed regimen at the completion of ECT for relapse prevention in patients with psychotic depression acutely treated with ECT. Although this report offers a view of the clinical practice of 4 academic medical centers, it also points to the need of randomized controlled trials on continuation pharmacotherapy after treatment of psychotic depression with ECT.

Anterior thalamic nuclei neurons sustain memory.

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis.