Effect of olanzapine exposure on relapse and brain structure in patients with major depressive disorder with psychotic features.

Some data suggest that antipsychotics may adversely affect brain structure. We examined the relationship among olanzapine exposure, relapse, and changes in brain structure in patients with major depressive disorder with psychotic features. We analyzed data from the Study of the Pharmacotherapy of Psychotic Depression II trial (STOP-PD II), a randomized, placebo-controlled trial in patients with psychotic depression who attained remission on sertraline and olanzapine and were randomized to continue sertraline plus olanzapine or placebo for 36 weeks. Olanzapine steady state concentration (SSC) were calculated based on sparsely-sampled levels. Rates of relapse and changes in brain structure were assessed as outcomes. There were significant associations between dosage and relapse rates (N = 118; HR = 0.94, 95% CI [0.897, 0.977], p = 0.002) or changes in left cortical thickness (N = 44; B = -2.0 × 10-3, 95% CI [-3.1 × 10-3, -9.6 × 10-4], p < 0.001) and between SSC and changes in left cortical thickness (N = 44; B = -8.7 × 10-4, 95% CI [-1.4 × 10-3, -3.6 × 10-4], p = 0.001). Similar results were found for the right cortex. These associations were no longer significant when the analysis was restricted to participants treated with olanzapine. Our findings suggest that, within its therapeutic range, the effect of olanzapine on relapse or cortical thickness does not depend on its dosage or SSC. Further research is needed on the effect of olanzapine and other antipsychotics on mood symptoms and brain structure.

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.

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.

Systemic lupus erythematosus phenotypes formed from machine learning with a specific focus on cognitive impairment.

OBJECTIVE: To phenotype SLE based on symptom burden (disease damage, system involvement and patient reported outcomes), with a specific focus on objective and subjective cognitive function. METHODS: SLE patients ages 18-65 years underwent objective cognitive assessment using the ACR Neuropsychological Battery (ACR-NB) and data were collected on demographic and clinical variables, disease burden/activity, health-related quality of life (HRQoL), depression, anxiety, fatigue and perceived cognitive deficits. Similarity network fusion (SNF) was used to identify patient subtypes. Differences between the subtypes were evaluated using Kruskal-Wallis and χ2 tests. RESULTS: Of the 238 patients, 90% were female, with a mean age of 41 years (s.d. 12) and a disease duration of 14 years (s.d. 10) at the study visit. The SNF analysis defined two subtypes (A and B) with distinct patterns in objective and subjective cognitive function, disease burden/damage, HRQoL, anxiety and depression. Subtype A performed worst on all significantly different tests of objective cognitive function (P < 0.03) compared with subtype B. Subtype A also had greater levels of subjective cognitive function (P < 0.001), disease burden/damage (P < 0.04), HRQoL (P < 0.001) and psychiatric measures (P < 0.001) compared with subtype B. CONCLUSION: This study demonstrates the complexity of cognitive impairment (CI) in SLE and that individual, multifactorial phenotypes exist. Those with greater disease burden, from SLE-specific factors or other factors associated with chronic conditions, report poorer cognitive functioning and perform worse on objective cognitive measures. By exploring different ways of phenotyping SLE we may better define CI in SLE. Ultimately this will aid our understanding of personalized CI trajectories and identification of appropriate treatments.

Association of mycophenolate and azathioprine use with cognitive function in systemic lupus.

OBJECTIVES: Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-CD. This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies. METHODS: Consecutive adult SLE patients presenting to a single healthcare center were considered for participation. The ACR neuropsychological battery for SLE was administered to consenting patients at 0, 6 and 12 months. Scores were compared with age- and sex-matched controls. Primary outcome was CD, defined as a z-score ≤-1.5 in two or more cognitive domains. Mixed-effects logistic regression models were constructed to estimate the odds of CD with respect to AZA and MMF use. RESULTS: A total of 300 participants representing 676 patient visits completed the study; 114 (38%) met criteria for CD at baseline. The cumulative AZA dose (g/kg) was associated with reduced odds of CD [odds ratio (OR) 0.76 (95% CI 0.58, 0.98), P = 0.04]. Years of AZA treatment was also associated with reduced odds of CD [OR 0.72 (95% CI 0.54, 0.97), P = 0.03]. MMF use was not associated with CD. CONCLUSION: AZA use was associated with significantly lower odds of SLE-CD, while MMF use was not. Additional studies are warranted to further investigate the relationship of AZA and SLE-CD.

Placebo Effect in Randomized Trials of Major Depressive Disorder With Psychotic Features: A Systematic Review and Descriptive Meta-Analysis.

BACKGROUND: In the 1980s, the response rate of major depressive disorder with psychotic features (MDD-Psy) to placebo pills was reported to be close to 0%. To our knowledge, this placebo response rate has not been systematically reassessed. We undertook a systematic review of randomized controlled trials (RCTs) that have used a placebo or sham control group for MDD-Psy. METHODS: We searched MEDLINE and identified 9 relevant publications reporting on 10 studies comparing a placebo or sham interventions versus an active intervention. We extracted reported rates of response or of dropout for all causes associated with placebo versus active intervention(s) and aggregated response and dropout rates across trials. RESULTS: Two sham-controlled electroconvulsive therapy (ECT) trials did not provide response rates. In the 3 pharmacotherapy studies published in the 1980s, 0 of 12 participants (0%) responded to placebo versus 13 of 38 (34.2%) responding to the active interventions. In contrast, 5 RCTs published in the 2000s, 114 of 339 participants (33.6%) randomized to placebo responded versus 149 of 373 participants (39.9%) randomized to active interventions; dropout rates were 71/236 (30.1%) for placebo versus 84/282 (29.8%) for the active interventions. CONCLUSIONS: As expected, response rates to placebo pills in RCTs for MDD-Psy increased markedly from the 1980s to the 2000s. Methodological issues in the design and conduct of more recent RCTs may have contributed to the high placebo response. However, one needs to consider this placebo response rate when interpreting the result of recent trials of MDD-Psy, which typically have not included a "pure" placebo condition.

Validation of the automated neuropsychological assessment metrics for assessing cognitive impairment in systemic lupus erythematosus.

OBJECTIVE: We previously demonstrated the utility of the Automated Neuropsychological Assessment Metrics (ANAM) for screening cognitive impairment (CI) in patients with systemic lupus erythematosus (SLE) and developed composite indices for interpreting ANAM results. Our objectives here were to provide further support for the ANAM's concurrent criterion validity against the American College of Rheumatology neuropsychological battery (ACR-NB), identify the most discriminatory subtests and scores of the ANAM for predicting CI, and provide a new approach to interpret ANAM results using Classification and Regression Tree (CART) analysis. METHODS: 300 adult SLE patients completed an adapted ACR-NB and ANAM on the same day. As per objectives, six models were built using combinations of ANAM subtests and scores and submitted to CART analysis. Area under the curve (AUC) was calculated to evaluate the ANAM's criterion validity compared to the adapted ACR-NB; the most discriminatory ANAM subtests and scores in each model were selected, and performance of models with the highest AUCs were compared to our previous composite indices; decision trees were generated for models with the highest AUCs. RESULTS: Two models had excellent AUCs of 86 and 89%. Eight most discriminatory ANAM subtests and scores were identified. Both models demonstrated higher AUCs against our previous composite indices. An adapted decision tree was created to simplify the interpretation of ANAM results. CONCLUSION: We provide further validity evidence for the ANAM as a valid CI screening tool in SLE. The decision tree improves interpretation of ANAM results, enhancing clinical utility.

Barriers and facilitators to person-centred infection prevention and control: results of a survey about the Dementia Isolation Toolkit.

BACKGROUND: People working in long-term care homes (LTCH) face difficult decisions balancing the risk of infection spread with the hardship imposed on residents by infection control and prevention (ICP) measures. The Dementia Isolation Toolkit (DIT) was developed to address the gap in ethical guidance on how to safely and effectively isolate people living with dementia while supporting their personhood. In this observational study, we report the results of a survey of LTCH staff on barriers and facilitators regarding isolating residents, and the impact of the DIT on staff moral distress. METHODS: We completed an online cross-sectional survey. Participants (n = 207) were staff working on-site in LTCH in Ontario, Canada since March 1, 2020, with direct or indirect experience with the isolation of residents. LTCH staff were recruited through provincial LTCH organizations, social media, and the DIT website. Survey results were summarized, and three groups compared, those: (1) unfamiliar with, (2) familiar with, and (3) users of the DIT. RESULTS: 61% of respondents identified distress of LTCH staff about the harmful effects of isolation on residents as a major barrier to effective isolation. Facilitators for isolation included delivery of 1:1 activity in the resident's room (81%) and designating essential caregivers to provide support (67%). Almost all respondents (84%) reported an increase in moral distress. DIT users were less likely to report an impact of moral distress on job satisfaction (odds ratio (OR) 0.41, 95% CI 0.19-0.87) with 48% of users reporting the DIT was helpful in reducing their level of moral distress. CONCLUSIONS: Isolation as an ICP measure in LTCH environments creates moral distress among staff which is a barrier to its effectiveness. ICP guidance to LTCH would be strengthened by the inclusion of a dementia-specific ethical framework that addresses how to minimize the harms of isolation on both residents and staff.

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.

Relationships Among History of Psychosis, Cognition and Functioning in Later-Life Remitted Major Depression.

OBJECTIVE: This study tested the hypotheses that, in older adults with remitted major depression, a history of psychotic features and poorer neuropsychological performance would be independently associated with poorer everyday functioning, but that neuropsychological performance would explain more of the variance in functioning than history of psychotic features. METHODS: This cross-sectional study included 73 patients aged 50 years or older with remitted psychotic major depression or nonpsychotic major depression. The dependent variables were subjective and objective measures of function. The independent variables were history of psychotic features during one or more major depressive episodes in the previous 10 years and neuropsychological performance. Linear regression models examined the association of independent variables with function, controlling for pertinent covariates. Effect sizes were calculated for the magnitude of difference in function between the patient participants and an age- and gender-matched nonpsychiatric group, and distribution of functioning scores were compared between groups. RESULTS: In separate models, history of psychotic features and poorer processing speed, executive function, and verbal learning were independently associated with poorer participant-reported functioning and performance-based functioning. However, the association of psychotic features with functioning was no longer statistically significant when tested in the same models as neuropsychological measures. Effect sizes of the difference in functioning between patients and the nonpsychiatric group were significantly larger for the remitted psychotic than the remitted nonpsychotic depression group; functioning scores were more heterogeneous in the remitted psychotic depression group. CONCLUSION: Patients with remitted psychotic depression exhibit greater, and clinically important, impairment in everyday functioning than those with remitted nonpsychotic depression. Neuropsychological impairment appears to contribute to this relationship.

Relationship of Hair Cortisol with History of Psychosis, Neuropsychological Performance and Functioning in Remitted Later-Life Major Depression.

INTRODUCTION: Major depressive disorder (MDD) is associated with hypothalamic-pituitary-adrenal axis dysfunction that may persist into remission. Preliminary evidence suggests that this dysfunction may be associated with impaired neuropsychological performance in remitted MDD. MDD with psychotic features ("psychotic depression") is associated with greater neuropsychological and functional impairment than nonpsychotic depression, including in remission. Therefore, the aim of this exploratory study was to examine the relationships among hair cortisol concentration (HCC) - a marker of longer term endogenous cortisol exposure - and history of psychotic features, neuropsychological performance, and functioning in remitted MDD. METHODS: This cross-sectional study compared the relationship between HCC and (i) history of psychosis, (ii) neuropsychological performance, and (iii) everyday functioning in a group of 60 participants with remitted later-life MDD using Pearson's correlation coefficients. This study also measured HCC in a group of 36 nonpsychiatric volunteers to examine the clinical significance of HCC in the patient group. RESULTS: There were no statistically significant correlations between HCC and history of psychotic features, neuropsychological performance, or functioning. Furthermore, there was no clinically meaningful difference in HCC between patients and nonpsychiatric volunteers. CONCLUSION: This study is the first to examine HCC in psychotic depression. The results do not support the hypothesis that impaired neuropsychological performance, and everyday function in remitted psychotic depression is due to a sustained elevation of cortisol.

Development and dissemination of an ethical guidance and person-centred isolation care planning tool to support the care of people with dementia during the COVID-19 pandemic.

BACKGROUND: Long-term care (LTC) residents have been disproportionately impacted by the COVID-19 pandemic, both from the virus itself and the restrictions in effect for infection prevention and control. Many barriers exist in LTC to prevent the effective isolation of suspect or confirmed COVID-19 cases. Furthermore, these measures have a severe impact on the well-being of LTC residents. Our aim was to develop a guide for long-term care to address the ethical challenges associated with isolating dementia patients during the pandemic. The Dementia Isolation Toolkit (DIT) was developed by members of the research team in partnership with LTC stakeholders to address: 1) the practical challenges of isolating or quarantining people with dementia in a compassionate, safe, and effective manner; and 2) the need for ethical guidance to support decision-making regarding isolation and infection control in LTC, to prevent indecision and moral distress. To develop the DIT the team reviewed and synthesized the literature on pandemic ethics in a plain-language document, which was then reviewed by our partners and stakeholders. The final ethical guidance tool includes a discussion of the ethics around infection control measures in a pandemic, an ethical decision-making tool, and a person-centred isolation care planning tool. The ethical guidance tool has been downloaded more than 6500 times since it was published (bit.ly/dementiatoolkit), and has been disseminated internationally. The worksheets are being used during outbreaks to support care and decision-making, as well as proactively, to prepare for outbreaks by developing isolation care plans. There is a need for support for ethical decision-making in the context of a pandemic, particularly in settings such as LTC. Future studies will evaluate the implementation of the tool and its impact in addressing moral distress in health care providers in long-term care.

Association between depression and anxiety with skin and musculoskeletal clinical phenotypes in systemic lupus erythematosus.

OBJECTIVES: To study the clinical phenotypes, determined based on cumulative disease activity manifestations, and sociodemographic factors associated with depression and anxiety in SLE. METHODS: Patients attending a single centre were assessed for depression and anxiety. SLE clinical phenotypes were based on the organ systems of cumulative 10-year SLE Disease Activity Index 2000 (SLEDAI-2K), prior to visit. Multivariable logistic regression analyses for depression, anxiety, and coexisting anxiety and depression were performed to study associated SLE clinical phenotypes and other factors. RESULTS: Among 341 patients, the prevalence of anxiety and depression was 34% and 27%, respectively, while 21% had coexisting anxiety and depression. Patients with skin involvement had significantly higher likelihood of anxiety compared with patients with no skin involvement [adjusted odds ratio (aOR) = 1.8; 95% CI: 1.1, 3.0]. Patients with skin involvement also had higher likelihood of having coexisting anxiety and depression (aOR = 2.0, 95% CI: 1.2, 3.9). Patients with musculoskeletal (MSK) (aOR = 1.9; 95% CI: 1.1, 3.5) and skin system (aOR = 1.8; 95% CI: 1.04, 3.2) involvement had higher likelihood of depression compared with patients without skin or musculoskeletal involvement. Employment status and fibromyalgia at the time of the visit, and inception status were significantly associated with anxiety, depression, and coexisting anxiety and depression, respectively. CONCLUSION: SLE clinical phenotypes, specifically skin or MSK systems, along with fibromyalgia, employment and shorter disease duration were associated with anxiety or depression. Routine patient screening, especially among patients with shorter disease duration, for these associations may facilitate the diagnosis of these mental health disorders, and allow for more timely diagnosis.

Management of Late-Life Depression in the Context of Cognitive Impairment: a Review of the Recent Literature.

PURPOSE OF REVIEW: Evidence regarding the treatment of late-life depression is not necessarily generalizable to persons with a neurocognitive disorder and comorbid depression. Thus, this article reviews recent evidence that pertains to the treatment of depression in older adults with neurocognitive disorders, and synthesizes and critically analyzes this literature to identify methodological issues and gaps for the purpose of future research. RECENT FINDINGS: Controlled trials and meta-analyses examining depression treatment in neurocognitive disorders, published between 2015 and 2019 (N = 16 reports), can be divided into those addressing pharmacotherapy, psychological and behavioral therapy, and somatic therapy. The evidence generally does not support benefit of antidepressant medication over placebo in treating depressive disorders in dementia. No pharmacological studies since 2015 have examined antidepressant medication in participants with mild cognitive impairment (MCI). Problem adaptation therapy demonstrates efficacy for depression in MCI and mild dementia. Other psychological and behavioral interventions for depressive symptoms in dementia demonstrate mixed findings. The only somatic treatment trials published since 2015 have assessed bright light therapy, with positive findings but methodological limitations. Psychological, behavioral, and somatic treatments represent promising treatment options for depression in neurocognitive disorders, but further studies are needed, particularly in participants with depressive disorders rather than subclinical depressive symptoms. Little is known about the treatment of depression in patients with MCI, and rigorous identification of MCI in late-life depression treatment trials will help to advance knowledge in this area. Addressing methodological issues, particularly the diagnosis and measurement of clinically significant depression in dementia, will help to move the field forward.

A Systematic Review of the Measurement of Function in Late-Life Depression.

Recovery of everyday premorbid function is a primary goal in the treatment of depression. Measurement of function is an important part of achieving this goal. A multitude of scales have been used to measure function in depression, reflecting the complex, multifaceted nature of functioning. Currently, however, there are no evidence-based guidelines to assist the researcher or clinician in deciding which instruments are best suited to measure function in late-life depression (LLD). Thus, the aims of this study are to 1) systematically review and identify the instrumental activities of daily living and social functioning assessment instruments used in the LLD literature; 2) identify and appraise the measurement properties of these instruments; and 3) suggest factors for LLD researchers and clinicians to consider when selecting functional assessment instruments and make pertinent recommendations. We performed a systematic review of MEDLINE and CINAHL to identify studies that i) incorporated subjects aged 60 years and older with a depressive disorder, and ii) measured instrumental activities of daily living and/or social functioning. Our search yielded 21 functional assessment instruments. Only two of these instruments, the 36-Item Short Form Survey and the Performance Assessment of Self-Care Skills, have formal validation data in LLD. Four additional instruments, although not formally validated, have relevant data regarding their measurement properties. The primary finding of this study is that very few functional assessment instruments have been validated in LLD, and the available measurement property data are mixed; there is a need for further instrument validation in late-life depression. With this caveat in mind, we provide evidence-based suggestions for researchers and clinicians assessing functioning in LLD patients.

Factors Associated With Global Variability in Electroconvulsive Therapy Utilization.

OBJECTIVES: The aims of this study were to investigate the social and economic factors that contribute to global variability in electroconvulsive therapy (ECT) utilization and to contrast these to the factors associated with antidepressant medication rates. METHODS: Rates of ECT and antidepressant utilization across nations and data on health, social, and economic indices were obtained from multiple international organizations including the World Health Organization and the Organization for Economic Co-operation and Development, as well as from the published literature. To assess whether relationships exist between selected indices and each of the outcome measures, a correlational analysis was conducted using Pearson correlation coefficients. Those that were significant at a level of P < 0.05 in the correlation analysis were selected for entry into the multivariate analyses. Selected predictor variables were entered into a stepwise multiple regression models for ECT and antidepressant utilization rates separately. RESULTS: A stepwise multiple regression analysis indicated that government expenditure on mental health was the only significant contributor to the model, explaining 34.2% of global variation in ECT use worldwide. Human Development Index was the only variable found to be significantly correlated with global antidepressant utilization, accounting for 71% of the variation in global antidepressant utilization. CONCLUSIONS: These findings suggest that across the globe ECT but not antidepressant medication utilization is associated with the degree to which a nation financially invests in mental health care for its citizens.