How Academic Health Systems Can Be Ready for the Next Pandemic.

The COVID-19 pandemic created significant challenges for academic health systems (AHSs) across their tripartite mission of providing clinical care, conducting research, and educating learners. Despite these challenges, AHSs played an invaluable role in responding to the pandemic. Clinicians worked tirelessly to care for patients, and institutions quickly reoriented their care delivery systems. Furthermore, AHSs played an important role in advancing science, launching studies and clinical trials to examine new vaccines and treatments for COVID-19. However, there is room for improvement; AHSs can use lessons learned from the COVID-19 pandemic to reshape their operations for the future. To prepare for the next pandemic, AHSs must modernize, adapt, and transform their clinical operations, research infrastructure, and educational programs to include public health and to build surveillance capacity for detecting, monitoring, and managing emerging outbreaks. In this Invited Commentary, the authors describe the opportunities AHSs have to build on their experiences during the COVID-19 pandemic and the ways they can take advantage of their unique strengths in each of their 3 mission areas. Within clinical care, AHSs can reach patients outside traditional clinical settings, build national and regional networks, advance data-driven insights, engage with the community, and support and protect the workforce. Within research, they can leverage data science and artificial intelligence, perform pandemic forecasting, leverage the social and behavioral sciences, conduct clinical trials, and build a research and development preparedness and operational plan. Within education, AHSs can promote remote learning, make interprofessional learning the norm, and build a system of continuing education.

A pilot randomized controlled trial using EEG-based brain-computer interface training for a Chinese-speaking group of healthy elderly.

BACKGROUND: There is growing evidence that cognitive training (CT) can improve the cognitive functioning of the elderly. CT may be influenced by cultural and linguistic factors, but research examining CT programs has mostly been conducted on Western populations. We have developed an innovative electroencephalography (EEG)-based brain-computer interface (BCI) CT program that has shown preliminary efficacy in improving cognition in 32 healthy English-speaking elderly adults in Singapore. In this second pilot trial, we examine the acceptability, safety, and preliminary efficacy of our BCI CT program in healthy Chinese-speaking Singaporean elderly. METHODS: Thirty-nine elderly participants were randomized into intervention (n=21) and wait-list control (n=18) arms. Intervention consisted of 24 half-hour sessions with our BCI-based CT training system to be completed in 8 weeks; the control arm received the same intervention after an initial 8-week waiting period. At the end of the training, a usability and acceptability questionnaire was administered. Efficacy was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which was translated and culturally adapted for the Chinese-speaking local population. Users were asked about any adverse events experienced after each session as a safety measure. RESULTS: The training was deemed easily usable and acceptable by senior users. The median difference in the change scores pre- and post-training of the modified RBANS total score was 8.0 (95% confidence interval [CI]: 0.0-16.0, P=0.042) higher in the intervention arm than waitlist control, while the mean difference was 9.0 (95% CI: 1.7-16.2, P=0.017). Ten (30.3%) participants reported a total of 16 adverse events - all of which were graded "mild" except for one graded "moderate". CONCLUSION: Our BCI training system shows potential in improving cognition in both English- and Chinese-speaking elderly, and deserves further evaluation in a Phase III trial. Overall, participants responded positively on the usability and acceptability questionnaire.

Proceedings of the 2013 CINP summit: innovative partnerships to accelerate CNS drug discovery for improved patient care.

Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21(st) century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues, Prevention, early diagnosis, and treatment, Linking science and regulation, Patient involvement in trial design, definition of endpoints, etc., Novel trial design, Reproduction and confirmation of data, Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority), Large-scale, global patient registries, Editorials on nomenclature, biomarkers, and diagnostic tools, and Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos, Switzerland. In this context Professor Barbara Sahakian recently made a formal presentation at the World Economic Forum (see Barbara Sahakian Blog from April 11, 2014, at https://forumblog.org/people/barbara-sahakian/) Full details of the discussions that formed the bases for these actions are presented in the main body of this document.

A brain-computer interface based cognitive training system for healthy elderly: a randomized control pilot study for usability and preliminary efficacy.

UNLABELLED: Cognitive decline in aging is a pressing issue associated with significant healthcare costs and deterioration in quality of life. Previously, we reported the successful use of a novel brain-computer interface (BCI) training system in improving symptoms of attention deficit hyperactivity disorder. Here, we examine the feasibility of the BCI system with a new game that incorporates memory training in improving memory and attention in a pilot sample of healthy elderly. This study investigates the safety, usability and acceptability of our BCI system to elderly, and obtains an efficacy estimate to warrant a phase III trial. Thirty-one healthy elderly were randomized into intervention (n = 15) and waitlist control arms (n = 16). Intervention consisted of an 8-week training comprising 24 half-hour sessions. A usability and acceptability questionnaire was administered at the end of training. Safety was investigated by querying users about adverse events after every session. Efficacy of the system was measured by the change of total score from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) before and after training. Feedback on the usability and acceptability questionnaire was positive. No adverse events were reported for all participants across all sessions. Though the median difference in the RBANS change scores between arms was not statistically significant, an effect size of 0.6SD was obtained, which reflects potential clinical utility according to Simon's randomized phase II trial design. Pooled data from both arms also showed that the median change in total scores pre and post-training was statistically significant (Mdn = 4.0; p<0.001). Specifically, there were significant improvements in immediate memory (p = 0.038), visuospatial/constructional (p = 0.014), attention (p = 0.039), and delayed memory (p<0.001) scores. Our BCI-based system shows promise in improving memory and attention in healthy elderly, and appears to be safe, user-friendly and acceptable to senior users. Given the efficacy signal, a phase III trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01661894.

A brain-computer interface based attention training program for treating attention deficit hyperactivity disorder.

UNLABELLED: Attention deficit hyperactivity disorder (ADHD) symptoms can be difficult to treat. We previously reported that a 20-session brain-computer interface (BCI) attention training programme improved ADHD symptoms. Here, we investigated a new more intensive BCI-based attention training game system on 20 unmedicated ADHD children (16 males, 4 females) with significant inattentive symptoms (combined and inattentive ADHD subtypes). This new system monitored attention through a head band with dry EEG sensors, which was used to drive a feed forward game. The system was calibrated for each user by measuring the EEG parameters during a Stroop task. Treatment consisted of an 8-week training comprising 24 sessions followed by 3 once-monthly booster training sessions. Following intervention, both parent-rated inattentive and hyperactive-impulsive symptoms on the ADHD Rating Scale showed significant improvement. At week 8, the mean improvement was -4.6 (5.9) and -4.7 (5.6) respectively for inattentive symptoms and hyperactive-impulsive symptoms (both p<0.01). Cohen's d effect size for inattentive symptoms was large at 0.78 at week 8 and 0.84 at week 24 (post-boosters). Further analysis showed that the change in the EEG based BCI ADHD severity measure correlated with the change ADHD Rating Scale scores. The BCI-based attention training game system is a potential new treatment for ADHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01344044.

Metabolomics: a global biochemical approach to the study of central nervous system diseases.

Metabolomics, the omics science of biochemistry, is a global approach to understanding regulation of metabolic pathways and metabolic networks of a biological system. Metabolomics complements data derived from genomics, transcriptomics, and proteomics to assist in providing a systems approach to the study of human health and disease. In this review we focus on applications of metabolomics for the study of diseases of the nervous system. We share concepts in metabolomics, tools used in metabolic profiling and early findings from the study of neuropsychiatric diseases, and drugs used to treat these diseases. Metabolomics emerges as another powerful tool in central nervous system research.

Towards a scientific taxonomy of depression.

Many concepts have been introduced into the classification of depression, including manic-depressive/bipolar disorder depression, etc. Kraepelin's original concept of manic-depressive disorder has evolved into the concept of polarity, and bipolar and unipolar disorders. Psychiatric classification is characterized by an inflation of the diagnostic categories, including subtypes of depression. This rapid multiplier effect is primarily descriptive, and there is a need to rethink, in a pragmatic fashion, the classification system, in order to develop one that is likely to be of utility and which has a scientific basis. Is the time now right to ask whether there are essential conditions relevant to depression? I think that it is, and here I will introduce the notion with two such conditions. The first is early life stress disorder, and the second vascular depression. These conditions have reached a point where the data supports them as distinct entities. In this paper, the rationale for this is discussed.

The vascular depression subtype: evidence of internal validity.

BACKGROUND: Vascular depression has been proposed as a unique diagnostic subtype in late life, yet no study has evaluated whether the specified clinical features associated with the illness are jointly indicative of an underlying diagnostic class. METHODS: We applied latent class analysis to two independent clinical samples: the prospective, cohort design, Neurocognitive Outcomes of Depression in the Elderly (NCODE) study and the 8-week, multicenter, double blind, placebo-controlled Old-Old study. RESULTS: A two-class model consisting of vascular and nonvascular depressed patients provided an excellent fit to the data in both studies, chi(2)(6) = 2.02, p = .90 in the NCODE study and chi(2)(6) = 7.024, p = .32 in the Old-Old study. Although all of the proposed features of vascular depression were useful in identifying the illness, deep white matter lesion burden emerged with perfect sensitivity (1.00) and near-perfect specificity (.95), making it the only indicator necessary to determine class membership. CONCLUSIONS: These findings, replicated across two independent clinical samples, provide the first support for the internal validity of vascular depression as a subtype of late-life depression.

Predicting antipsychotic use in children.

UNLABELLED: Psychotropic medications are increasingly being used by children and adolescents. In an earlier report, we noted that boys were receiving atypical antipsychotics more frequently than were girls, (70% of the claims). Since diagnosis was not available in the data, we were unable to ascertain the reasons for this. In the present analysis, we examined a large clinical mental health database to ascertain the reason for antipsychotic use.We evaluated the extent to which race, gender, age and type of diagnosis accounted for atypical antipsychotic use in children. METHODS: The authors used an anonymous clinical database created at Duke University Medical Center. The database is based on the clinical document of care in the Department of Psychiatry. The data are de-identified per HIPAA guidelines and has an IRB exemption for use in clinical research. Patients analyzed were seen from 1999 to 2005 and were below the age of 18 at the time of clinical care. A total 3,268 patients, with a total of 7,701 visits comprise the analysis sample. Age, gender, race, and diagnosis were extracted as predictors of use of atypical antipsychotics. RESULTS: Males and older children were also more likely to use an atypical. African Americans were slightly more likely to use an atypical than whites. Patients whose diagnoses were classified as either psychotic or internalizing were also more likely to use an antipsychotic. CONCLUSION: The underlying reasons for the high level of use of atypicals in boys and in African Americans need to be investigated further.

Response inhibition predicts poor antidepressant treatment response in very old depressed patients.

OBJECTIVE: There have been mixed findings regarding the prognostic significance of age of onset, executive dysfunction, and hyperintensity burden on treatment outcome in late-life depression. METHODS: Growth curve models were fit to data from the only 8-week, double-blind, placebo controlled trial of citalopram (20-40 mg/day) in patients aged 75 years and older with unipolar depression. Baseline assessment included Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (to determine age at onset), Stroop Color-Word Test (to assess the response inhibition component of execution dysfunction), and structural magnetic resonance imaging (to determine hyperintensity burden). RESULTS: In the citalopram condition, patients with response inhibition (most impaired quartile) scored higher at endpoint than those without response inhibition. There were no effects for age of onset or hyperintensity load on response in the citalopram condition. In the placebo condition, patients with early-onset depression had higher depression scores at endpoint than patients with late-onset depression. CONCLUSION: Only response inhibition, a fundamental executive function, predicted poor treatment response to antidepressant medication. Although patients with response inhibition also showed deficits in reaction time, adjusting for reaction time in our final response inhibition model did not substantively change the findings.

Concept of disease in geriatric psychiatry.

The concept of disease in geriatric psychiatry has to keep up with the rapid expansion in knowledge about the putative etiology of various diseases of interest. This article reviews the new knowledge that has been acquired about dementia. The proposed classification system has two axes: one for clinical manifestations and the other for etiology. Implementing this nomenclature will allow rapid adaptation of new knowledge for causation while at the same time communicating information on the clinical state. This should improve our ability to incorporate and communicate new knowledge in a dynamic format. In turn, this strategy should improve our ability to discern particular features of a disease and refine our notion of its clinical presentation and lead toward novel and improved treatments for our patients.

Lobar distribution of lesion volumes in late-life depression: the Biomedical Informatics Research Network (BIRN).

White matter hyperintense lesions on T2-weighted images are associated with late-life depression. Little work has been carried out examining differences in lesion location between elderly individuals with and without depression. In contrast to previous studies examining total brain white matter lesion volume, this study examined lobar differences in white matter lesion volumes derived from brain magnetic resonance imaging. This study examined 49 subjects with a DSM-IV diagnosis of major depression and 50 comparison subjects without depression. All participants were age 60 years or older. White matter lesion volumes were measured in each hemisphere using a semiautomated segmentation process and localized to lobar regions using a lobar atlas created for this sample using the imaging tools provided by the Biomedical Informatics Research Network (BIRN). The lobar lesion volumes were compared against depression status. After controlling for age and hypertension, subjects with depression exhibited significantly greater total white matter lesion volume in both hemispheres and in both frontal lobes than did control subjects. Although a similar trend was observed in the parietal lobes, the difference did not reach a level of statistical significance. Models of the temporal and occipital lobes were not statistically significant. Older individuals with depression have greater white matter disease than healthy controls, predominantly in the frontal lobes. These changes are thought to disrupt neural circuits involved in mood regulation, thus increasing the risk of developing depression.

Mood disorders in the medically ill: scientific review and recommendations.

OBJECTIVE: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES: Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Treatment of depression in the medically ill.

Most studies on treatment methods in elderly depressive patients have included primarily patients in good physical health, excluding medical comorbidity, despite the fact that depression with medical comorbidity is the norm rather than the exception. In addition, depression is known to increase disability and mortality among the medically ill. This, therefore, becomes an extremely important issue. Although data are limited, the available evidence suggests that depression concomitant with medical illness can be treated. One or more of the selective serotonin reuptake inhibitors have demonstrated potential usefulness in depressed patients with ischemic heart disease, diabetes, dementia, and Parkinson's disease and in patients after stroke and after myocardial infarction. Large-scale trials are needed to assess not only the safety and effectiveness of agents for the treatment of depression in comorbid illness, but also the effects of depression on the course of the medical illness itself.

Prominent reduction in pyramidal neurons density in the orbitofrontal cortex of elderly depressed patients.

BACKGROUND: Elderly depressed patients have more vascular hyperintensities in frontal white matter and basal ganglia than elderly control subjects. Cell pathology that might be related to increased vascular hyperintensities has not been examined. METHODS: Postmortem samples from the orbitofrontal cortex (ORB) were collected in 15 elderly subjects with major depressive disorder (MDD) and 11 age-matched control subjects. Cell packing density of neurons and glia, density of pyramidal and nonpyramidal neurons, and cortical and laminar width were measured. RESULTS: The overall (layers I-VI) packing density of ORB neurons with pyramidal morphology was markedly decreased in MDD (by 30%) as compared with control subjects. Further laminar analysis of pyramidal neurons density revealed significant reductions in layers IIIc and V in MDD. In contrast, in MDD the density of nonpyramidal neurons and glia and cortical and laminar width were comparable to control values. CONCLUSIONS: In elderly subjects with depression, the density of pyramidal neurons in the ORB was particularly low in cortical layers V and III, the origin of prefronto-striatal and prefronto-cortical and prefronto-amygdalar projections. Degeneration of neurons furnishing these projections might be related to the white matter hyperintensities previously observed. Neuronal pathology seems to be more severe in elderly than in younger subjects with MDD.

Magnitude of placebo response and drug-placebo differences across psychiatric disorders.

BACKGROUND: Placebo response, drug response, and drug-placebo differences appear to vary among psychiatric conditions. METHOD: We evaluated the Food and Drug Administration (FDA) Summary Basis of Approval (SBA) reports to compare the magnitude of placebo response, magnitude of psychotopic drug response, and drug placebo differences among various diagnostic groups such as depression, anxiety, and psychotic disorders. RESULTS: Six diagnostic groups (psychosis, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), depression, post-traumatic stress disorder, panic) varied in response to both placebo and active drug treatments. Response to placebo was high among patients participating in GAD, depression, and panic disorder clinical trials. Conversely, patients participating in psychotic disorder and OCD trials experienced low response to placebo. CONCLUSION: Our findings indicate that the magnitude of placebo response and drug response were heterogeneous and were statistically significantly different among various psychiatric disorders. Although a noticeable degree of heterogeneity was detected in the drug-placebo ratio among various disorders, the differences did not reach statistical significance. This finding suggests that placebo use should be continued for newer agents being tested for all of the psychiatric disorders. These findings may help in the development of psychopharmacology trial designs and in the deliberations of ethics committees.