Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).

A Cross-Sectional Decision-Making Approach to Inform Neuropsychological Battery Development in Professional Hockey.

OBJECTIVE: Neuropsychologists commonly use a large battery of tests to inform clinical decisions. Decision analysis can be used to determine which individual tests play a role in the decision-making process. The objective of this project was to conduct quantitative and qualitative decision analysis of decisions by team neuropsychologists with professional hockey players being evaluated as part of the National Hockey League (NHL)/NHL Players Association Concussion Protocol. METHOD: We extracted neuropsychological data from an NHL clinical program database. Team neuropsychologists evaluated concussed players using a hybrid neuropsychological test battery. The neuropsychologists then determined whether players were experiencing concussion-related cognitive difficulties. Logistic regression was used to examine which tests accounted for unique variance in the decision-making process. We also conducted a survey of NHL neuropsychologists, asking them to rate the usefulness of each test in the battery. RESULTS: Five of the fifteen measures accounted for unique variance in team neuropsychologists' decisions, including the ImPACT Verbal Memory Composite, Visual Motor Composite, Reaction Time Composite, Symptom Score, and Brief Visuospatial Memory Test-Revised Delayed Recall. Notable discrepancies were uncovered between quantitative indications of usefulness and self-reported qualitative perceptions of test usefulness when making decisions. Qualitatively, clinicians reported that the Hopkins Verbal Learning Test-Revised, Symbol Digit Modalities Test, ImPACT Reaction Time, and Color Trails 2 were the most useful tests when making decisions. CONCLUSIONS: Along with validation studies, decision analysis can be used as part of a comprehensive evaluation process to inform the development of best-practice batteries for use among athletes with sports concussion.

Disability measurement in Multiple Sclerosis patients 55 years and older: What is the Expanded Disability Status Scale really telling clinicians?

BACKGROUND: The Expanded Disability Status Scale (EDSS) measures disease progression in Multiple Sclerosis (MS). EDSS changes are assumed to be due to worsening MS-related disability. Strict interpretation of this premise may include some normal findings as abnormal, inflating the disability score. Further, determining the cause of neurologic symptoms can be difficult in an older population with comorbid illness and polypharmacy. OBJECTIVE: To examine the association between EDSS, age, comorbidities and polypharmacy. METHODS: 106 people, 55 years and older, with and without MS were administered the EDSS and a validated comorbidity questionnaire. Polypharmacy was also assessed. RESULTS: Median EDSS scores were 6.0 in people with MS and 3.0 in people without MS. No participant in our cohort had an EDSS of 0. Higher EDSS scores were associated with older age and more polypharmacy. Pyramidal and cerebellar functional systems accounted for the largest percentage of unique variance between groups. CONCLUSION: Older individuals with and without MS demonstrated significant disability on the EDSS. These findings indicate that EDSS scores may be partially due to factors other than MS. Our understanding of disease course and disability may benefit from the development of normative EDSS scores to correct for these factors.

Computer-Based Executive Function Training for Combat Veterans With PTSD: A Pilot Clinical Trial Assessing Feasibility and Predictors of Dropout.

Background: While evidence-based PTSD treatments are often efficacious, 20-50% of individuals continue to experience significant symptoms following treatment. Further, these treatments do not directly target associated neuropsychological deficits. Here, we describe the methods and feasibility for computer-based executive function training (EFT), a potential alternative or adjunctive PTSD treatment. Methods: Male combat veterans with full or partial PTSD (n = 20) and combat-exposed controls (used for normative comparison; n = 20) completed clinical, neuropsychological and functional neuroimaging assessments. Those with PTSD were assigned to EFT (n = 13) or placebo training (word games; n = 7) at home for 6 weeks, followed by repeat assessment. Baseline predictors of treatment completion were explored using logistic regressions. Individual feedback and changes in clinical symptoms, neuropsychological function, and neural activation patterns are described. Results: Dropout rates for EFT and placebo training were 38.5 and 57.1%, respectively. Baseline clinical severity and brain activation (i.e., prefrontal-insula-amygdala networks) during an emotional anticipation task were predictive of treatment completion. Decreases in clinical symptoms were observed following treatment in both groups. EFT participants improved on training tasks but not on traditional neuropsychological assessments. All training completers indicated liking EFT, and indicated they would engage in EFT (alone or as adjunctive treatment) if offered. Conclusion: Results provide an initial framework to explore the feasibility of placebo-controlled, computerized, home-based executive function training (EFT) on psychological and neuropsychological function and brain activation in combat veterans with PTSD. Clinical severity and neural reactivity to emotional stimuli may indicate which veterans will complete home-based computerized interventions. While EFT may serve as a potential alternative or adjunctive PTSD treatment, further research is warranted to address compliance and determine whether EFT may benefit functioning above and beyond placebo interventions.

PTSD and cognitive symptoms relate to inhibition-related prefrontal activation and functional connectivity.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with reduced executive functioning and verbal memory performance, as well as abnormal task-specific activity in prefrontal cortex (PFC) and anterior cingulate cortices (ACC). The current study examined how PTSD symptoms and neuropsychological performance in combat veterans relates to (1) medial PFC and ACC activity during cognitive inhibition, and (2) task-independent PFC functional connectivity. METHODS: Thirty-nine male combat veterans with varying levels of PTSD symptoms completed the multisource interference task during functional magnetic resonance imaging. Robust regression analyses were used to assess relationships between percent signal change (PSC: incongruent-congruent) and both PTSD severity and neuropsychological performance. Analyses were conducted voxel-wise and for PSC extracted from medial PFC and ACC regions of interest. Resting-state scans were available for veterans with PTSD. Regions identified via task-based analyses were used as seeds for resting-state connectivity analyses. RESULTS: Worse PTSD severity and neuropsychological performance related to less medial PFC and rostral ACC activity during interference processing, driven partly by increased activation to congruent trials. Worse PTSD severity related to reduced functional connectivity between these regions and bilateral, lateral PFC (Brodmann area 10). Worse neuropsychological performance related to reduced functional connectivity between these regions and the inferior frontal gyrus. CONCLUSIONS: PTSD and associated neuropsychological deficits may result from difficulties regulating medial PFC regions associated with "default mode," or self-referential processing. Further clarification of functional coupling deficits between default mode and executive control networks in PTSD may enhance understanding of neuropsychological and emotional symptoms and provide novel treatment targets.

A pilot study to improve adherence among MS patients who discontinue treatment against medical advice.

Between 30 and 50% of MS patients may prematurely discontinue disease modifying therapies. Little research has examined how to best talk with patients who have discontinued treatment against medical advice. The aim of this pilot study was to determine whether telephone counseling increases disease modifying therapy (DMT) re-initiation among nonadherent patients with multiple sclerosis (MS). Participants were eligible if they had relapsing-remitting disease, had stopped taking a DMT, and had no plan to re-initiate treatment despite a provider recommendation. Following a baseline assessment, 81 patients were randomly assigned to either five 20 min, weekly sessions of Motivational Interviewing/Cognitive Behavioral Therapy (MI-CBT) or Treatment as Usual (TAU) with brief education. At 10 weeks, patients initially assigned to TAU switched over to MI-CBT. Compared to patients in the TAU group, patients undergoing MI-CBT were significantly more likely to indicate they were re-initiating DMT (41.7 vs. 14.3%). These significant results were replicated among patients crossing over from TAU to MI-CBT. Treatment satisfaction was high, with 97% of participants reporting that they would recommend MI-CBT to other patients with MS. Results of this pilot study provide initial support for the use of MI-CBT among MS patients who have discontinued treatment against medical advice.Clinicaltrials.gov: NCT01925690.

Persistent nonmalignant pain management using nonsteroidal anti-inflammatory drugs in older patients and use of inappropriate adjuvant medications.

OBJECTIVE: Due to the high risk of life-threatening side effects, nonsteroidal anti-inflammatory drugs (NSAIDs) are not favored for treating persistent nonmalignant pain in the elderly. We report national prescription trends with determinants of NSAIDs prescription for persistent nonmalignant pain among older patients (age 65 and over) in the US outpatient setting. METHODS: A cross-sectional analysis was performed using National Ambulatory Medical Care Survey data. Prescriptions for NSAIDs, opioids, and adjuvant agents were identified using five-digit National Ambulatory Medical Care Survey drug codes. RESULTS: About 89% of the 206,879,848 weighted visits in the US from 2000 to 2007 recorded NSAIDs prescriptions in patients (mean age =75.4 years). Most NSAIDs users had Medicare (75%), and about 25% were prescribed with adjuvant medications considered inappropriate for their age. Compared to men, women were 1.79 times more likely to be prescribed NSAIDs. CONCLUSION: The high percentage of NSAIDs prescription in older patients is alarming. We recommend investigating the appropriateness of the high prevalence of NSAIDs use among older patients reported in our study.