Despite Recommendations, Anticholinergics Account for the Majority of Prescriptions to Treat Overactive Bladder in the United States.

IMPORTANCE: There are significant associations between anticholinergic medication use and an increased risk of cognitive impairment and dementia. Many experts now advocate minimizing the use of anticholinergic medications to treat overactive bladder (OAB) in elderly women. OBJECTIVE: The aim of this study was to describe temporal and geographic trends in the pharmacologic treatment of OAB for patients 65 years or older across the United States. STUDY DESIGN: The U.S. Centers for Medicare & Medicaid Services publishes annual Medicare Provider Utilization and Payment Data. The data set includes the number of unique Part D beneficiaries 65 years or older with at least 1 claim for a drug and the number of 30-day fills dispensed. The database also includes the U.S. state and rural-urban commuting area designation of the prescriber. RESULTS: From 2013 to 2019, Medicare Part D beneficiaries 65 years or older received 47.7 million 30-day fills for the treatment of OAB. In 2013, anticholinergics represented 98% of the total 30-day fills (5.6 million) for OAB. The use of ß3 agonists was nearly 24 times greater in 2019 than in 2013. Geographic variation in prescribing practices was evident. CONCLUSIONS: The number of anticholinergics dispensed for the treatment of OAB remained relatively stable, and there was a substantial increase in the use of ß3 agonists. Percentages of anticholinergics dispensed varied among states. More patients are being treated for OAB; however, anticholinergics comprised the majority of prescriptions for treatment in 2019.

Associations of PM2.5 intensity and duration with cognitive impairment: A longitudinal analysis of middle-aged and older adults in China.

Long-term exposure to air pollution is associated with a higher risk of cognitive impairment; however, the understanding of this association is incomplete. We aimed to explore the relationship between fine particulate matter (PM2.5) exposure and cognitive function using a prospective cohort of ageing adults, including 19,389 respondents in four waves of the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018) linked with the historical PM2.5 concentrations (2000-2018) in China. By extending the measurement of PM2.5 exposure from exposure intensity (averaged PM2.5 concentrations) to exposure duration (the number of months with higher PM2.5 concentrations), we employed two linear models, the fixed-effect and mixed-effect linear models, to estimate the associations between PM2.5 exposure and cognitive impairment, with adjustments for individual and regional covariates. Our findings show that the higher PM2.5 intensity was associated with worse cognitive function, but the associations were only statistically significant in a longer exposure period (more than one year), especially in the 10-year exposure (Coefficient: -0.13; 95% Confidence Interval: -0.22, -0.04). Similar patterns were seen for fully adjusted models of PM2.5 duration: a longer duration in PM2.5 exposure was associated with lower cognitive scores, and the duration with higher cut-off points had stronger effects on cognitive function except for the duration at 75 µg/m3, suggesting a possible coincidence of increasing air pollution and economic development. The stronger exposure to PM2.5 was associated with poorer cognitive function among Chinese adults, while more work is necessary to explore the causal effect of air pollution, independent of individual and contextual background characteristics.

Design and optimization of myricetin encapsulated nanostructured lipid carriers: In-vivo assessment against cognitive impairment in amyloid beta (1-42) intoxicated rats.

AIMS: This research aimed to evaluate the potential of MY loaded nanostructured lipid carrier (MY-NLCs) to ameliorate the bioavailability in the brain and cognitive impairment in Aß induced Alzheimer''s model. MATERIALS AND METHODS: MY-NLCs were prepared with precirol ATO 5, labrafac lipophile WL 1349, and tween 80 as solid lipid, liquid lipid, and surfactant respectively. The formulation was optimized with central composite design (CCD) and characterized by different parameters. Cellular toxicity and uptake studies were evaluated in SH-SY5Y cells. MY concentration in plasma and brain was analyzed after the i.p. administration of MYS and MY-NLCs (40 mg/kg) in Sprague-Dawley rats (n = 3). Further, the pharmacodynamic studies were evaluated in the (Aß1--42) induced (5 µg/5 µl, ICV, unilateral) Alzheimer''s rat model (n = 6) and cognitive performance was assessed using Morris water maze test followed by histological and neurotransmitters analyses in rats'' brain. KEY FINDINGS: The optimized MY-NLCs exhibited 89.7 ± 26.0 nm particle size, 80.81 ± 10.39% entrapment efficiency, and 5.08 ± 1.0% of drug loading capacity. The in-vitro release studies revealed a biphasic release pattern and also demonstrated distinct cellular internalization in SH-SY5Y cells. MY-NLCs exhibited 2.77 folds higher AUC 0-24 in plasma and drug targeting efficiency for MY into the brain was found 127.05% as compared to MYS. The mitigating potential of MY-NLCs (10 mg/kg) was also significantly observed in behavioral parameters and in the regulation of neurotransmitters levels in rat brain. SIGNIFICANCE: MY-NLCs would be explored as an alternative promising drug delivery platform for several neurodegenerative payloads.

Anticholinergic burden: First comprehensive analysis using claims data shows large variation by age and sex.

PURPOSE: The cumulative effect of medication inhibiting acetylcholine activity-also known as anticholinergic burden (AB)-can lead to functional and cognitive decline, falls, and death. Given that studies on the population prevalence of AB are rare, we aimed to describe it in a large and unselected population sample. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD) with claims data from ~20% of the German population we analyzed outpatient drug dispensations in 2016. Based on the Anticholinergic Cognitive Burden (ACB) scale, we classified persons into four categories and determined the cumulative AB as continuous variable. RESULTS: Among 16,470,946 persons (54% female), the prevalence of clinically relevant AB (ACB≥3) was 10% (women) and 7% (men). Below age 40 it was highest in persons ≤18 years (6% both sexes). At older ages (50-59 vs. 90-99 years), prevalence of ACB≥3 increased from 7% to 26% (men) and from 10% to 32% (women). Medication classes contributing to the cumulative AB differed by age: antihistamines, antibiotics, glucocorticoids (≤19 years), antidepressants (20-49 years), antidepressants, cardiovascular medication, antidiabetics (50-64 years), and additionally medication for urinary incontinence/overactive bladder (≥65 years). Medication dispensed by general physicians contributed most to the cumulative AB. CONCLUSION: Although a clinically relevant AB is particularly common in older persons, prevalence in younger age groups was up to 7%. Given the risks associated with AB in older persons, targeted interventions at the prescriber level are needed. Furthermore, risks associated with AB in younger persons should be explored.

Assessment of cognitive and psychomotor impairment, subjective effects, and blood THC concentrations following acute administration of oral and vaporized cannabis.

BACKGROUND: Cannabis legalization is expanding, but there are no established methods for detecting cannabis impairment. AIM: Characterize the acute impairing effects of oral and vaporized cannabis using various performance tests. METHODS: Participants (N = 20, 10 men/10 women) who were infrequent cannabis users ingested cannabis brownies (0, 10, and 25 mg Δ-9-tetrahydrocannabinol, THC) and inhaled vaporized cannabis (0, 5, and 20 mg THC) in six double-blind outpatient sessions. Cognitive/psychomotor impairment was assessed with a battery of computerized tasks sensitive to cannabis effects, a novel test (the DRiving Under the Influence of Drugs, DRUID®), and field sobriety tests. Blood THC concentrations and subjective drug effects were evaluated. RESULTS: Low oral/vaporized doses did not impair cognitive/psychomotor performance relative to placebo but produced positive subjective effects. High oral/vaporized doses impaired cognitive/psychomotor performance and increased positive and negative subjective effects. The DRUID® was the most sensitive test to cannabis impairment, as it detected significant differences between placebo and active doses within both routes of administration. Women displayed more impairment on the DRUID® than men at the high vaporized dose only. Field sobriety tests showed little sensitivity to cannabis-induced impairment. Blood THC concentrations were far lower after cannabis ingestion versus inhalation. After inhalation, blood THC concentrations typically returned to baseline well before pharmacodynamic effects subsided. CONCLUSIONS: Standard approaches for identifying impairment due to cannabis exposure (i.e. blood THC and field sobriety tests) have severe limitations. There is a need to identify novel biomarkers of cannabis exposure and/or behavioral tests like the DRUID® that can reliably and accurately detect cannabis impairment at the roadside and in the workplace.

Exposure to Anticholinergic and Sedative Drugs and Healthcare Costs in Older Patients with Neurocognitive Disorders.

BACKGROUND: Literature supports an increasing number of older patients living with neurocognitive disorders alongside with their annual worldwide costs. Therapeutic management of behavioral and psychological symptoms includes the use of anticholinergic and sedative drugs for which significant exposure is negatively associated with clinical outcomes. OBJECTIVE: The aim of this study was to assess the healthcare costs differences related to an increase in the exposure to anticholinergic and sedative drugs in older patients with neurocognitive disorder. METHODS: A longitudinal study was conducted during 3 years on 1,604 participants of the MEMORA cohort linked with both regional public health insurance and hospital discharge databases between 2012 and 2017. Direct medical and non-medical costs were included. Exposure to anticholinergic and sedative drugs was measured by the drug burden index (DBI). RESULTS: Costs difference associated with a DBI≥0.5 were + 338€ (p < 0.001). After adjustment on comorbidities, NCD stage, cognitive impairment, functional limitation, polypharmacy, and sociodemographic characteristics, a DBI≥0.5 was found to be an independent predictor of an increase of total healthcare costs by 22%(p < 0.001). CONCLUSION: Anticholinergic and sedative drugs have a substantial economic burden among older patients with neurocognitive disorder. More studies are required to assess the clinical and economic impact of an efficient strategy based on the reduction of the exposure to anticholinergic and sedative drugs and the promotion of non-pharmacological interventions.

Medication Management Performance in Parkinson's Disease: Examination of Process Errors.

OBJECTIVE: Individuals with Parkinson's disease (PD) are at risk for increased medication mismanagement, which can lead to worse clinical outcomes. However, the nature of the errors (i.e., undertaking or overtaking medications) contributing to mismanagement and their relationship to cognition in PD is unknown. Therefore, this study sought to examine errors committed on the Medication Management Ability Assessment (MMAA) between PD participants with normal cognition (PD-NC) or mild cognitive impairment (PD-MCI) relative to healthy adults (HA). METHOD: HA (n = 74), PD-NC (n = 102), and PD-MCI (n = 45) participants were administered the MMAA to assess undertaking, overtaking, and overall errors as well as overall performance (total score). Additionally, participants were administered a comprehensive neuropsychological battery from which cognitive composites of Attention, Learning, Memory, Language, Visuospatial, and Executive Functioning were derived. RESULTS: Separate negative binomial regression analyses indicated the PD-MCI group performed significantly worse overall on the MMAA (total score) and committed more undertaking and overall errors relative to HA and PD-NC. In the PD-MCI group, poorer MMAA performance was associated with worse delayed memory performance, whereas cognitive performance was not related to MMAA in HA or PC-NC. CONCLUSION: Compared to PD and healthy adults with normal cognition, PD-MCI patients exhibited greater difficulty with medication management, particularly with undertaking medications. Poorer medication management in PD-MCI was associated with worse delayed recall. Thus, PD-MCI patients experiencing memory problems may require additional assistance with their medications. Findings have clinical relevance suggesting that objective measures of medication errors may assist clinicians in identifying PD patients needing adherence strategies.

Pharmacist Identification of Medication Therapy Problems Involving Cognition Among Older Adults Followed by a Home-Based Care Team.

BACKGROUND: Dementia, depression, and delirium alone or in combination (3Ds) can threaten independence among older adults, and polypharmacy may further accelerate decline. Clinical pharmacists can play an important role on multidisciplinary home-based care teams by identifying medication therapy problems (MTPs) involving cognition. Within a larger ongoing clinical trial, this paper describes cognition-related MTPs and pharmacist recommendations among older adults with 3Ds followed by a home-based care team. METHODS: We conducted a retrospective analysis of medication data among Medicare Advantage members aged ≥ 65 years living at home in Connecticut with International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes related to 3Ds; analyses include the first 105 subjects randomized to the home-based care team from March 2017 to January 2019. Advanced practice registered nurses conducted in-home medication reconciliations along with medical and cognitive assessments. Clinical pharmacists then conducted medication reviews centered on agents treating or exacerbating 3Ds. After review by the study advanced practice registered nurse, geriatrician, and psychiatrist, salient recommendations were forwarded to primary care providers for consideration. Medication therapy problems related to cognition were retrospectively abstracted and classified as: (1) indication: underuse or overuse; (2) effectiveness: ineffective agent or low dose (mainly for antidepressants); and (3) safety: undesirable effect (e.g., impaired cognition, dementia treatment side effects), unsafe medication (e.g., potentially inappropriate medications that can harm cognition), drug interaction, or high dose. RESULTS: Pharmacists identified 166 cognitive MTPs, with a mean (standard deviation) of 1.58 (1.35) [range 0-6] MTPs per subject. Indication MTPs represented 34% of total MTPs, of which 79% involved underuse and 21% overuse; effectiveness represented 13% of total MTPs; and safety represented over half (52%) of all MTPs, with benzodiazepines and anticholinergics frequently implicated. Recommendations commonly included medication reduction (discontinuation 23% and dose reduction 19%). We found MTPs involving cognition among most (79%) patients. CONCLUSIONS: Our study findings support the role of pharmacists on multidisciplinary teams to identify cognitively harmful medications, dementia treatment side effects, and untreated cognitive conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02945085.

Zolpidem Versus Trazodone Initiation and the Risk of Fall-Related Fractures among Individuals Receiving Maintenance Hemodialysis.

BACKGROUND AND OBJECTIVES: Zolpidem, a nonbenzodiazepine hypnotic, and trazodone, a sedating antidepressant, are the most common medications used to treat insomnia in the United States. Both drugs have side effect profiles (e.g., drowsiness, dizziness, and cognitive and motor impairment) that can heighten the risk of falls and fractures. Despite widespread zolpidem and trazodone use, little is known about the comparative safety of these medications in patients receiving hemodialysis, a vulnerable population with an exceedingly high fracture rate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the United States Renal Data System registry (2013-2016), we conducted a retrospective cohort study to investigate the association between the initiation of zolpidem versus trazodone therapy and the 30-day risk of hospitalized fall-related fractures among Medicare-enrolled patients receiving maintenance hemodialysis. We used an active comparator new-user design and estimated 30-day inverse probability of treatment-weighted hazard ratios and risk differences. We treated death as a competing event. RESULTS: A total of 31,055 patients were included: 18,941 zolpidem initiators (61%) and 12,114 trazodone initiators (39%). During the 30-day follow-up period, 101 fall-related fractures occurred. Zolpidem versus trazodone initiation was associated with a higher risk of hospitalized fall-related fracture (weighted hazard ratio, 1.71; 95% confidence interval, 1.11 to 2.63; weighted risk difference, 0.17%; 95% confidence interval, 0.07% to 0.29%). This association was more pronounced among individuals prescribed higher zolpidem doses (hazard ratio, 1.85; 95% confidence interval, 1.10 to 3.01; and risk difference, 0.20%; 95% confidence interval, 0.04% to 0.38% for higher-dose zolpidem versus trazodone; and hazard ratio, 1.60; 95% confidence interval, 1.01 to 2.55 and risk difference, 0.14%; 95% confidence interval, 0.03% to 0.27% for lower-dose zolpidem versus trazodone). Sensitivity analyses using longer follow-up durations yielded similar results. CONCLUSIONS: Among individuals receiving maintenance hemodialysis, zolpidem initiators had a higher risk of hospitalized fall-related fracture compared with trazodone initiators. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_12_18_CJN10070620_final.mp3.

The association between antidepressants use and development of cognitive impairment among older women diagnosed with breast cancer.

PURPOSE: This study aimed to evaluate the association between the development of cognitive impairment and the use of antidepressants among older women with breast cancer. METHODS: This retrospective cohort study used the United States National Cancer Institute's Surveillance, Epidemiology, and End Results-Medicare database to identify women who were 67 years old and older and had breast cancer between 2008 and 2013. Propensity scoring was used to account for confounding pre-treatment factors, and Cox proportional hazards modeling was used to examine the risk of developing cognitive impairment among patients based on whether they used antidepressants. RESULTS: A total of 3174 women taking antidepressants (mean age 75.2 ± 6.4) were matched with 3174 women not taking antidepressants (mean age 75.4 ± 6.7). Antidepressant use was associated with a significantly increased risk of cognitive impairment (hazard ratio [HR]: 1.33, 95%; confidence interval [CI]: 1.18-1.48). Additionally, we found that older women without a history of depression or anxiety who use antidepressants have a higher risk of developing cognitive impairment than those who did not use antidepressants (HR: 1.53, 95%; CI: 1.34-1.75 and HR: 1.39, 95%; CI: 1.23-1.56, respectively). Subgroup analysis showed that the use of non-tricyclic antidepressants (TCAs) was associated with a higher risk of cognitive impairment. CONCLUSION: We found that non-TCA antidepressant use in older women with breast cancer was associated with a higher risk of cognitive impairment. This association was also observed among older women without depression or anxiety who used antidepressants.

One-Year Evaluation of a Targeted Medication Therapy Management Intervention for Older Adults.

BACKGROUND: Older adults are especially susceptible to adverse effects of inappropriate medication therapy, and anticholinergic medications are common culprits for cognitive dysfunction due to their action on the central nervous system. Medication therapy management (MTM) interventions can aid in deprescribing and reducing inappropriate medication use in older adults. However, there is sparse literature on the long-term sustainability of these interventions. OBJECTIVES: To (a) investigate whether the deprescribing of anticholinergic medications during an 8-week randomized controlled trial (RCT) of a targeted MTM intervention is sustained at 1-year postintervention follow-up and (b) compare anticholinergic utilization trends in the study population with a large sample of similar individuals not exposed to the intervention. METHODS: Participants in the targeted MTM (tMTM) RCT had normal cognition or mild cognitive impairment and were recruited from enrollees in a longitudinal study at the University of Kentucky Alzheimer's Disease Center (ADC) and thus have pertinent medical information gathered approximately annually. In this posttrial observational follow-up, sustainability of the anticholinergic deprescribing intervention was assessed in participants in the RCT, and anticholinergic medication use trends were described from the RCT baseline (which occurred immediately following an ADC visit) to the next annual visit in all participants. Mean change in anticholinergic burden from RCT baseline to the next annual visit was estimated using analysis of covariance, and participants were compared with 2 external samples. Anticholinergic burden was measured using the Anticholinergic Drug Scale (ADS). The odds of decreasing baseline anticholinergic burden and number of total and strong anticholinergic medications at the follow-up study time point was assessed using logistic regression. RESULTS: Of the deprescribing changes made during the initial RCT, 50% were sustained after 1 year. Participants in the tMTM trial reported decreases in the use of anticholinergic antihistamines and bladder agents (-6.5 and -4.4%, respectively), but there was no change in the use of anticholinergic agents targeted at the central nervous system. While the anticholinergic burden of RCT participants decreased over 1 year (adjusted mean ADS change [95% CI] = -0.33 [-0.72, 0.07]), it was not different than the change observed in 2 external samples at the trial center (-0.20 [-0.42, 0.02]) and nationally (-0.33 [-0.39, -0.26]). There were no statistically significant differences between trial participants and external samples in the odds of decreasing anticholinergic burden nor in decreasing the number of total, or strongly anticholinergic, medications at the 1-year follow-up. CONCLUSIONS: This study demonstrates that the sustainability of deprescribing is limited to the period of intervention, rather than affording lasting effects even over periods as short as 1 year, which was demonstrated not only in the small group of RCT participants but also by comparison with external groups. Future work should extend the duration of intervention and follow-up periods for MTM interventions to allow further insights regarding the sustainability of deprescribing efforts in older adults. DISCLOSURES: The original trial was supported by a pilot study award from the University of Kentucky Center for Clinical and Translational Sciences (UL1TR000117). Additional support for this study was provided by the National Institutes of Health/National Institute on Aging (R01 AG054130). Jicha reports contract research for Esai, Biohaven, Alltech, Suven, Novartis, and Lilly. The other authors have nothing to disclose.

Assessment of the Dose-Response Relationship Between Folate Exposure and Cognitive Impairment: Synthesizing Data from Documented Studies.

The dose-response relationship between folate levels and cognitive impairment among individuals with vitamin B12 deficiency is an essential component of a risk-benefit analysis approach to regulatory and policy recommendations regarding folic acid fortification. Epidemiological studies provide data that are potentially useful for addressing this research question, but the lack of analysis and reporting of data in a manner suitable for dose-response purposes hinders the application of the traditional evidence synthesis process. This study aimed to estimate a quantitative dose-response relationship between folate exposure and the risk of cognitive impairment among older adults with vitamin B12 deficiency using "probabilistic meta-analysis," a novel approach for synthesizing data from observational studies. Second-order multistage regression was identified as the best-fit model for the association between the probability of cognitive impairment and serum folate levels based on data generated by randomly sampling probabilistic distributions with parameters estimated based on summarized information reported in relevant publications. The findings indicate a "J-shape" effect of serum folate levels on the occurrence of cognitive impairment. In particular, an excessive level of folate exposure is predicted to be associated with a higher risk of cognitive impairment, albeit with greater uncertainty than the association between low folate exposure and cognitive impairment. This study directly contributes to the development of a practical solution to synthesize observational evidence for dose-response assessment purposes, which will help strengthen future nutritional risk assessments for the purpose of informing decisions on nutrient fortification in food.

Anticholinergic burden and risk of cognitive impairment in elderly nursing home residents with depression.

BACKGROUND: Although the adverse cognitive effects of anticholinergic medications in the elderly are well-documented, little is known regarding the cognitive impact of anticholinergics among nursing home residents with depression. OBJECTIVE: This study examined the risk of mild-to-moderate cognitive impairment due to anticholinergic burden among elderly nursing home residents with depression. METHODS: A population-based nested case-control study was conducted using Minimum Data Set (MDS)-linked Medicare data where the base cohort included patients ≥ 65 years with depression who had intact cognition (MDS Cognition score of 0 or 1) and no dementia. Cases were identified as those who had mild-to-moderate cognition (MDS Cognition score of 2-4). Each case was matched on age and sex to one control using incidence density sampling. The study evaluated cumulative anticholinergic burden (defined as score of 3 or more) within 30, 60 and 90 days preceding the event date based on the Anticholinergic Drug Scale (ADS). Conditional logistic regression model stratified on matched case-control sets was performed to evalaute cognitive impairment due to cumulative anticholinergic burden after controlling for other risk factors. RESULTS: The study sample included 3707 cases with mild-to-moderate cognition and 3707 matched controls with intact cognition. Bivariate analysis showed significant association between cumulative anticholinergic exposure and cognitive impairment (Odds Ratio [OR], 1.15; 95% Confidence Interval [CI],1.04-1.30); after controlling for potential risk factors, cumulative anticholinergic exposure 30 days preceding the event was no longer associated with cognitive impairment, (aOR, 1.07; 95% CI, 0.95-1.21). However, the odds of cognitive impairment increased with cumulative anticholinergic exposure 60 days (aOR 1.16; 1.04-1.30) and 90 days (aOR 1.28; 1.14-1.44) before the event date. CONCLUSION: Cumulative anticholinergic use for prolonged exposure periods was associated with modestly increased risk of cognitive impairment in elderly residents with depression who had intact cognition. The findings suggest the need to be cautious when prescribing multiple anticholinergic drugs in residents, including those with intact cognition.

Validation of the Japanese Version of the Functional Assessment of Cancer Therapy-Cognitive Function Version 3.

CONTEXT: Cancer therapy-induced cognitive impairment adversely affects the quality of life of patients with cancer but cannot be detected by neuropsychological tests. OBJECTIVES: This study aimed to validate a Japanese version of the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) version 3, which is a self-report measure of the cognitive concerns of patients with cancer. METHODS: The FACT-Cog was translated into Japanese and pilot tested with five patients with breast cancer and five patients with hematologic malignancy. Study participants were recruited in Hiroshima University Hospital and Kagawa Breast Clinic in Hiroshima, Japan. Patients with breast cancer (N = 236) responded to the resultant assessment and Functional Assessment of Cancer Therapy-General version 4. The internal consistency and concurrent and construct validity of the FACT-Cog were examined. RESULTS: The Cronbach's alphas of the four FACT-Cog subscales, namely, CogPCI, CogOth, CogPCA, and CogQOL, were 0.95, 0.73, 0.93, and 0.88, respectively. The item-to-domain correlations ranged from 0.211 to 0.920. Most of the FACT-Cog subscales were significantly correlated with other subscale and total scores (r = 0.133-0.425). Structural equation modeling was barely acceptable (χ2 = 1361.8, df = 489, P < 0.001; goodness of fit index = 0.731, adjusted goodness of fit index = 0.691, comparative fit index = 0.848, root-mean-square error of approximation = 0.087). CONCLUSION: The Japanese version of the FACT-Cog is a valid and reliable self-report measure of the cognitive function of patients with breast cancer. Its utility to clinicians and researchers in measuring the cognitive concerns of patients with cancer in Japan will serve as a further test of its validity.

Quantitative assessment of cerebral connectivity deficiency and cognitive impairment in children with prenatal alcohol exposure.

It is common knowledge that alcohol consumption during pregnancy would cause cognitive impairment in children. However, recent works suggested that the risk of drinking during pregnancy may have been exaggerated. It is critical to determine whether and up to which amount the consumption of alcohol will affect the cognitive development of children. We evaluate time-varying functional connectivity using magnetoencephalogram data from somatosensory evoked response experiments for 19 teenage subjects with prenatal alcohol exposure and 21 healthy control teenage subjects using a new time-varying connectivity approach, combining renormalised partial directed coherence with state space modeling. Children exposed to alcohol prenatally are at risk of developing a Fetal Alcohol Spectrum Disorder (FASD) characterized by cerebral connectivity deficiency and impaired cognitive abilities. Through a comparison study of teenage subjects exposed to alcohol prenatally with healthy control subjects, we establish that the inter-hemispheric connectivity is deficient for the former, which may lead to disruption in the cortical inter-hemispheric connectivity and deficits in higher order cognitive functions as measured by an IQ test, for example. We provide quantitative evidence that the disruption is correlated with cognitive deficits. These findings could lead to a novel, highly sensitive biomarker for FASD and support a recommendation of no safe amount of alcohol consumption during pregnancy.

The Relation Between ADHD Medication and Mild Cognitive Impairment, as Assessed by the Montreal Cognitive Assessment (MoCA), in Patients Entering Substance Use Disorder Inpatient Treatment.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) frequently co-occurs with substance use disorders and has some overlapping symptoms with mild cognitive impairment, including executive functions. We wanted to investigate whether patients with ADHD have an excess risk of mild cognitive impairment-like symptoms, as defined by the Montreal Cognitive Assessment (MoCA). Second, we assessed the impact of ADHD medication on the dichotomized MoCA for patients with ADHD. METHODS: The participants in this study were 129 inpatients at seven treatment clinics in Norway. All were screened with the MoCA. We calculated relative risk estimates (RR) for scoring in the mild cognitive impairment range (< 26) for those having ADHD. Finally, we calculated the RR for the patients within the ADHD group who were taking medication. RESULTS: Of the 129 participants included in the analyses, 38 (29.5%) scored below the MoCA threshold (< 26), and 24 (18.6%) had ADHD that was diagnosed before or during the inpatient treatment. Of the 105 participants without ADHD, 31 (29.5%) scored below the threshold. Seven (29.2%) of those with ADHD scored below the threshold. The risk of scoring in the mild cognitive impairment range for those with and without ADHD was equal (RR = 0.98). Of the 24 patients with ADHD, 9 (37.5%) were taking medication at the time of testing. One of the patients taking medication scored below the threshold compared to six of those not taking medication. This suggests a 72% lower risk of mild cognitive impairment-like symptoms when taking medication (RR = 0.28); however, the effect was not significant. CONCLUSIONS: We revealed no excess risk of mild cognitive impairment-like symptoms for the ADHD group. However, within the ADHD group, there was a possible lower risk of mild cognitive impairment-like symptoms for patients taking medication. These results suggest that there may be a confounding overlap of symptoms between ADHD and cognitive function screens that necessitates adequate assessment and treatment of ADHD before screening or measuring cognitive function.

Differential Prescribing of Antimuscarinic Agents in Older Adults with Cognitive Impairment.

BACKGROUND: Oral oxybutynin has been associated with the development of cognitive impairment. OBJECTIVE: The objective of this study was to describe the use of oral oxybutynin versus other antimuscarinics (e.g., tolterodine, darifenacin, solifenacin, trospium, fesoterodine, transdermal oxybutynin) in older adults with documented cognitive impairment. METHODS: This is a population-based retrospective analysis of antimuscarinic new users aged ≥ 66 years from January 2008 to December 2011 (n = 42,886) using a 5% random sample of Medicare claims linked with Part D data. Cognitive impairment was defined as a diagnosis of mild cognitive impairment, dementia, use of antidementia medication, and memory loss/drug-induced cognitive conditions in the year prior to the initial antimuscarinic claim. We used multivariable generalized linear models to assess indicators of cognitive impairment associated with initiation of oral oxybutynin versus other antimuscarinics after adjusting for comorbid conditions. RESULTS: In total, 33% received oral oxybutynin as initial therapy. Cognitive impairment was documented in 10,259 (23.9%) patients prior to antimuscarinic therapy. Patients with cognitive impairment were 5% more likely to initiate another antimuscarinic versus oral oxybutynin (relative risk [RR] 1.05; 95% confidence interval [CI] 1.03-1.06). The proportion of patients with cognitive impairment initiated on oral oxybutynin increased from 24.1% in 2008 to 41.1% in 2011. The total cost of oral oxybutynin, in $US, year 2011 values, decreased by 10.5%, whereas the total cost of other antimuscarinics increased by 50.3% from 2008 to 2011. CONCLUSION: Our findings suggest opportunities for quality improvement of antimuscarinic prescribing in older adults, but this may be hampered by cost and formulary restrictions.

Cognitive screening in substance users: Diagnostic accuracies of the Mini-Mental State Examination, Addenbrooke's Cognitive Examination-Revised, and Montreal Cognitive Assessment.

INTRODUCTION: Despite the considerable prevalence of cognitive impairment in substance-using populations, there has been little investigation of the utility of cognitive screening measures within this context. In the present study the accuracy of three cognitive screening measures in this population was examined-the Mini-Mental State Examination (MMSE), the Addenbrooke's Cognitive Examination-Revised (ACE-R), and the Montreal Cognitive Assessment (MoCA). METHOD: A sample of 30 treatment-seeking substance users and 20 healthy individuals living in the community were administered the screening measures and a neuropsychological battery (NPB). Agreement of classification of cognitive impairment by the screening measures and NPB was examined. RESULTS: Results indicated that the ACE-R and MoCA had good discriminative ability in detection of cognitive impairment, with areas under the receiver-operating characteristic (ROC) curve of .85 (95% confidence interval, CI [.75. .94] and .84 (95% CI [.71, .93]) respectively. The MMSE had fair discriminative ability (.78, 95% CI [.65, .93]). The optimal cut-score for the ACE-R was 93 (impairment = score of 92 or less), at which it correctly classified 89% of individuals as cognitively impaired or intact, while the optimal cut-score for the MoCA was <26 or <27 depending on preference for either specificity or sensitivity. The optimal cut-score for the MMSE was <29; however, this had low sensitivity despite good specificity. CONCLUSIONS: These findings suggest that the MoCA and ACE-R are both valid and time-efficient screening tools to detect cognitive impairment in the context of substance use.

Characterizing the Interrelationships of Prescription Opioid and Benzodiazepine Drugs With Worker Health and Workplace Hazards.

OBJECTIVE: Prescription opioid and benzodiazepine drug use, which has risen significantly, can affect worker health. Exploration of the scientific literature assessed (1) interrelationships of such drug use, occupational risk factors, and illness and injury, and (2) occupational and personal risk factor combinations that can affect their use. METHODS: The scientific literature from 2000 to 2015 was searched to determine any interrelationships. RESULTS: Evidence for eight conceptual models emerged based on the search yield of 133 articles. These models summarize interrelationships among prescription opioid and benzodiazepine use with occupational injury and illness. Factors associated with the use of these drugs included fatigue, impaired cognition, falls, motor vehicle crashes, and the use of multiple providers. CONCLUSION: Prescription opioid and benzodiazepine drugs may be both a personal risk factor for work-related injury and a consequence of workplace exposures.

Challenges and opportunities for the development of new antipsychotic drugs.

In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a single diagnostic entity; the needs for in depth clinical phenotyping to leverage the findings of schizophrenia genetics and advance the understanding of the disease biology; the symptom domains that are the major sources of disability in order to improve functional outcomes beyond current treatment options. In spite of the progress achieved during the last century the task ahead is still daunting and will require the efforts of scientists and clinicians through inclusive public-private partnerships and consortia to create the scientific basis for new therapeutic approaches to schizophrenia.