Lateral inhibition, mediated by Notch signaling, leads to the selection of cells that are permitted to become neurons within domains defined by proneural gene expression. Reduced lateral inhibition in zebrafish mib mutant embryos permits too many neural progenitors to differentiate as neurons. Positional cloning of mib revealed that it is a gene in the Notch pathway that encodes a RING ubiquitin ligase. Mib interacts with the intracellular domain of Delta to promote its ubiquitylation and internalization. Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells. These observations support a model for Notch activation where the Delta-Notch interaction is followed by endocytosis of Delta and transendocytosis of the Notch extracellular domain by the signaling cell. This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells.

IMPORTANCE Antipsychotic medications are associated with increased mortality in older adults with dementia, yet their absolute effect on risk relative to no treatment or an alternative psychotropic is unclear.OBJECTIVE To determine the absolute mortality risk increase and number needed to harm (NNH) (ie, number of patients who receive treatment that would be associated with 1 death) of antipsychotic, valproic acid and its derivatives, and antidepressant use in patients with dementia relative to either no treatment or antidepressant treatment.

Opioid mortality rates continue to increase throughout the United States 1 ; however, growth in buprenorphine hydrochloride treatment for opioid use disorder (OUD) might be limited to communities with higher income and low percentages of racial/ethnic minorities. 2 Buprenorphine, a partial opioid agonist, is 1 of 3 evidence-based medications for treating OUD and can legally be prescribed in office-based settings. To our knowledge, no national studies have examined the differences in the receipt of buprenorphine prescription by race/ethnicity and payment in office-based settings, in which most patients with buprenorphine prescription receive care. 3 In this article, we present changes in buprenorphine treatment at office-based visits in the United States since 2004 as well as the race/ethnicity and payment characteristics currently associated with its receipt.

Objective: Determine the prevalence of benzodiazepine use, including both use as-prescribed and misuse; characterize misuse; determine whether and how misuse varies by age. Methods: Cross-sectional analysis of the 2015 and 2016 National Survey on Drug Use and Health (NSDUH), a nationally-representative sample of U.S. adults (n=86,186). Measurements included past-year prescription benzodiazepine use and misuse (i.e., use "any way a doctor did not direct"), along with substance use and use disorders, mental illness, and demographic characteristics. Misuse was compared between younger (18-49) and older (≥50) adults. Results: 30.6 million adults (12.6%) reported past-year benzodiazepine use annually: 25.3 million (10.4%) as-prescribed and 5.3 million (2.2%) with misuse. Misuse accounted for 17.2% of benzodiazepine use overall. Adults 50-64 had the highest prescribed use (12.9%). Those 18-25 had the highest misuse (5.2%), while adults ≥65 had the lowest (0.6%). Misuse and abuse or dependence of prescription stimulants or opioids were strongly associated with benzodiazepine misuse. Misuse without a prescription was the most common type of misuse, while a friend or relative was the most common source. Adults ≥50 were more likely to use a benzodiazepine more often than prescribed and to help with sleep. Conclusions: Benzodiazepine use in the U.S. is higher than previously reported and misuse accounted for nearly 20% of use overall. Use among adults 50-64 has now exceeded use by those ≥65. Clinicians should monitor patients also prescribed stimulants or opioids for benzodiazepine misuse. Improved access to behavioral interventions for sleep or anxiety may reduce some misuse.

Dementia Care in Nursing Homes (hereafter referred to as the partnership) was established to improve the quality of care for patients with dementia, measured by the rate of antipsychotic prescribing. OBJECTIVE To determine the association of the partnership with trends in prescribing of antipsychotic and other psychotropic medication among older adults in long-term care. DESIGN, SETTING, AND PARTICIPANTS This interrupted time-series analysis of a 20% Medicare sample from January 1, 2009, to December 31, 2014, was conducted among 637 426 fee-for-service Medicare beneficiaries in long-term care with Part D coverage. Data analysis was conducted from May 1, 2017, to January 9, 2018. MAIN OUTCOMES AND MEASURES Quarterly prevalence of use of antipsychotic and nonantipsychotic psychotropic medications (antidepressants, mood stabilizers [eg, valproic acid and carbamazepine], benzodiazepines, and other anxiolytics or sedative-hypnotics). RESULTS Among the 637 426 individuals in the study (446 538 women and 190 888 men; mean [SD] age at entering nursing home, 79.3 [12.1] years), psychotropic use was declining before initiation of the partnership with the exception of mood stabilizers. In the first quarter of 2009, a total of 31 056 of 145 841 patients (21.3%) were prescribed antipsychotics, which declined at a quarterly rate of-0.53% (95% CI,-0.63% to-0.44%; P < .001) until the start of the partnership. At that point, the quarterly rate of decline decreased to-0.29% (95% CI,-0.39% to-0.20%; P < .001), a postpartnership slowing of 0.24% per quarter (95% CI, 0.09%-0.39%; P = .003). The use of mood stabilizers was growing before initiation of the partnership and then accelerated after initiation of the partnership (rate, 0.22%; 95% CI, 0.18%-0.25%; P < .001; rate change, 0.14%; 95% CI, 0.10%-0.18%; P < .001), reaching 71 492 of 355 716 patients (20.1%) by the final quarter of 2014. Antidepressants were the most commonly prescribed medication overall: in the beginning of 2009, a total of 75 841 of 145 841 patients (52.0%) were prescribed antidepressants. As with antipsychotics, antidepressant use declined both before and after initiation of the partnership, but the decrease slowed (rate change, 0.34%; 95% CI, 0.18%-0.50%; P < .001). Findings were similar when limited to patients with dementia. CONCLUSIONS AND RELEVANCE Prescribing of psychotropic medications to patients in long-term care has declined, although the partnership did not accelerate this decrease. However, the use of mood stabilizers, possibly as a substitute for antipsychotics, increased and accelerated after initiation of the partnership in both long-term care residents overall and in those with dementia. Measuring use of antipsychotics alone may be an inadequate proxy for quality of care and may have contributed to a shift in prescribing to alternative medications with a poorer risk-benefit balance.

Objective To determine the national prevalence of psychotropic use and association with neuropsychiatric symptoms among patients with dementia. Methods Participants diagnosed with dementia (n=414) in the Aging, Demographics, and Memory Study, a nationally-representative survey of US adults >70 years old. Diagnosis was based on in-person clinical assessment and informant interview. Information collected included demographics, place of residence, 10-item Neuropsychiatric Inventory (NPI), and prescribed medications (antipsychotic, sedative-hypnotic, antidepressant, mood stabilizer). Results Of 414 participants with dementia, 41.4% were prescribed a psychotropic medication, including 84.0% of nursing home residents and 28.6% of community-dwellers. 23.5% were prescribed an antidepressant. Compared to the total NPI score of those on no medication (4.5), those on antipsychotics and those on sedative-hypnotics had much higher scores (respectively: 12.6, p<0.001; 11.8, p=0.03), though those antidepressants did not (6.86, p=0.15). A larger proportion of patients on antipsychotics exhibited psychosis and agitation compared with those on no medication, while those on antidepressants exhibited more depressive symptoms. In multivariable logistic regression that included dementia severity and nursing home residence, nursing home residence was the characteristic most strongly associated with psychotropic use (odds ratio ranging from 8.96 [p<0.001] for antipsychotics to 15.59 [p<0.001] for sedative-hypnotics). More intense psychotic symptoms and agitation were associated with antipsychotic use; more intense anxiety and agitation were associated with sedative-hypnotic use. More intense depression and apathy were not associated with antidepressant use. Conclusions In this nationally-representative sample, 41.4% of patients were taking psychotropic medication. While associated with NPS, nursing home residence was most strongly tied to use.

No abstract

Objective To describe how use of antidepressants, benzodiazepines, and other anxiolytic/sedative-hypnotics among older adults (age ≥65) has changed over time among visits to primary care providers and psychiatrists in the United States. Method Data came from the National Ambulatory Medical Care Survey (years 2003–2005 and 2010–2012), a nationally-representative cross-section of outpatient physician visits. Analysis focused on visits to primary care providers (n=14,282) and psychiatrists (n=1,095) at which an antidepressant, benzodiazepine, or other anxiolytic/sedative-hypnotic was prescribed, which were stratified by demographic and clinical characteristic (including ICD-9-CM diagnosis) and compared across study intervals. Odds of medication use were calculated for each stratum, adjusting for demographic and clinical characteristics. Results The visit rate by older adults to primary care providers where any of the medications were prescribed rose from 16.4% to 21.8% (AOR 1.43, p<0.001), while remaining steady among psychiatrists (75.4% v. 68.5%; AOR 0.69, p=0.11). Primary care visits rose for antidepressants (9.9% to 12.3%; AOR 1.28, p=0.01) and other anxiolytic/sedative-hypnotics (3.4% to 4.7%; AOR 1.39, p=0.01), but the largest growth was among benzodiazepines (5.6% to 8.7%; AOR 1.62, p<0.001). Among patients in primary care, increases primarily occurred among men, non-Hispanic white patients, and both those with pain diagnoses as well as those without any mental health or pain diagnoses. Conclusion From 2003–2012, use of the most common psychotropic medications among older adults seen in primary care increased, concentrated among patients with no mental health or pain diagnosis. As the population of older adults grows and receives mental health treatment in primary care, it is critical to examine the appropriateness of psychotropic use.