Localization of PPM1H phosphatase tunes Parkinson's disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis.

PPM1H phosphatase reverses Parkinson's disease-associated, Leucine Rich Repeat Kinase 2-mediated Rab GTPase phosphorylation. We show here that PPM1H relies on an N-terminal amphipathic helix for Golgi localization. The amphipathic helix enables PPM1H to bind to liposomes in vitro, and small, highly curved liposomes stimulate PPM1H activity. We artificially anchored PPM1H to the Golgi, mitochondria, or mother centriole. Our data show that regulation of Rab10 GTPase phosphorylation requires PPM1H access to Rab10 at or near the mother centriole. Moreover, poor colocalization of Rab12 explains in part why it is a poor substrate for PPM1H in cells but not in vitro. These data support a model in which localization drives PPM1H substrate selection and centriolar PPM1H is critical for regulation of Rab GTPase-regulated ciliogenesis. Moreover, Golgi localized PPM1H may maintain active Rab GTPases on the Golgi to carry out their nonciliogenesis-related functions in membrane trafficking.

Genome-wide screen reveals Rab12 GTPase as a critical activator of Parkinson's disease-linked LRRK2 kinase.

Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases, particularly Rab10 and Rab8A, and we showed previously that these phosphoRabs play an important role in LRRK2 membrane recruitment and activation (Vides et al., 2022). To learn more about LRRK2 pathway regulation, we carried out an unbiased, CRISPR-based genome-wide screen to identify modifiers of cellular phosphoRab10 levels. A flow cytometry assay was developed to detect changes in phosphoRab10 levels in pools of mouse NIH-3T3 cells harboring unique CRISPR guide sequences. Multiple negative and positive regulators were identified; surprisingly, knockout of the Rab12 gene was especially effective in decreasing phosphoRab10 levels in multiple cell types and knockout mouse tissues. Rab-driven increases in phosphoRab10 were specific for Rab12, LRRK2-dependent and PPM1H phosphatase-reversible, and did not require Rab12 phosphorylation; they were seen with wild type and pathogenic G2019S and R1441C LRRK2. As expected for a protein that regulates LRRK2 activity, Rab12 also influenced primary cilia formation. AlphaFold modeling revealed a novel Rab12 binding site in the LRRK2 Armadillo domain, and we show that residues predicted to be essential for Rab12 interaction at this site influence phosphoRab10 and phosphoRab12 levels in a manner distinct from Rab29 activation of LRRK2. Our data show that Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation and could serve as a new therapeutic target for a novel class of LRRK2 inhibitors that do not target the kinase domain.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation.

Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease, and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al., 2017). Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation. Here, we define the precise Rab29 binding region of the LRRK2 Armadillo domain between residues 360-450 and show that this domain, termed 'site #1,' can also bind additional LRRK2 substrates, Rab8A and Rab10. Moreover, we identify a distinct, N-terminal, higher-affinity interaction interface between LRRK2 phosphorylated Rab8 and Rab10 termed 'site #2' that can retain LRRK2 on membranes in cells to catalyze multiple, subsequent phosphorylation events. Kinase inhibitor washout experiments demonstrate that rapid recovery of kinase activity in cells depends on the ability of LRRK2 to associate with phosphorylated Rab proteins, and phosphorylated Rab8A stimulates LRRK2 phosphorylation of Rab10 in vitro. Reconstitution of purified LRRK2 recruitment onto planar lipid bilayers decorated with Rab10 protein demonstrates cooperative association of only active LRRK2 with phospho-Rab10-containing membrane surfaces. These experiments reveal a feed-forward pathway that provides spatial control and membrane activation of LRRK2 kinase activity.

Dermatology: how to manage acne in skin of colour.

Acne vulgaris is a prevalent dermatological condition worldwide but is especially challenging to treat in individuals with skin of colour (SOC). Corresponding to Fitzpatrick skin phototypes III-VI, people of African, Asian, Middle Eastern and Hispanic ethnicity are considered to have SOC. With the additional risk of postinflammatory hyperpigmentation (PIH) as a consequence of inflammatory acne or its respective treatment, managing acne in this population holds significant importance. PIH adversely impacts self-esteem and quality of life and, thus, is usually the patient's priority of treatment. Available acne treatments are similar for all skin types. However, some are more beneficial for individuals with SOC, in particular by targeting both active acne lesions and PIH. The acne treatment literature was searched for topical and systemic treatments that were specifically studied in the SOC population. These treatments included topical agents, such as retinoids and azelaic acid, in addition to topical antibiotics and benzoyl peroxide. Newer formulations and combined regimens reported effective in reducing lesions are less likely to induce PIH and may treat pre-existing PIH. Moisturiser use, titrating doses and patient education are strategies to minimize irritation and improve adherence. In addition, systemic therapies, including oral antibiotics, isotretinoin, oral contraceptives and spironolactone, are efficacious for refractory acne or more severe cases but specific studies in SOC are lacking. Chemical peels may improve acne and target PIH directly. Overall, based on limited evidence, topical and systemic therapies are well tolerated in the SOC population but efficacy should be balanced with the risk of adverse effects. This narrative review aims to highlight formulations and combination therapies that are effective and safe for treating acne and PIH in patients with SOC.

Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates.

WWP2 is a HECT E3 ligase that targets protein Lys residues for ubiquitination and is comprised of an N-terminal C2 domain, four central WW domains, and a C-terminal catalytic HECT domain. The peptide segment between the middle WW domains, the 2,3-linker, is known to autoinhibit the catalytic domain, and this autoinhibition can be relieved by phosphorylation at Tyr369. Several protein substrates of WWP2 have been identified, including the tumor suppressor lipid phosphatase PTEN, but the full substrate landscape and biological functions of WWP2 remain to be elucidated. Here, we used protein microarray technology and the activated enzyme phosphomimetic mutant WWP2Y369E to identify potential WWP2 substrates. We identified 31 substrate hits for WWP2Y369E using protein microarrays, of which three were known autophagy receptors (NDP52, OPTN, and SQSTM1). These three hits were validated with in vitro and cell-based transfection assays and the Lys ubiquitination sites on these proteins were mapped by mass spectrometry. Among the mapped ubiquitin sites on these autophagy receptors, many had been previously identified in the endogenous proteins. Finally, we observed that WWP2 KO SH-SH5Y neuroblastoma cells using CRISPR-Cas9 showed a defect in mitophagy, which could be rescued by WWP2Y369E transfection. These studies suggest that WWP2-mediated ubiquitination of the autophagy receptors NDP52, OPTN, and SQSTM1 may positively contribute to the regulation of autophagy.

Trends in Antipsychotic and Mood Stabilizer Prescribing in Long-Term Care in the U.S.: 2011-2014.

OBJECTIVE: The Centers for Medicare and Medicaid Services' National Partnership to Improve Dementia Care in Nursing Homes focuses on but is not limited to long-term care (LTC) residents with dementia; the potential impact on residents with other diagnoses is unclear. We sought to determine whether resident subpopulations experienced changes in antipsychotic and mood stabilizer prescribing. DESIGN: Repeated cross-sectional analysis of a 20% Medicare sample, 2011-2014. SETTING AND PARTICIPANT: Fee-for-service Medicare beneficiaries with Part D coverage in LTC (n = 562,485) and a secondary analysis limited to persons with depression or bipolar disorder (n = 139,071). METHODS: Main outcome was quarterly predicted probability of treatment with an antipsychotic or mood stabilizer. RESULTS: From 2011 to 2014, the adjusted predicted probability (APP) of antipsychotic treatment fell from 0.120 [95% confidence interval (CI) 0.119-0.121] to 0.100 (95% CI 0.099-0.101; P < .001). Use decreased for all age, sex, and racial/ethnic groups; the decline was larger for persons with dementia (P < .001). The APP of mood stabilizer use grew from 0.140 (95% CI 0.139-0.141) to 0.185 (95% CI 0.184-0.186), growth slightly larger among persons without dementia (P < .001). Among persons with depression or bipolar disorder, the APP of antipsychotic treatment increased from 0.081 (95% CI 0.079-0.082) to 0.087 (95% CI 0.085-0.088; P < .001); APP of mood stabilizer treatment grew more, from 0.193 (95% CI 0.190-0.196) to 0.251 (0.248-0.253; P < .001). Quetiapine was the most commonly prescribed antipsychotic. The most widely prescribed mood stabilizer was gabapentin, prescribed to 70.5% of those who received a mood stabilizer by the end of 2014. CONCLUSIONS AND IMPLICATIONS: The likelihood of antipsychotic and mood stabilizer treatment did not decline for residents with depression or bipolar disorder, for whom such prescribing may be appropriate but who were not excluded from the Partnership's antipsychotic quality measure. Growth in mood stabilizer use was widespread, and largely driven by growth in gabapentin prescribing.

Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases.

NEDD4-1 E3 ubiquitin protein ligase (NEDD4-1) and WW domain-containing E3 ubiquitin ligase (WWP2) are HECT family ubiquitin E3 ligases. They catalyze Lys ubiquitination of themselves and other proteins and are important in cell growth and differentiation. Regulation of NEDD4-1 and WWP2 catalytic activities is important for controlling cellular protein homeostasis, and their dysregulation may lead to cancer and other diseases. Previous work has implicated noncatalytic regions, including the C2 domain and/or WW domain linkers in NEDD4-1 and WWP2, in contributing to autoinhibition of the catalytic HECT domains by intramolecular interactions. Here, we explored the molecular mechanisms of these NEDD4-1 and WWP2 regulatory regions and their interplay with allosteric binding proteins such as Nedd4 family-interacting protein (NDFIP1), engineered ubiquitin variants, and linker phosphomimics. We found that in addition to influencing catalytic activities, the WW domain linker regions in NEDD4-1 and WWP2 can impact product distribution, including the degree of polyubiquitination and Lys-48 versus Lys-63 linkages. We show that allosteric activation by NDFIP1 or engineered ubiquitin variants is largely mediated by relief of WW domain linker autoinhibition. WWP2-mediated ubiquitination of WW domain-binding protein 2 (WBP2), phosphatase and tensin homolog (PTEN), and p62 proteins by WWP2 suggests that substrate ubiquitination can also be influenced by WW linker autoinhibition, although to differing extents. Overall, our results provide a deeper understanding of the intricate and multifaceted set of regulatory mechanisms in the control of NEDD4-1-related ubiquitin ligases.

Predicting Risk of Potentially Preventable Hospitalization in Older Adults with Dementia.

OBJECTIVES: Reducing potentially preventable hospitalization (PPH) among older adults with dementia is a goal of Healthy People 2020, yet no tools specifically identify patients with dementia at highest risk. The objective was to develop a risk prediction model to identify older adults with dementia at high imminent risk of PPH. DESIGN: A 30-day risk prediction model was developed using multivariable logistic regression. Patients from fiscal years (FY) 2009 to 2011 were split into development and validation cohorts; FY2012 was used for prediction. SETTING: Community-dwelling older adults (≥65 years of age) with dementia who received care through the Veterans Health Administration. PARTICIPANTS: There were 1 793 783 participants. MEASUREMENTS: Characteristics associated with hospitalization risk were (1) age and other demographic factors; (2) outpatient, emergency department, and inpatient utilization; (3) medical and psychiatric diagnoses; and (4) prescribed medication use including changes to psychotropic medications (eg, initiation or dosage increase). Model discrimination was determined by the C statistic for each of the three cohorts. Finally, to determine whether predicted 30-day risk strata were stable over time, the observed PPH rate was calculated out to 1 year. RESULTS: In the development cohort, .6% of patients experienced PPH within 30 days. The C statistic for the development cohort was .83 (95% confidence interval [CI] = .83-.84) and .83 in the prediction cohort (95% CI = .82-.84). Patients in the top 10% of predicted 30-day PPH risk accounted for more than 50% of 30-day PPH admissions in all three cohorts. In addition, those predicted to be at elevated 30-day risk remained at higher risk throughout a year of follow-up. CONCLUSION: It is possible to identify older adults with dementia at high risk of imminent PPH, and their risk remains elevated for an entire year. Given the negative outcomes associated with acute hospitalization for those with dementia, healthcare systems and providers may be able to engage these high-risk patients proactively to avoid unnecessary hospitalization. J Am Geriatr Soc 67:2077-2084, 2019.

The Start Predicts the Finish: Factors Associated With Antidepressant Nonadherence Among Older Veterans During the Acute and Maintenance Treatment Phases.

OBJECTIVE: To best prevent depression relapse and reduce recurrence, an understanding of the factors associated with continued maintenance treatment is needed. This study compared factors associated with antidepressant nonadherence during the acute (ie, during the first 4 months) and maintenance (ie, during 12 months) treatment phase among older veterans with depression. METHODS: In this prospective, observational study of 278 older veterans with depression (Patient Health Questionnaire-9 score ≥ 5), patients had been given a new antidepressant prescription between 2008 and 2011. Participants completed initial and follow-up interviews at 4 and 12 months. Medication adherence was assessed by the Brief Medication Questionnaire. A generalized estimating equation was used to determine patient factors associated with nonadherence at each time point. RESULTS: Nearly a third of veterans were nonadherent at 4- and 12-month follow-up. In adjusted analyses, nonadherence was significantly associated with African American race (adjusted odds ratio [AOR] = 2.69, 95% CI, 1.30-5.57; P = .01), being unmarried (AOR = 1.84; 95% CI, 1.16-2.92; P = .049), greater medical comorbidity (AOR = 1.30; 95% CI, 1.13-1.49; P < .001), functional impairment (AOR = 1.34; 95% CI, 1.10-1.63; P = .01), and self-reported side effects (AOR = 2.48; 95% CI, 1.57-3.94; P < .001) at both 4 and 12 months. Depression or anxiety severity did not predict antidepressant adherence at either time point. CONCLUSIONS: Rates of and factors associated with antidepressant nonadherence were similar at 4 and 12 months. Further work is needed to develop tailored treatment programs to engage older veterans at higher risk of nonadherence in the early treatment period, which may ultimately help to both achieve remission and reduce relapse and recurrence.

Effect of the WeCareAdvisor™ on family caregiver outcomes in dementia: a pilot randomized controlled trial.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are universal and associated with multiple negative outcomes. This pilot randomized controlled trial (RCT) evaluated the effect of using the WeCareAdvisor, an innovative web-based tool developed to enable family caregivers to assess, manage, and track BPSD. METHODS: This RCT enrolled 57 dementia family caregivers from community and clinical settings in Ann Arbor, Michigan and Baltimore, Maryland. Participants were randomly assigned to immediate use of the WeCareAdvisor tool (WCA, n = 27) or a Waitlist control group (n = 30) that received the tool after a one-month waiting period. Outcomes for the caregiver and the person they were caring for were assessed at baseline (T0) and one-month followup for both the WCA (T1) and Waitlist control (T2) groups. RESULTS: Caregiver mean age was 65.9 ± 14.0 years old. About half (49%) were spouses. Baseline characteristics were comparable between groups except for mean caregiver confidence which was higher in the control group (WCA 35.0 ± 10.0 vs. Waitlist control 39.7 ± 6.9, p = 0.04). There were no significant differences between the WCA and control groups in characteristics of the person with dementia. After their one-month of tool use (T1), WCA caregivers showed significant within group improvement in caregiver distress (- 6.08 ± 6.31 points, t = - 4.82, p < 0.0001) and behavioral frequency (- 3.60 ± 5.05, t = - 3.56, p = 0.002), severity (- 3.24 ± 3.87, t = - 4.19, p = 0.0003) and total behavioral score (- 6.80 ± 10.73, t = - 3.17, p = 004). In the same timeframe, Waitlist control caregivers showed a significant decrease in confidence (- 6.40 ± 10.30, t = - 3.40, p = 0.002). The WCA group showed greater improvement in distress compared to the Waitlist group (T0-T1; t = - 2.49, p = 0.02), which remained significant after adjusting for site and baseline distress. There were no significant between-group differences in caregiver confidence or other secondary outcomes. After their one month of tool use (T2), the Waitlist group also showed significant improvement in caregiver distress (- 3.72 ± 7.53, t = - 2.66, p = 0.013), stress (- 0.41 ± 1.02, t = - 2.19, p = 0.037), confidence (4.38 ± 5.17, t = 4.56, p < 0.0001), burden (- 2.76 ± 7.26, t = - 2.05, p = 0.05), negative communication (- 1.48 ± 2.96, t = - 2.70, p = 0.012) and behavioral frequency (- 1.86 ± 4.58, t = - 2.19, p = 0.037); distress remained significant after adjustment. CONCLUSIONS: In this pilot RCT, WCA use resulted in a significant decrease in caregiver distress. Future research will identify whether longer use of WCA can impact other caregiver and behavioral outcomes. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02420535 (Date of registry: 4/20/2015, prior to the start of the clinical trial).

Association of the Centers for Medicare & Medicaid Services' National Partnership to Improve Dementia Care With the Use of Antipsychotics and Other Psychotropics in Long-term Care in the United States From 2009 to 2014.

Importance: The Centers for Medicare & Medicaid Services' National Partnership to Improve 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.

Adherence to Depression Treatment in Primary Care: A Randomized Clinical Trial.

Importance: Nonadherence to antidepressant medication is common and leads to poor outcomes. Early nonadherence is especially problematic. Objective: To test the effectiveness of a psychosocial intervention to improve early adherence among older patients whose primary care physician newly initiated an antidepressant for depression. Design, Setting, and Participants: The Treatment Initiation and Participation Program (TIP) was offered in a 2-site randomized clinical effectiveness study between January 2011 and December 2014 at primary care practices in New York, New York, and Ann Arbor, Michigan. Analyses began in February 2016. All participants were middle-aged and older adults (aged ≥55 years) who received newly initiated depression treatment by their primary care physician and recruited within 10 days of their prescription. Analyses were intention-to-treat. Interventions: Participants were randomly assigned to the intervention (TIP) or treatment as usual. Participants in the TIP group identified and addressed barriers to adherence, including stigma, misconceptions, and fears about treatment, before developing a personalized adherence strategy. The Treatment Initiation and Participation Program was delivered in three 30-minute contacts scheduled during a 6-week period just after the antidepressant was prescribed. Main Outcomes and Measures: The primary outcome was self-reported adherence on the Brief Medication Questionnaire, with adequate early adherence defined as taking 80% or more of the prescribed doses at 6 and 12 weeks. The secondary outcome was depression severity. Results: In total, 231 middle-aged and older adults (167 women [72.3%] and 64 men [27.7%]) without significant cognitive impairment were randomly assigned to the TIP intervention (n = 115) or treatment as usual (n = 116). Participants had a mean (SD) age of 67.3 (8.4) years. Participants in the TIP group were 5 times more likely to be adherent at 6 weeks (odds ratio, 5.54; 95% CI, 2.57 to 11.96; χ21 = 19.05; P < .001) and 3 times more likely to be adherent at both 6 and 12 weeks (odds ratio, 3.27; 95% CI, 1.73 to 6.17; χ21 = 13.34; P < .001). Participants in the TIP group showed a significant earlier reduction (24.9%) in depressive symptoms (95% CI, 13.9 to 35.9; t337 = 4.46; adjusted P < .001). In both groups, participants who were 80% adherent at weeks 6 and 12 had a 15% greater improvement in depressive symptoms from baseline over the course of treatment (95% CI, -0.2 to -30; t369 = 1.93; P = .051). Conclusions and Relevance: The Treatment Initiation and Participation Program is an effective intervention to improve early adherence to pharmacotherapy. Improved adherence can promote improvement in depression. Trial Registration: clinicaltrials.gov Identifier: NCT01301859.

With a little help from my friends?: racial and gender differences in the role of social support in later-life depression medication adherence.

BACKGROUND: Social support has been shown to be an important factor in improving depression symptom outcomes, yet less is known regarding its impact on antidepressant medication adherence. This study sought to evaluate the role of perceived social support on adherence to new antidepressant medication prescriptions in later-life depression. METHODS: Data from two prospective observational studies of participants ≥60 years old, diagnosed with depression, and recently prescribed a new antidepressant (N = 452). Perceived social support was measured using a subscale of the Duke Social Support Index and medication adherence was assessed using a validated self-report measure. RESULTS: At four-month follow up, 68% of patients reported that they were adherent to antidepressant medication. Examining the overall sample, logistic regression analysis demonstrated no significant relationship between perceived social support and medication adherence. However, when stratifying the sample by social support, race, and gender, adherence significantly differed by race and gender in those with inadequate social support: Among those with low social support, African-American females were significantly less likely to adhere to depression treatment than white females (OR = 4.82, 95% CI = 1.14-20.28, p = 0.032) and white males (OR = 3.50, 95% CI = 1.03-11.92, p = 0.045). CONCLUSIONS: There is a significant difference in antidepressant medication adherence by race and gender in those with inadequate social support. Tailored treatment interventions for low social support should be sensitive to racial and gender differences.

Antipsychotic Use and Physical Morbidity in Parkinson Disease.

OBJECTIVE: To determine if antipsychotic (AP) use in Parkinson disease (PD) patients is associated with increased physical morbidity. METHODS: Veterans Health Administration data (1999-2010) was used to examine physical morbidity risk associated with AP use in idiopathic PD patients with stable recent physical health. We compared 180-day morbidity rates in patients initiating an AP with matched non-AP users who survived for 180 days (matched on age, sex, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new non-psychiatric medications; covarying for psychosis). Outcomes were 180-day emergency department (ED), and inpatient and outpatient visits. RESULTS: There were 6,679 matched PD pairs. Any AP use was associated with an increased risk of ED visit (HR: 1.64, 95% CI: 1.51, 1.77), inpatient care (HR: 1.58, 95% CI: 1.46, 1.71), and outpatient visits (IRR: 1.08, 95% CI: 1.05, 1.12). The risk was significantly higher for atypical AP use compared with nonuse for all three morbidity outcomes, and was similar for atypical and typical AP use. CONCLUSIONS: Any AP use, and atypical AP use, are associated with significantly increased physical morbidity risk in PD patients, as evidenced by increased ED, inpatient, and outpatient visits. These findings, which require replication, extend the risk associated with use of APs in this population from mortality to a broader range of adverse outcomes, and further highlight the need to use APs cautiously in PD patients.

Management of older adults with dementia who present to emergency services with neuropsychiatric symptoms.

OBJECTIVE: Our aim is to evaluate if and how neuropsychiatric symptoms (NPS) of dementia influence the management and disposition of older adults who present to emergency care settings. METHODS: This is a retrospective cohort study that involved the medical and psychiatric emergency departments of a tertiary academic medical center. Participants included patients ≥65 years of age with dementia who presented between 1 February 2012 and 16 July 2014 (n = 347). Subjects with documented NPS (n = 78) were compared with a group of subjects without documented NPS (n = 78) randomly selected from the overall group with dementia. The groups with and without NPS were compared on demographic, clinical, management, and disposition characteristics. RESULTS: Patients with NPS were more likely to have additional diagnostic testing performed and receive psychotropic medications including benzodiazepines and antipsychotics. Significantly fewer patients with NPS (59.0%) returned to their original setting from the emergency department than patients without NPS (76.9%). Among patients with NPS, those who had a motor disturbance were more likely to receive psychotropic medications than patients who did not have a motor disturbance. Depression/dysphoria, anxiety, disinhibition, irritability/lability, and motor disturbance were all associated with transfer from medical to psychiatric emergency department. Patients with depression/dysphoria or anxiety were more likely to be psychiatrically hospitalized. CONCLUSIONS: There are significant differences in the management of dementia with and without NPS in the emergency room setting. Developing and implementing successful methods to manage NPS in the emergency department and outpatient setting could potentially lead to less emergent psychotropic administration and reduce hospitalizations. Copyright © 2016 John Wiley & Sons, Ltd.

Unintended Consequences of Adjusting Citalopram Prescriptions Following the 2011 FDA Warning.

OBJECTIVES: In 2011, the U.S. Food and Drug Administration (FDA) issued a safety announcement cautioning providers against prescribing citalopram above 40 mg per day given concerns for QT prolongation. We assessed the impact of a health system quality improvement initiative to identify patients taking higher than the recommended dose of citalopram. DESIGN: Retrospective cohort study. SETTING: Nine primary care clinics within the University of Michigan from March 2012 to February 2013. PARTICIPANTS: Adult patients taking a higher-than-recommended dose of citalopram following the FDA warning in 2011 (N = 199). MEASUREMENTS: Frequency of EKG monitoring, clinical factors associated with patients whose citalopram dose or use was adjusted, and potential impact of these changes on overall health care utilization was assessed. RESULTS: In patients prescribed higher-than-recommended doses of citalopram and who received a note from a pharmacist regarding the FDA warnings, only 8.5% received electrocardiogram (EKG) monitoring. Patients who were converted to an alternative antidepressant from citalopram were more likely to receive subsequent new prescriptions for benzodiazepines and sedative hypnotics (χ2 = 7.9, p = 0.048). Patients who had any adjustments to their antidepressant medication had greater overall health care utilization (OR: 25.0; 95% CI: 5.7-109.6; p < 0.001) than patients remaining on the same dose of citalopram. CONCLUSIONS: Despite a targeted quality intervention to address the FDA warning regarding citalopram, the warning was associated with low levels of EKG monitoring, increased anxiolytic and sedative medication use, and higher healthcare utilization. This finding may represent destabilization of patients on previously therapeutic doses of their antidepressant and an unintended consequence of the FDA warning.

Predictors of Antidepressant Nonadherence Among Older Veterans With Depression.

OBJECTIVE: Most depression among older adults is treated in primary care, and many patients do not adhere to medication treatment. The U.S. Department of Veterans Affairs (VA) has recently introduced initiatives to address such treatment gaps. This study examined patient-reported antidepressant nonadherence during the acute treatment period (first four months after a prescription) and identified predictors of nonadherence in a sample of older veterans. METHODS: This was a prospective, observational study of 311 participants ages 60 and older who received care at three VA medical centers and who had a diagnosis of clinically significant depression and were given a new outpatient antidepressant prescription. Participants completed an initial interview and a follow-up interview at four months after treatment recommendation. Antidepressant adherence was measured with a well-validated self-report measure. RESULTS: At four months, 29% of participants reported nonadherence to their antidepressant medication. In unadjusted analyses, nonadherence was significantly associated with being African American, having no spouse or significant other, having greater general medical comorbidity, and receiving the prescription in a primary care setting (versus a specialty mental health setting). In logistic regression models controlling for several variables (demographic, illness, and functional status variables; type of antidepressant; contact with a therapist; medical setting; and site of recruitment), two predictors remained significantly associated with nonadherence: African-American race (odds ratio [OR]=4.23, p<.001) and general medical comorbidity (OR=1.33, p=.002). CONCLUSIONS: The two main predictors of nonadherence among older adults with depression were African-American race and general medical comorbidity. Results suggest that significant needs remain for important patient subgroups to improve antidepressant adherence.