Identification of structural and regulatory cell-shape determinants in Haloferax volcanii.

Archaea play indispensable roles in global biogeochemical cycles, yet many crucial cellular processes, including cell-shape determination, are poorly understood. Haloferax volcanii, a model haloarchaeon, forms rods and disks, depending on growth conditions. Here, we used a combination of iterative proteomics, genetics, and live-cell imaging to identify mutants that only form rods or disks. We compared the proteomes of the mutants with wild-type cells across growth phases, thereby distinguishing between protein abundance changes specific to cell shape and those related to growth phases. The results identified a diverse set of proteins, including predicted transporters, transducers, signaling components, and transcriptional regulators, as important for cell-shape determination. Through phenotypic characterization of deletion strains, we established that rod-determining factor A (RdfA) and disk-determining factor A (DdfA) are required for the formation of rods and disks, respectively. We also identified structural proteins, including an actin homolog that plays a role in disk-shape morphogenesis, which we named volactin. Using live-cell imaging, we determined volactin's cellular localization and showed its dynamic polymerization and depolymerization. Our results provide insights into archaeal cell-shape determination, with possible implications for understanding the evolution of cell morphology regulation across domains.

Endocytic myosin-1 is a force-insensitive, power-generating motor.

Myosins are required for clathrin-mediated endocytosis, but their precise molecular roles in this process are not known. This is, in part, because the biophysical properties of the relevant motors have not been investigated. Myosins have diverse mechanochemical activities, ranging from powerful contractility against mechanical loads to force-sensitive anchoring. To better understand the essential molecular contribution of myosin to endocytosis, we studied the in vitro force-dependent kinetics of the Saccharomyces cerevisiae endocytic type I myosin called Myo5, a motor whose role in clathrin-mediated endocytosis has been meticulously studied in vivo. We report that Myo5 is a low-duty-ratio motor that is activated ∼10-fold by phosphorylation and that its working stroke and actin-detachment kinetics are relatively force-insensitive. Strikingly, the in vitro mechanochemistry of Myo5 is more like that of cardiac myosin than that of slow anchoring myosin-1s found on endosomal membranes. We, therefore, propose that Myo5 generates power to augment actin assembly-based forces during endocytosis in cells.

Lorazepam use during clinical trials of adults with bipolar mania episodes.

Background: Lorazepam has commonly been prescribed to reduce agitation during bipolar 1 mania trials. Its use has varied considerably by trial methodology and in clinical practice. Methods: The extent and amount of lorazepam treatment was recorded and analyzed from available brief, controlled trials of acute bipolar mania and in clinical reports in adults. Results: In 3-week, placebo-controlled clinical trials (n = 19), most manic subjects (79%) were treated with lorazepam to reduce agitation. This treatment was most prominent during the antimanic drug wash-out phase that preceded placebo-controlled trials. Doses of lorazepam administered during the first 7-10 days of the pre-trial and the early trial phases averaged 2.2 mg/day. These doses were one-third the lorazepam/clonazepam doses administered during placebo-controlled, non-washout trials. Far higher benzodiazepine doses for manic agitation were noted in emergency department reports. Intake enrollment was strikingly restricted only in placebo-controlled trials that used pretrial drug wash-out. Conclusions: Medication treatment conclusions from placebo-controlled, drug washout trials are not representative of clinical treatment for acute bipolar mania.

Endocytic myosin-1 is a force-insensitive, power-generating motor.

Myosins are required for clathrin-mediated endocytosis, but their precise molecular roles in this process are not known. This is, in part, because the biophysical properties of the relevant motors have not been investigated. Myosins have diverse mechanochemical activities, ranging from powerful contractility against mechanical loads to force-sensitive anchoring. To better understand the essential molecular contribution of myosin to endocytosis, we studied the in vitro force-dependent kinetics of the Saccharomyces cerevisiae endocytic type I myosin called Myo5, a motor whose role in clathrin-mediated endocytosis has been meticulously studied in vivo. We report that Myo5 is a low-duty-ratio motor that is activated ∼10-fold by phosphorylation, and that its working stroke and actin-detachment kinetics are relatively force-insensitive. Strikingly, the in vitro mechanochemistry of Myo5 is more like that of cardiac myosin than like that of slow anchoring myosin-1s found on endosomal membranes. We therefore propose that Myo5 generates power to augment actin assembly-based forces during endocytosis in cells. Summary: Pedersen, Snoberger et al. measure the force-sensitivity of the yeast endocytic the myosin-1 called Myo5 and find that it is more likely to generate power than to serve as a force-sensitive anchor in cells. Implications for Myo5's role in clathrin-mediated endocytosis are discussed.

Psychotropic Polypharmacy in the US Pediatric Population: A Methodologic Critique and Commentary.

Background: Psychotropic concomitant medication use for the treatment of youth with emotional and behavioral disorders has grown significantly in the U.S. over the past 25 years. The use of pharmacy claims to analyze these trends requires the following: age of the selected population, overlapping days of use, and precision of the outcome itself. This review will also address the gaps in reporting of pediatric psychotropic polypharmacy. Methods: An electronic literature search was undertaken for the period 2000 through 2020 using keywords such as "pediatric," "concomitant," "polypharmacy," "multiple medications," and "concurrent psychotropic"; Relevant references in textbooks were also used. Only English language and U.S. studies were included, resulting in 35 inter-class studies. Results: Studies were organized into seven groups according to data sources and clinical topics: (1) population surveys; (2a) multi-state publicly insured populations; (2b) single/two state studies; (3) privately insured populations; (4) diagnosed populations; (5) foster care populations; (6) special settings. Across 20 years it is apparent that pediatric psychotropic polypharmacy affects substantially more children and adolescents today than had been the case. As many as 300,000 youth now receive 3 or more classes concomitantly. The duration of concomitant use is relatively long, e.g., 69-89% of annual medicated days. Finally, more adverse event reports were associated with 3-class compared with 2-class drug regimens. Discussion: Factors that contribute to the growth of pediatric psychotropic polypharmacy include: (1) predominance of the biological model in psychiatric practice; (2) invalid assumptions on efficacy of combinations, (3) limited professional awareness of metabolic and neurological adverse drug events, and (4) infrequent use of appropriate deprescribing. Conclusion: A review of publications documenting U.S. pediatric psychotropic polypharmacy written over the last 20 years supports the need to standardize the methodologies used. The design of population-based studies should maximize information on the number of youth receiving regimens of 3-, 4-, and 5 or more concomitant classes and the duration of such use. Next, far more post-marketing research is needed to address the effectiveness, safety and tolerability of complex drug regimens prescribed for youngsters.

A Critique on Psychiatric Inpatient Admissions for Suicidality in Youth.

ABSTRACT: For the last few decades, psychiatric inpatient admissions for the treatment of suicidality in US youth have been increasing. Nonetheless, since 2007, the national rate of completed suicides by youth has steadily and sizably increased. Therefore, a literature review was performed to evaluate the usefulness of the psychiatric inpatient admission of suicidal youths. The analysis concluded that suicidality is surprisingly common in youth, completed suicide is very uncommon in early adolescence, suicidal ideation is a major reason in early adolescence for inpatient admission, girls are admitted to psychiatric inpatient units three times more than boys even though boys complete suicide four times more than girls, inpatient stays average 6 days and are quite expensive, and repeat attempts after inpatient treatment are common. Thus, filling more beds for youth with suicidality lacks evidence of a public health, long-term benefit. Expanding the focus in psychiatry to population efforts including means reductions is recommended.

Antidepressant Use in Medicaid-Insured Youth: Trends, Covariates, and Future Research Needs.

BACKGROUND: Detailed research on long-term antidepressant (AD) trends within a single large US Medicaid population of youth has not heretofore been reported. METHODS: Administrative claims data for eight annual timepoints across 28 years (1987-2014) were organized for youth (<20 years old) who were continuously enrolled during each study year in a mid-Atlantic state Medicaid program. Total annual AD prevalence and age-, gender-, race-, eligibility group-, and diagnosis-specific prevalence were formed from bivariate analyses; logistic regression assessed the change in use (2007-2014) adjusted for covariates. AD-polypharmacy data were assessed in 2014. RESULTS: The major findings are: 1) AD use in state Medicaid enrollees grew 14-fold between 1987 and 2014. Data from 2014 revealed significantly increased odds of youth with SSRI/SNRI dispensings compared to 2007 (AOR=1.15 95% CI 1.11-1.19), representing 78% of total AD users. 2) Recent AD increases were greatest for 15-19-year olds. 3) AD use in girls passed up AD use in boys for the first time in 2014. 4) In 2014, ADs for foster care (12.7%) were 6 times greater than for their income-eligible Medicaid-counterparts. 5) In 2014, a quarter of AD-medicated youth were diagnosed with a behavior disorder. 6) More than 40 percent of AD medicated youth had >=1 other concomitant psychotropic classes for 60 or more days. CONCLUSIONS: Second-generation antidepressant use in Medicaid-insured youth has increased despite growing questions that pediatric AD benefits may not outweigh harms. These patterns support the call for publicly funded, independent investigator-conducted post-marketing outcomes research.

Short- and Long-Term Antidepressant Clinical Trials for Major Depressive Disorder in Youth: Findings and Concerns.

The diagnosis of major depressive disorder (MDD) in U.S. youth is increasing as is the rate of antidepressant medication (ADM) treatment for the disorder. Fluoxetine and escitalopram are FDA approved for the short term and maintenance treatment of MDD in youth. Placebo-controlled short-term ADM trials represent the basis for Food and Drug Administration (FDA) approval. Meta-analyses in 2007 and 2016 revealed that short-term ADM treatment of youth diagnosed with MDD resulted in no meaningful benefit for children and only marginal benefit for adolescents. Placebo substitution trials of ADM short-term responders represent the basis for FDA approval of ADM maintenance treatment. These ADM placebo substitution maintenance trials for youth with MDD are characterized by high dropout rates, a rapid withdrawal that often can follow the switch to placebo, and relapse rates that are not dissimilar from those in the natural course of the disorder. Without the evidence from problematic ADM placebo substitution trials, there is no acceptable support for the inclusion of ADM in maintenance treatment for MDD in youth.

Overprescribed Medications for US Adults: Four Major Examples.

To understand possible medication overprescribing, it would be important to know which classes are the most prescribed, for which indications, for what duration, and for which age groups. Among the 10 most frequently prescribed medication classes for US adults, four were evaluated for overprescribing, and systematically assessed in relation to their primary indication. The assessment included usage patterns, trends, age of recipients, treatment duration, and benefits versus adverse consequences. The findings in this selective review are supported by an extensive search of the medical literature. The four selected medication categories and their most common indication included opioids for chronic pain, proton pump inhibitors for indigestion, levothyroxine for subclinical hypothyroidism, and antidepressants for subsyndromal levels of depression. These medications, grouped by their most frequent indication along with polypharmacy, have experienced major prescription increases in recent years, particularly among older patients. Most concerning is that they have been frequently prescribed for extended periods, usually with inadequate evidence of benefit. High drug usage patterns can aid in quantifying overprescribing within polypharmacy by age group.

Cardiovascular Events Following Treatment Initiation with Atypical Antipsychotic Medications in Publicly Insured U.S. Youth.

OBJECTIVE: To assess the risk of incident cardiovascular events that led to hospitalizations or emergency department visits following atypical antipsychotic (AAP) treatment initiation in youth according to dose, duration of use, and concomitant use of leading psychotropic medication classes. METHODS: We used computerized Medicaid claims to conduct a retrospective cohort study of youth (5-20 years) who initiated AAP treatment. AAP use was operationalized in a time-dependent manner according to current vs. former use, average daily dose (in risperidone dose equivalents), and duration of use. In a secondary analysis, concomitant use of (1) stimulants and (2) serotonin-reuptake inhibitors (SSRI/SNRIs) with AAPs was also assessed. To account for confounding, disease risk score methodology was used in discrete time failure models. RESULTS: There were 74,700 youth who initiated AAP treatment (average follow-up = 24.8 months). During follow-up, the risk of cardiovascular events was significantly greater during current than former AAP use (RR = 1.55, 95% CI = 1.09-2.21). Furthermore, for current users of AAPs, the risk of cardiovascular events intensified with average daily dose (RR = 2.04, 95% CI = 1.11-3.77 for >3.75 mg/day vs. ≤1.25 mg/day). The risk of cardiovascular events did not significantly differ according to duration of AAP use. In AAP-treated youth, concomitant SSRI/SNRI use was associated with an increased risk of cardiovascular events (RR = 1.61, 95% CI = 1.01-2.57). By contrast, stimulant use concomitant with AAPs was not significantly associated with an increased risk of cardiovascular events. CONCLUSIONS: In publicly insured U.S. youth, current AAP use was associated with an increased risk of incident cardiovascular events, which intensified with increasing dose and with concomitant SSRI/SNRI use. Prudent interpretation of these findings suggests that further research is needed to identify youth subpopulations with the greatest risk of developing AAP treatment-emergent cardiovascular events.

Comparing Nurse Practitioner and Physician Prescribing of Psychotropic Medications for Medicaid-Insured Youths.

Objective: To describe psychotropic medication prescribing practices of nurse practitioners (NP) and physicians for Medicaid-insured youths in 2012-2014 in a mid-Atlantic state where NP independent prescribing is authorized. Method: From annual computerized administrative claims data in a mid-Atlantic state, we analyzed 1,034,798 dispensed psychotropic medications prescribed by NPs and physicians for 61,526 continuously enrolled Medicaid-insured youths aged 2-17 years. Demographic and clinical characteristics of psychotropic medication users were compared for youths who received psychotropic medication dispensings by NP-only, physician-only, or by both providers using descriptive statistics and generalized estimating equations. We then characterized psychotropic medication prescribing practices by providers within each specialty. Results: From 2012 to 2014, the number of psychotropic medication dispensings increased from 346,922 to 349,080. There was a 50.9% increase in the proportion of psychotropic medications prescribed by psychiatric NPs (from 5.9% to 8.8%) and a 28.6% proportional increase by non-psychiatric NPs (from 4.9% to 6.3%). By contrast, the proportion of psychotropic medications prescribed by psychiatrists and by non-psychiatric physicians declined (56.9%-53.0% and 32.3%-31.8%, respectively). Youths diagnosed with depression or anxiety were more commonly treated by NP-only than by physician-only (AOR = 1.33, 95% CI = 1.24-1.43), whereas youths with two or more psychiatric comorbidities were significantly more commonly treated by both NP and physician providers (AOR = 1.44, 95% CI = 1.39-1.50). Psychiatric specialists prescribed the bulk of antidepressants (82.0%) and lithium (92.3%), with much lower prescribing by non-psychiatric specialists (18.0% and 7.7%, respectively). Antipsychotic orders originated from psychiatric specialists 7.4 times more than from their non-psychiatric specialty counterparts, whether physician or NP. Conclusions: NPs, relative to physicians, have taken an increasing role in prescribing psychotropic medications for Medicaid-insured youths. The quality of NP prescribing practices deserves further attention.

Is ADHD Really Increasing in Youth?

OBJECTIVE: It would be useful to compare temporal changes in the diagnostic prevalence of ADHD obtained from identical population surveys with time-trend survey findings based on individual ADHD features. METHOD: Changes in the diagnostic prevalence of ADHD over time were recorded from parent reports and from physician office visit data. Associated features of ADHD were temporally recorded from standardized teacher, parent, and youth surveys. RESULTS: Time-trend diagnostic findings on ADHD prevalence based on 6 parent surveys and 12 outpatient physician office visit surveys revealed consistent rate increases. By contrast, 26 sets of standard ratings of the primary and associated features of ADHD assessed systematically by different teachers, parents, and students during different years indicated little change. CONCLUSION: Time-trend national surveys of ADHD in youth over the last two decades reveal consistent increases in its diagnostic prevalence, whereas time-trend findings for individual ADHD-related symptoms remained relatively stable.

The Impact of a State Medicaid Peer-Review Authorization Program on Pediatric Use of Antipsychotic Medications.

OBJECTIVE: This cross-sectional study assessed the impact of a peer-review program on the prevalence of pediatric antipsychotic use among Medicaid-insured youths in a Mid-Atlantic state. METHODS: Medicaid claims (2010-2014) were assessed among continuously enrolled youths in the 12 months before and after implementation of peer review. The study identified children ages zero to four preimplementation (N=118,815) and postimplementation (N=121,431), ages five to nine preimplementation (N=98,681) and postimplementation (N=107,872), and ages 10 to 17 preimplementation (N=154,696) and postimplementation (N=161,370). (Age ranges are inclusive of the final number). In each age group, multivariable logistic regression models with generalized estimating equations assessed the change in annual prevalence of antipsychotic use pre- to postimplementation. Use of other leading psychotropic classes and antipsychotic prescribing by medical specialty were also examined. RESULTS: The annual pre- to postimplementation prevalence of antipsychotic use decreased significantly, from .07% to .03% (adjusted odds ratio [AOR]=.41) among children ages zero to four, from 1.57% to .86% (AOR=.54) among those ages five to nine, and from 3.28% to 2.40% (AOR=.72) among those ages 10 to 17. With the exception of alpha-agonist use, which increased postimplementation (AOR=1.30) among those ages zero to four, no clinically significant pre-post change was noted in other leading psychotropic classes among children ages zero to four and 10 to 17. By contrast, postimplementation use of other psychotropic medications decreased among those ages five to nine (AOR=.73). CONCLUSIONS: A state Medicaid peer-review program resulted in decreased antipsychotic use across all age groups, particularly among children younger than ten. No notable substitution of other psychotropic classes for antipsychotics was observed.

Association of Antidepressant Medications With Incident Type 2 Diabetes Among Medicaid-Insured Youths.

Importance: Antidepressants are one of the most commonly prescribed classes of psychotropic medications among US youths. For adults, there is emerging evidence on the increased risk of type 2 diabetes in association with antidepressant use. However, little is known about the antidepressant treatment-emergent risk of type 2 diabetes among youths. Objective: To assess the association between antidepressant use and the risk of incident type 2 diabetes in youths by antidepressant subclass and according to duration of use, cumulative dose, and average daily dose. Design, Setting, and Participants: A retrospective cohort study was conducted using Medicaid claims data from 4 geographically diverse, large states of youths 5 to 20 years of age who initiated antidepressant treatment from January 1, 2005, to December 31, 2009. Exposures: Antidepressant use (selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic or other cyclic antidepressants, and other antidepressants) was assessed using the following 4 time-varying measures: current or former use, duration of use, cumulative dose, and average daily dose. Main Outcomes and Measures: Incident type 2 diabetes was assessed using discrete-time failure models, adjusting for disease risk score estimated using more than 125 baseline and time-dependent covariates. Results: In this cohort of 119 608 youths aged 5 to 20 years who initiated antidepressant treatment (59 087 female youths and 60 521 male youths; 54.7% between 5 and 14 years of age) with a mean follow-up of 22.8 months, 79 285 [66.3%] had SSRI or SNRI exposure. The risk of type 2 diabetes was significantly greater during current use than former use of SSRIs or SNRIs (absolute risk, 1.29 per 10 000 person-months vs 0.64 per 10 000 person-months; adjusted relative risk [RR], 1.88; 95% CI, 1.34-2.64) and tricyclic or other cyclic antidepressants (absolute risk, 0.89 per 10 000 person-months vs 0.48 per 10 000 person-months; RR, 2.15; 95% CI, 1.06-4.36), but not of other antidepressants (absolute risk, 1.15 per 10 000 person-months vs 1.12 per 10 000 person-months; RR, 0.99; 95% CI, 0.66-1.50). Furthermore, for youths currently using SSRIs or SNRIs, the risk of type 2 diabetes increased with the duration of use (RR, 2.66; 95% CI, 1.45-4.88 for >210 days and RR, 2.56; 95% CI, 1.29-5.08 for 151-210 days compared with 1-90 days) and with the cumulative dose (RR, 2.44; 95% CI, 1.35-4.43 for >4500 mg and RR, 2.17; 95% CI, 1.07-4.40 for 3001-4500 mg compared with 1-1500 mg in fluoxetine hydrochloride dose equivalents). By contrast, neither the duration nor the cumulative dose of other antidepressants was associated with an increased risk of type 2 diabetes. The risk of type 2 diabetes increased significantly with the average daily dose among youths with more than 150 days of SSRI or SNRI use (RR, 2.39; 95% CI, 1.04-5.52 for >15.0 vs ≤15.0 mg/d) but not among youths with 1 to 150 days of SSRI or SNRI use. Conclusions and Relevance: In a large cohort of youths insured by Medicaid, the use of SSRIs or SNRIs-the most commonly used antidepressant subclass-was associated with an increased risk of type 2 diabetes that intensified with increasing duration of use, cumulative dose, and average daily dose.

Concomitant Use of Atypical Antipsychotics With Other Psychotropic Medication Classes and the Risk of Type 2 Diabetes Mellitus.

OBJECTIVE: More than half of youth treated with atypical antipsychotic (AAP) medications are also treated with concomitant antidepressants or stimulants. This study assessed the association between antidepressant or stimulant use concomitant with AAPs and the risk of incident type 2 diabetes mellitus (T2DM). METHOD: Medicaid Analytic eXtract data were used to conduct a retrospective cohort study of youth (aged 5-20 years) who initiated AAP treatment. In AAP-treated youth, concomitant antidepressant (selective serotonin reuptake inhibitors [SSRI]/serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic/other cyclic antidepressants [TCAs], and other antidepressants) or stimulant use was assessed. The risk of incident T2DM was estimated using discrete time failure models, adjusting for disease risk score estimated using >125 baseline and time-dependent covariates. RESULTS: Among 73,224 AAP initiators, 43.0% had concomitant antidepressant use (76.4% were SSRI/SNRIs) and 43.8% had concomitant stimulant use. The study cohort had an average follow-up of 24.8 months (median = 22.0 months, interquartile range [IQR] = 10.0-38.0 months). In current AAP-treated youth, concomitant SSRI/SNRI (relative risk [RR] = 1.84, 95% CI = 1.30-2.59) or TCA use (RR = 2.75, 95% CI = 1.28-5.87) was associated with an increased risk of T2DM. By contrast, concomitant use of other antidepressants or stimulants with AAPs was not associated with an increased risk of T2DM. In concomitant users of AAPs and SSRI/SNRIs, the risk of T2DM increased with the duration of SSRI/SNRI use (RR = 2.35, 95% CI = 1.15-4.83 for ≥180 days vs. 1-180 days) as well as with the cumulative SSRI/SNRI dose (RR = 1.99, 95% CI = 1.08-3.67 for >2,700 mg vs. 1-2,700 mg fluoxetine dose equivalents), after adjusting for the duration and cumulative dose of AAP use. By contrast, in concomitant users of AAPs and stimulants, neither duration nor cumulative dose of stimulants was associated with an increased risk of T2DM. CONCLUSION: In AAP-treated Medicaid-insured youth, concomitant SSRI/SNRI use was associated with a heightened risk of T2DM, which intensified with increasing duration and dose.

Differing antidepressant maintenance methodologies.

BACKGROUND: The principle evidence that antidepressant medication (ADM) is an effective maintenance treatment for adults with major depressive disorder (MDD) is from placebo substitution trials. These trials enter responders from ADM efficacy trials into randomized, double-blind placebo-controlled (RDBPC) effectiveness trials to measure the rate of MDD relapse over time. However, other randomized maintenance trial methodologies merit consideration and comparison. METHODS: A systematic review of ADM randomized maintenance trials included research reports from multiple databases. Relapse rate was the main effectiveness outcome assessed. RESULTS: Five ADM randomized maintenance methodologies for MDD responders are described and compared for outcome. These effectiveness trials include: placebo-substitution, ADM/placebo extension, ADM extension, ADM vs. psychotherapy, and treatment as usual. The placebo-substitution trials for those abruptly switched to placebo resulted in unusually high (46%) rates of relapse over 6-12months, twice the continuing ADM rate. These trials were characterized by selective screening, high attrition, an anxious anticipation of a switch to placebo, and a risk of drug withdrawal symptoms. Selectively screened ADM efficacy responders who entered into 4-12month extension trials experienced relapse rates averaging ~10% with a low attrition rate. Non-industry sponsored randomized trials of adults with multiple prior MDD episodes who were treated with ADM maintenance for 1-2years experienced relapse rates averaging 40%. CONCLUSIONS: Placebo substitution trial methodology represents only one approach to assess ADM maintenance. Antidepressant maintenance research for adults with MDD should be evaluated for industry sponsorship, attrition, the impact of the switch to placebo, and major relapse differences in MDD subpopulations.

Nurse Practitioner Independent Practice Authority and Mental Health Service Delivery in U.S. Community Health Centers.

OBJECTIVE: Little is known about how nurse practitioner independent practice authority (NP-IPA) influences patient care. This study examined the effect of NP-IPA on patterns of mental health-related visits provided by NPs in U.S. community health centers (CHCs). METHODS: State NP regulatory information was linked to National Ambulatory Medical Care Survey data on NP- and physician-provided visits (N=61,457) in CHCs from 2006 through 2011. The proportion of NP-provided versus physician-provided mental health-related visits in states with NP-IPA was compared with the proportion in states without NP-IPA. The adjusted odds of mental health-related visits in CHCs provided by NPs in states with and without NP-IPA were compared by using multiple logistic regression models while accounting for the complex survey design. RESULTS: Between 2006 and 2011, the odds of NP- versus physician-provided mental health-related visits in CHCs were more than two times greater in states with NP-IPA than in states with no NP-IPA (adjusted odds ratio [OR]= 2.43, 95% confidence interval [CI]=1.12-4.60). In contrast, no significant difference between states with and without NP-IPA was noted in non-mental health-related CHC visits provided by NPs. Among all mental health-related visits, the odds of visits in which psychotropic medications were prescribed by an NP were more than three times higher in states with NP-IPA than in those without NP-IPA (adjusted OR=3.14, CI=1.50-6.54). CONCLUSIONS: Compared with physicians, NPs provided proportionally more CHC mental health-related visits in states with NP-IPA than in states without NP-IPA.

Hispanic Residential Isolation, ADHD Diagnosis and Stimulant Treatment among Medicaid-Insured Youth.

OBJECTIVE: This study aimed to evaluate a conceptual framework that assessed the effect of Hispanic residential isolation on Attention Deficit Hyperactivity Disorder (ADHD) health service utilization among 2.2 million publicly insured youth. DESIGN: Cross-sectional. SETTING: Medicaid administrative claims data for ambulatory care services from a US Pacific state linked with US census data. PARTICIPANTS: Youth, aged 2-17 years, continuously enrolled in 2009. MAIN OUTCOME MEASURES: The percent annual prevalence and odds of ADHD diagnosis and stimulant use according to two measures of racial/ethnic residential isolation: 1) the county-level Hispanic isolation index (HI) defined as the population density of Hispanic residents in relation to other racial/ethnic groups in a county (<.5; .5-.64; ≥.65); and 2) the proportion of Hispanic residents in a ZIP code tabulation area (<25%; 25%-50%; >50%). RESULTS: Among the 47,364 youth with a clinician-reported ADHD diagnosis, 60% received a stimulant treatment (N = 28,334). As the county level HI increased, Hispanic residents of ethnically isolated locales were significantly less likely to receive an ADHD diagnosis (adjusted odds ratio [AOR]=.92 [95% CI=.88-.96]) and stimulant use (AOR=.61 [95% CI=.59-.64]) compared with Hispanic youth in less isolated areas. At the ZIP code level, a similar pattern of reduced ADHD diagnosis (AOR=.81 [95% CI=.77-.86]) and reduced stimulant use (AOR=.65 [95% CI=.61-.69]) was observed as Hispanic residential isolation increased from the least isolated to the most isolated ZIP code areas. CONCLUSIONS: These findings highlight the opportunity for Big Data to advance mental health research on strategies to reduce racial/ethnic health disparities, particularly for poor and vulnerable youth. Further exploration of racial/ethnic residential isolation in other large data sources is needed to guide future policy development and to target culturally sensitive interventions.

Raising the Minimum Effective Dose of Serotonin Reuptake Inhibitor Antidepressants: Adverse Drug Events.

This review focuses on the dose-response of serotonin reuptake inhibitor (SRI) antidepressants for efficacy and for adverse drug events (ADEs). Dose-response is identified by placebo-controlled, double-blind, fixed-dose clinical trials comparing various doses for efficacy and for ADEs. Reports from the great majority of clinical trials have consistently found that the minimum SRI effective dose is usually optimal for efficacy in the treatment of depression disorders, even though most American medical practitioners raise the dose when early antidepressant treatment results are negative or partial. To better understand this issue, the medical literature was comprehensively reviewed to ascertain the degree to which SRI medications resulted in a flat dose response for efficacy and then to identify specific ADEs that are dose-dependent. Strong evidence from fixed-dose trial data for the efficacy of nonascendant, minimum effective doses of SRIs was found for the treatment of both major depression and anxiety disorders. Particularly important was the finding that most SRI ADEs have an ascending dose-response curve. These ADEs include sexual dysfunction, hypertension, cardiac conduction risks, hyperglycemia, decreased bone density, sweating, withdrawal symptoms, and agitation. Thus, routinely raising the SRI dose above the minimum effective dose for efficacy can be counter-productive.