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.

Myosin VI dimerization triggers an unfolding of a three-helix bundle in order to extend its reach.

Myosin VI challenges the prevailing theory of how myosin motors move on actin: the lever arm hypothesis. While the reverse directionality and large powerstroke of myosin VI can be attributed to unusual properties of a subdomain of the motor (converter with a unique insert), these adaptations cannot account for the large step size on actin. Either the lever arm hypothesis needs modification, or myosin VI has some unique form of extension of its lever arm. We determined the structure of the region immediately distal to the lever arm of the motor and show that it is a three-helix bundle. Based on C-terminal truncations that display the normal range of step sizes on actin, CD, fluorescence studies, and a partial deletion of the bundle, we demonstrate that this bundle unfolds upon dimerization of two myosin VI monomers. This unconventional mechanism generates an extension of the lever arm of myosin VI.

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.

Antipsychotic prescribing for behavioral disorders in US youth: physician specialty, insurance coverage, and complex regimens.

PURPOSE: To assess antipsychotic prescribing patterns according to insurance coverage type and physician specialty in the outpatient treatment of behavioral disorders (BD) in US youth. METHODS: We used 2003-2010 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data to compare antipsychotic prescribing in the outpatient treatment of BD in youth (6-19 years) according to insurance coverage (public vs. private) and physician specialty (psychiatrist vs. non-psychiatrist) using population-weighted Chi-square and multivariable analyses. Also, we examined co-prescribing of antipsychotics with other psychotropic medication classes. Subgroup analyses were conducted in BD visits with no other clinician-reported psychiatric diagnosis (non-comorbid BD visits). RESULTS: A large majority (71.0%) of BD visits were provided by non-psychiatrists. However, psychiatrists prescribed antipsychotics far more frequently than non-psychiatrists (24.2% vs. 4.6%; adjusted odds ratio (AOR) = 5.1 [95% confidence interval (CI), 2.8-9.2]) in total BD visits as well as in non-comorbid BD visits (18.6% vs. 3.6%; AOR = 5.8 [95% CI, 3.2-10.5]). Antipsychotic prescribing was nearly two-fold greater in visits by publicly insured 6-12 year olds (11.3% vs. 5.8%; AOR = 1.9 [95% CI, 1.1-3.5]) and 13-19 year olds (16.2% vs. 8.9%; AOR = 2.0 [95% CI, 1.1-3.6]) compared with their privately insured counterparts. In more than one-third of antipsychotic-prescribed BD visits, antipsychotics were prescribed concomitantly with ≥2 psychotropic medication classes regardless of age group, insurance coverage, or even in the absence of psychiatric comorbidities. CONCLUSION: In outpatient visits by youth for BD, antipsychotics were primarily prescribed by psychiatrists, concomitantly, and for the publicly insured. These treatment patterns merit further investigation.

Visualization of the dynamics of fibrin clot growth 1 molecule at a time by total internal reflection fluorescence microscopy.

Individual fluorescently labeled fibrin(ogen) molecules and their assembly to make a clot were observed by total internal reflection fluorescence microscopy (TIRFM). We used the bleaching of the fluorescent labels to determine the number of active fluorophores attached nonspecifically to each molecule. From the total intensity of bleaching steps, as single-molecule signature events, and the distribution of active labeling, we developed a new single-molecule intensity calibration, which accounts for all molecules, including those "not seen." Live observation of fibrin polymerization in TIRFM by diffusive mixing of thrombin and plasma revealed the real-time growth kinetics of individual fibrin fibers quantitatively at the molecular level. Some fibers thickened in time to thousands of molecules across, equivalent to hundreds of nanometers in diameter, whereas others reached an early stationary state at smaller diameters. This new approach to determine the molecular dynamics of fiber growth provides information important for understanding clotting mechanisms and the associated clinical implications.

Myosin Va and myosin VI coordinate their steps while engaged in an in vitro tug of war during cargo transport.

Myosin Va (myoV) and myosin VI (myoVI) are processive molecular motors that transport cargo in opposite directions on actin tracks. Because these motors may bind to the same cargo in vivo, we developed an in vitro "tug of war" to characterize the stepping dynamics of single quantum-dot-labeled myoV and myoVI motors linked to a common cargo. MyoV dominates its myoVI partner 79% of the time. Regardless of which motor wins, its stepping rate slows due to the resistive load of the losing motor (myoV, 2.1 pN; myoVI, 1.4 pN). Interestingly, the losing motor steps backward in synchrony with the winning motor. With ADP present, myoVI acts as an anchor to prevent myoV from stepping forward. This model system emphasizes the physical communication between opposing motors bound to a common cargo and highlights the potential for modulating this interaction by changes in the cell's ionic milieu.

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.

Number needed to harm: its limitations in psychotropic drug safety research.

Commonly used statistical measures to quantify the likelihood of an adverse drug event (ADE) from clinical trials include risk ratio; odds ratio; and number needed to harm (NNH), the reciprocal of absolute risk. This critical review focused on NNH, specifically on its limitations in controlled trials with psychotropic medication. Data for this evaluation were obtained primarily from articles in MEDLINE from 1988 to 2012. Limitations of NNH were found to include the following: a) arbitrary binary cutoffs for continuous measures, b) limited use of confidence intervals, c) limited adjustments for potential baseline confounders, d) limited adjustments for differences in dose and treatment duration, e) rare consideration of high attrition rates, f) variable use of the term harm, g) oversimplified single harm comparisons, h) frequent biased design and reporting, i) undue emphasis on less severe ADEs, j) application primarily to short-term clinical trials, and k) little or no generalizability in community practice. In sum, the NNH metric supplies very limited information on the risks of psychotropic medication. Postmarketing surveillance of community treatment populations using case-control methodology provides far more useful data on serious ADEs.

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 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.

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.

Age-grouped differences in bipolar mania.

OBJECTIVE: This review of published studies compares scores on individual items of mania rating scales that systematically recorded symptom severity in persons diagnosed with bipolar disorder to identify age-grouped differences. METHODS: An extensive literature search identified item scores from mania rating scales, with a particular emphasis on baseline Young Mania Rating Scale (YMRS) item scores in published double-blind, placebo-controlled studies of bipolar I manic disorder. These baseline YMRS item scores were assessed as a proportion of the total YMRS score and compared by age group. Additional YMRS item/total scores in subjects with bipolar spectrum disorders were added to expand the analysis. RESULTS: Preadolescents with bipolar disorder had significantly higher YMRS item scores than adolescents on aggression, irritability, and motor activity. Young Mania Rating Scale baseline item scores relative to the YMRS total score revealed that adolescents diagnosed with bipolar I mania scored comparatively higher than did adults on YMRS aggression and irritability items, whereas adults with bipolar I manic disorder scored comparatively higher on the grandiosity and sexual interest items. Age-grouped findings from subjects diagnosed with bipolar I, II, and Not Otherwise Specified (NOS) disorders yielded similar age-grouped results. CONCLUSION: In age-grouped YMRS item assessments of bipolar mania, anger dyscontrol was most prominent for youth, whereas disordered thought content was paramount for adults.

Cargo binding induces dimerization of myosin VI.

Although myosin VI has properties that would allow it to function optimally as a dimer, full-length myosin VI exists as a monomer in isolation. Based on the ability of myosin VI monomers to dimerize when held in close proximity, we postulated that cargo binding normally regulates dimerization of myosin VI. We tested this hypothesis by expressing a known dimeric cargo adaptor protein of myosin VI, optineurin, and the myosin VI-binding segment from a monomeric cargo adaptor protein, Dab2. In the presence of these adaptor proteins, full-length myosin VI has ATPase properties of a dimer, appears as a dimer in electron micrographs, and moves processively on actin filaments. The results support a model in which cargo binding exposes internal dimerization sequences within full-length myosin VI. Because, unexpectedly, a monomeric fragment of Dab2 triggers dimerization, it would appear that myosin VI is designed to function as a dimer in cells.

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.

Impact of the 2004 Food and Drug Administration pediatric suicidality warning on antidepressant and psychotherapy treatment for new-onset depression.

OBJECTIVE: To assess the national impact of the March 2004 Food and Drug Administration (FDA) antidepressant suicidality warning on the outpatient treatment of new-onset depression in youth. METHOD: A repeated measures, longitudinal design in a cohort of youth diagnosed with new-onset depression was used to assess pre- and post-FDA warning effects. US commercial insurance enrollees in the i3 INNOVUS database from January 2003 through December 2006 were examined. The study population included youth 2- to 17-years old with a new-onset depression diagnosis from July 2003 through June 2006 (N = 40,309). The main independent variables were the warning period (post- vs. pre-FDA warning) and age group (children vs. adolescents). The main outcome measures were youth with antidepressant dispensings and psychotherapy visits measured in 30-day intervals across 36 months following a new-onset diagnosis of any depressive disorder (N = 40,309) and specifically major depressive disorder (MDD) (N = 11,532). RESULTS: Compared to youth with a new-onset diagnosis of depression in the pre-FDA warning period, youth with new-onset diagnosis of depression during the postwarning period had (1) A significantly lower likelihood of antidepressant use: (odds ratio [OR] = 0.85 [0.81-0.89]); When youth with the diagnosis of depression were separated into those with MDD and those with less severe depression diagnoses, only the latter had a significant postwarning antidepressant decline. (2) A significant increase in the odds of a psychotherapy visit (children, OR = 1.31 [1.23-1.40]; adolescents OR = 1.19 [1.15-1.24]). CONCLUSIONS: The FDA suicidality warning was associated with an overall decrease in antidepressant treatment for youth with a clinician-reported diagnosis of depression, but not for those with MDD. Also, following the warning, psychotherapy without medication increased.

Mood swing and mood stabilizer: how specific are these terms?

BACKGROUND: In the DSM-IIIR in 1987, the category title for depressive and bipolar disorders was changed from affective disorders to mood disorders. Within a short period of time thereafter, mood swing and mood stabilizer became very commonly used terms in psychiatry with bipolar implications. METHODS: Terms and definitions in recent texts, articles, and dictionaries pertaining to mood fluctuations have been reviewed. RESULTS: The term mood was seldom part of psychiatric terminology until the late 1970s. Mood swing and mood stabilizer as used in the psychiatric literature are primarily nonspecific and often misleading concepts--particularly as a basis for treatment decisions. Affective fluctuations and shifts to irritability and/or anger in persons with personality and depressive disorders are being viewed by many in the mental health field as cyclically biphasic--between depressed to elated--which is clearly at variance with research findings. CONCLUSIONS: More data-based research on mood variations is needed to authoritatively remedy this situation.

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.

Cross-correlated TIRF/AFM reveals asymmetric distribution of force-generating heads along self-assembled, "synthetic" myosin filaments.

Myosin-II's rod-like tail drives filament assembly with a head arrangement that is often considered to be a symmetric bipole that generates equal and opposite contractile forces on actin. Self-assembled myosin filaments are shown here to be asymmetric in physiological buffer based on cross-correlated images from both atomic force microscopy and total internal reflection fluorescence. Quantitative cross-correlation of these orthogonal methods produces structural information unavailable to either method alone in showing that fluorescence intensity along the filament length is proportional to height. This implies that myosin heads form a shell around the filament axis, consistent with F-actin binding. A motor density of approximately 50-100 heads/micrometer is further estimated but with an average of 32% more motors on one half of any given filament compared to the other, regardless of length. A purely entropic pyramidal lattice model is developed and mapped onto the Dyck paths problem that qualitatively captures this lack of length dependence and the distribution of filament asymmetries. Such strongly asymmetric bipoles are likely to produce an unbalanced contractile force in cells and in actin-myosin gels and thereby contribute to motility as well as cytoskeletal tension.

MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments.

MAP2 and tau exhibit microtubule-stabilizing activities that are implicated in the development and maintenance of neuronal axons and dendrites. The proteins share a homologous COOH-terminal domain, composed of three or four microtubule binding repeats separated by inter-repeats (IRs). To investigate how MAP2 and tau stabilize microtubules, we calculated 3D maps of microtubules fully decorated with MAP2c or tau using cryo-EM and helical image analysis. Comparing these maps with an undecorated microtubule map revealed additional densities along protofilament ridges on the microtubule exterior, indicating that MAP2c and tau form an ordered structure when they bind microtubules. Localization of undecagold attached to the second IR of MAP2c showed that IRs also lie along the ridges, not between protofilaments. The densities attributable to the microtubule-associated proteins lie in close proximity to helices 11 and 12 and the COOH terminus of tubulin. Our data further suggest that the evolutionarily maintained differences observed in the repeat domain may be important for the specific targeting of different repeats to either alpha or beta tubulin. These results provide strong evidence suggesting that MAP2c and tau stabilize microtubules by binding along individual protofilaments, possibly by bridging the tubulin interfaces.