Psychometric evaluation of the Suicide Cognitions Scale-Revised (SCS-R).

The measurement of self-reported suicide risk can be complicated in medical settings due to patient apprehension about the potential consequences of self-disclosure. The Suicide Cognitions Scale (SCS) was designed to assess suicide risk by measuring a range of suicidogenic cognitions (e.g., hopelessness, perceived burdensomeness) collectively referred to as the suicidal belief system. The SCS's concurrent, known groups, and prospective validity for suicidal thoughts and behaviors have previously been supported. The present study examined the factor structure, known-groups, and concurrent validity of a revised, 16-item version of the SCS (SCS-R), which removed two items that explicitly used the word "suicide" and changed item scoring from a 1-5 to 0-4 scale, thereby improving the interpretation of scores. In a sample of 2,690 primary care patients presenting for routine medical care at one of six US military clinics, results of bifactor analysis supported the scale's unidimensionality. The SCS-R significantly differentiated participants with a history of suicide attempts and was significantly correlated with frequency of thoughts about death and self-harm during the previous 2 weeks. Results align with earlier research and provide psychometric support for the SCS-R.

Improving Suicide Risk Screening to Identify the Highest Risk Patients: Results From the PRImary Care Screening Methods (PRISM) Study.

PURPOSE: Over 95% of patients who screen positive on the Patient Health Questionnaire-9 (PHQ-9) suicide risk item do not attempt or die by suicide, which could lead to unnecessary treatment and/or misallocation of limited resources. The present study seeks to determine if suicide risk screening can be meaningfully improved to identify the highest-risk patients. METHODS: Patients eligible to receive medical treatment from the US Department of Defense medical system were recruited from 6 military primary care clinics located at 5 military installations around the United States. Patients completed self-report measures including the PHQ-9 and 16 items from the Suicide Cognitions Scale (SCS) during routine primary care clinic visits. Postbaseline suicidal behaviors (suicide attempts, interrupted attempts, and aborted attempts) were assessed by evaluators who were blind to screening results using the Self-Injurious Thoughts and Behaviors Interview. RESULTS: Among 2,744 patients, 13 (0.5%) engaged in suicidal behavior in the 30 days after screening and 28 (1.0%) displayed suicidal behavior in the 90 days after screening. Multiple SCS items differentiated patients with suicidal behavior less than 30 days after screening positive for suicide risk. Augmenting the PHQ-9 suicide risk item with SCS items improved the identification of patients who were most likely to have suicidal behavior within a month of screening positive without sacrificing sensitivity. CONCLUSION: Among primary care patients who screen positive for suicide risk on the PHQ-9, SCS items improved screening efficiency by identifying those patients who are most likely to engage in suicidal behavior within the next 30 days.

The Effect of Propofol on a Forced Swim Test in Mice at 24 Hours.

BACKGROUND: There are few rapidly acting treatments for acute suicidality or treatment-resistant depression. Propofol (2,6-diisopropylphenol) is an intravenous anesthetic agent used in outpatient settings. It is a gamma-aminobutyric acid type A agonist and has affinity at the N-methyl-D-aspartate receptor. Elevation in mood and sociality in humans has been observed following propofol-induced anesthesia. Other authors reported an open-label study of repeated dosing of propofol in treatment-resistant depression in which several patients experienced sustained improvement. Recently, we reported that in a rodent model of despair, a forced swim test, 45 minutes after administration of 50 mg/kg propofol, immobility time was significantly reduced. OBJECTIVE: The objective of the experiment was to determine whether the antidepressant-like effects of a single dose of propofol in mice are sustained for 24 hours. METHODS: The time spent immobile during a forced swim test 24 hours after intraperitoneal administration of a single dose of propofol 50 mg/kg or 0.9% saline was evaluated in 24 adult male mice (C57/BL6). Immobility time was quantified and evaluated with a custom video analysis software program. RESULTS: Propofol-treated mice were immobile for a mean (SEM) time of 115 (13) seconds, whereas saline-treated mice were immobile for a mean (SEM) time of 94 (14) seconds. A 2-tailed unpaired t test found no significant difference between the treatment groups (t = 1.07, df = 22; P = 0.30). CONCLUSIONS: Twenty-four hours after intraperitoneal administration, the effect of propofol on immobility time was not statistically significantly different from vehicle. However, given our previous report of at least a short-term benefit of propofol on struggling time in the forced swim time and an encouraging pilot study in humans with treatment-resistant depression, further evaluation of propofol's antidepressant potential may be warranted.

AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.

Haloperidol plus promethazine for psychosis-induced aggression.

BACKGROUND: Health services often manage agitated or violent people, and such behaviour is particularly prevalent in emergency psychiatric services (10%). The drugs used in such situations should ensure that the person becomes calm swiftly and safely. OBJECTIVES: To examine whether haloperidol plus promethazine is an effective treatment for psychosis-induced aggression. SEARCH METHODS: On 6 May 2015 we searched the Cochrane Schizophrenia Group's Register of Trials, which is compiled by systematic searches of major resources (including MEDLINE, EMBASE, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. SELECTION CRITERIA: All randomised clinical trials with useable data focusing on haloperidol plus promethazine for psychosis-induced aggression. DATA COLLECTION AND ANALYSIS: We independently extracted data. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We found two new randomised controlled trials (RCTs) from the 2015 update searching. The review now includes six studies, randomising 1367 participants and presenting data relevant to six comparisons.When haloperidol plus promethazine was compared with haloperidol alone for psychosis-induced aggression for the outcome not tranquil or asleep at 30 minutes, the combination treatment was clearly more effective (n=316, 1 RCT, RR 0.65, 95% CI 0.49 to 0.87, high-quality evidence). There were 10 occurrences of acute dystonia in the haloperidol alone arm and none in the combination group. The trial was stopped early as haloperidol alone was considered to be too toxic.When haloperidol plus promethazine was compared with olanzapine, high-quality data showed both approaches to be tranquillising. It was suggested that the combination of haloperidol plus promethazine was more effective, but the difference between the two approaches did not reach conventional levels of statistical significance (n=300, 1 RCT, RR 0.60, 95% CI 0.22 to 1.61, high-quality evidence). Lower-quality data suggested that the risk of unwanted excessive sedation was less with the combination approach (n=116, 2 RCTs, RR 0.67, 95% CI 0.12 to 3.84).When haloperidol plus promethazine was compared with ziprasidone all data were of lesser quality. We identified no binary data for the outcome tranquil or asleep. The average sedation score (Ramsay Sedation Scale) was lower for the combination approach but not to conventional levels of statistical significance (n=60, 1 RCT, MD -0.1, 95% CI - 0.58 to 0.38). These data were of low quality and it is unclear what they mean in clinical terms. The haloperidol plus promethazine combination appeared to cause less excessive sedation but again the difference did not reach conventional levels of statistical significance (n=111, 2 RCTs, RR 0.30, 95% CI 0.06 to 1.43).We found few data for the comparison of haloperidol plus promethazine versus haloperidol plus midazolam. Average Ramsay Sedation Scale scores suggest the combination of haloperidol plus midazolam to be the most sedating (n=60, 1 RCT, MD - 0.6, 95% CI -1.13 to -0.07, low-quality evidence). The risk of excessive sedation was considerably less with haloperidol plus promethazine (n=117, 2 RCTs, RR 0.12, 95% CI 0.03 to 0.49, low-quality evidence). Haloperidol plus promethazine seemed to decrease the risk of needing restraints by around 12 hours (n=60, 1 RCT, RR 0.24, 95% CI 0.10 to 0.55, low-quality evidence). It may be that use of midazolam with haloperidol sedates swiftly, but this effect does not last long.When haloperidol plus promethazine was compared with lorazepam, haloperidol plus promethazine seemed to more effectively cause sedation or tranquillisation by 30 minutes (n=200, 1 RCT, RR 0.26, 95% CI 0.10 to 0.68, high-quality evidence). The secondary outcome of needing restraints or seclusion by 12 hours was not clearly different between groups, with about 10% in each group needing this intrusive intervention (moderate-quality evidence). Sedation data were not reported, however, the combination group did have less 'any serious adverse event' in 24-hour follow-up, but there were not clear differences between the groups and we are unsure exactly what the adverse effect was. There were no deaths.When haloperidol plus promethazine was compared with midazolam, there was clear evidence that midazolam is more swiftly tranquillising of an aggressive situation than haloperidol plus promethazine (n=301, 1 RCT, RR 2.90, 95% CI 1.75 to 4.8, high-quality evidence). On its own, midazolam seems to be swift and effective in tranquillising people who are aggressive due to psychosis. There was no difference in risk of serious adverse event overall (n=301, 1 RCT, RR 1.01, 95% CI 0.06 to 15.95, high-quality evidence). However, 1 in 150 participants allocated haloperidol plus promethazine had a swiftly reversed seizure, and 1 in 151 given midazolam had swiftly reversed respiratory arrest. AUTHORS' CONCLUSIONS: Haloperidol plus promethazine is effective and safe, and its use is based on good evidence. Benzodiazepines work, with midazolam being particularly swift, but both midazolam and lorazepam cause respiratory depression. Olanzapine intramuscular and ziprasidone intramuscular do seem to be viable options and their action is swift, but resumption of aggression with subsequent need to re-inject was more likely than with haloperidol plus promethazine. Haloperidol used on its own without something to offset its frequent and serious adverse effects does seem difficult to justify.

Solution properties and electrospinning of phosphonium gemini surfactants.

Bis(diphenylphosphino)alkanes quantitatively react with excess 1-bromododecane to prepare novel phosphonium gemini surfactants with spacer lengths ranging from 2 to 4 methylenes (12-2/3/4-12P). Dodecyltriphenylphosphonium bromide (DTPP), a monomeric surfactant analog, was readily water soluble, however, in sharp contrast, phosphonium gemini surfactants were poorly soluble in water due to two hydrophobic tails and relatively hydrophobic cationic head groups containing phenyl substituents. Isothermal titration calorimetry did not reveal a measurable critical micelle concentration for the 12-2-12P phosphonium gemini surfactant in water at 25 °C. Subsequent studies in 50/50 v/v water-methanol at 25 °C showed a CMC of 1.0 mM for 12-2-12P. All phosphonium gemini surfactants effectively complexed nucleic acids, but failed to deliver nucleic acids in vitro to HeLa cells. The solution behavior of phosphonium gemini surfactants was investigated in chloroform, which is an organic solvent where reverse micellar structures are favored. Solution rheology in chloroform explored the solution behavior of the phosphonium gemini surfactants compared to DTPP. The 12-2-12P and 12-3-12P gemini surfactants were successfully electrospun from chloroform to generate uniform fibers while 12-4-12P gemini surfactant and DTPP only electrosprayed to form droplets.

Does Suicide Risk Screening Improve the Identification of Primary Care Patients Who Will Attempt Suicide Versus Depression Screening Alone?

OBJECTIVE: The effectiveness of suicide risk screening relative to depression screening alone among primary care patients has not been tested rigorously. This study compared the performance of multiple depression screening methods (Patient Health Questionnaire [PHQ]-2, PHQ-8, and PHQ-9) and multiple suicide risk screening methods (PHQ-9 item 9 and suicide-focused screening of "thoughts of killing yourself" during the entire lifespan, within the past month, and within the past week) in a convenience sample of primary care patients. METHODS: A total of 2,744 patients (military personnel, family members, and retirees) from six military primary care clinics completed the PHQ-9 and screening for suicidal ideation (SI) during routine clinic visits. Follow-up phone interviews were conducted for one year post-baseline to assess the incidence of suicide attempts, the study's primary outcome. Sensitivity, specificity, accuracy, and F1 statistics were calculated for each screening method for identifying patients who attempted suicide. RESULTS: More than 65% of patients who screened positive for SI also screened positive for depression on the PHQ-9. Depression screening with the PHQ-9 correctly identified more patients who attempted suicide during follow-up than the PHQ-2, past week SI, and past month SI. The PHQ-9 correctly identified more patients who attempted suicide within 3 months than lifetime SI, but lifetime SI correctly identified more patients who attempted suicide within 6 and 12 months. CONCLUSION: Depression screening with the PHQ-9 was the most effective strategy for identifying patients who attempted suicide in the near term. Universal suicide risk screening is unlikely to meaningfully improve identification of higher-risk patients beyond PHQ-9 depression screening.

Rapid intensification of suicide risk preceding suicidal behavior among primary care patients.

BACKGROUND: Approximately half of those who attempt suicide report experiencing suicidal ideation and suicidal planning in advance; others deny these experiences. Some researchers have hypothesized that rapid intensification is due to past suicidal ideation and/or behaviors that are "mentally shelved" but remain available for rapid access later. METHOD: To evaluate this hypothesis, we examined (a) temporal sequencing of suicidal ideation, suicidal planning, and suicidal behavior, and (b) speed of emergence of suicidal behavior in a prospective cohort study of 2744 primary care patients. RESULTS: Of 52 patients reporting suicidal behavior during follow-up, 20 (38.5%) reported suicidal ideation and planning prior to their suicidal behavior, 23 (44.2%) reported suicidal ideation but not planning, and nine (17.3%) denied both suicidal ideation and planning. Over half (n = 30, 57.7%) reported the onset of suicidal ideation and/or planning on the same day as or after their suicidal behavior (i.e., rapid intensification). Rapid intensification was not associated with increased likelihood of reporting recent or past suicidal ideation, planning, or behaviors, suggesting rapid intensification does not depend on prior experience with suicidal ideation and/or behaviors. CONCLUSION: Detecting primary care patients at risk for this form of suicidal behavior may be limited even with universal suicide risk screening.

Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.

OBJECTIVE: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. METHODS: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. RESULTS: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). CONCLUSIONS: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Phosphonium-containing polyelectrolytes for nonviral gene delivery.

Nonviral gene therapy focuses intensely on nitrogen-containing macromolecules and lipids to condense and deliver DNA as a therapeutic for genetic human diseases. For the first time, DNA binding and gene transfection experiments compared phosphonium-containing macromolecules with their respective ammonium analogs. Conventional free radical polymerization of quaternized 4-vinylbenzyl chloride monomers afforded phosphonium- and ammonium-containing homopolymers for gene transfection experiments of HeLa cells. Aqueous size exclusion chromatography confirmed similar absolute molecular weights for all polyelectrolytes. DNA gel shift assays and luciferase expression assays revealed phosphonium-containing polymers bound DNA at lower charge ratios and displayed improved luciferase expression relative to the ammonium analogs. The triethyl-based vectors for both cations failed to transfect HeLa cells, whereas tributyl-based vectors successfully transfected HeLa cells similar to Superfect demonstrating the influence of the alkyl substituent lengths on the efficacy of the gene delivery vehicle. Cellular uptake of Cy5-labeled DNA highlighted successful cellular uptake of triethyl-based polyplexes, showing that intracellular mechanisms presumably prevented luciferase expression. Endocytic inhibition studies using genistein, methyl ß-cyclodextrin, or amantadine demonstrated the caveolae-mediated pathway as the preferred cellular uptake mechanism for the delivery vehicles examined. Our studies demonstrated that changing the polymeric cation from ammonium to phosphonium enables an unexplored array of synthetic vectors for enhanced DNA binding and transfection that may transform the field of nonviral gene delivery.

Phosphonium-containing diblock copolymers for enhanced colloidal stability and efficient nucleic acid delivery.

RAFT polymerization successfully controlled the synthesis of phosphonium-based AB diblock copolymers for nonviral gene delivery. A stabilizing block of either oligo(ethylene glycol(9)) methyl ether methacrylate or 2-(methacryloxy)ethyl phosphorylcholine provided colloidal stability, and the phosphonium-containing cationic block of 4-vinylbenzyltributylphosphonium chloride induced electrostatic nucleic acid complexation. RAFT polymerization generated well-defined stabilizing blocks (M(n) = 25000 g/mol) and subsequent chain extension synthesized diblock copolymers with DPs of 25, 50, and 75 for the phosphonium-containing block. All diblock copolymers bound DNA efficiently at ± ratios of 1.0 in H(2)O, and polyplexes generated at ± ratios of 2.0 displayed hydrodynamic diameters between 100 and 200 nm. The resulting polyplexes exhibited excellent colloidal stability under physiological salt or serum conditions, and they maintained constant hydrodynamic diameters over 24 h. Cellular uptake studies using Cy5-labeled DNA confirmed reduced cellular uptake in COS-7 and HeLa cells and, consequently, resulted in low transfection in these cell lines. Serum transfection in HepaRG cells, which are a predictive cell line for in vivo transfection studies, showed successful transfection using all diblock copolymers with luciferase expression on the same order of magnitude as Jet-PEI. All diblock copolymers exhibited low cytotoxicity (>80% cell viability). Promising in vitro transfection and cytotoxicity results suggest future studies involving the in vivo applicability of these phosphonium-based diblock copolymer delivery vehicles.

Suicide Risk Among Hospitalized Versus Discharged Deliberate Self-Harm Patients: Generalized Random Forest Analysis Using a Large Claims Data Set.

INTRODUCTION: Suicide rates are extremely high among emergency department patients seen for deliberate self-harm. Inpatient hospitalization is often recommended for these patients, but evidence on the suicide prevention impacts of hospitalization is scarce. Confounding by indication and challenges to implementing randomized designs are barriers to advances in this field. METHODS: Investigators used 2009-2012 statewide data on 57,312 self-harm emergency department patients from California, linked to mortality records. Naive 12-month and 30-day suicide risks were estimated among patients who were hospitalized versus those who were discharged. Then, generalized random forest methods were applied to estimate the average treatment impacts of hospitalization on suicide, conditioning on observable covariates. Associations were calculated separately for sex- and age-specific subgroups. Analyses were conducted in February 2019-August 2021. RESULTS: In naive analyses, suicide risk was significantly higher in hospitalized than in discharged patients in each subgroup. In 12-month models accounting for the observed covariates through generalized random forest methods, hospitalized male patients had 5.4 more suicides per 1,000 patients (95% CI=3.0, 7.8), hospitalized patients aged 10-29 years had 2.4 more suicides per 1,000 (95% CI=1.1, 3.6), and those aged ≥50 years had 5.8 more suicides per 1,000 (95% CI=0.5, 11.2) than corresponding discharged patients. Hospitalization was not significantly associated with suicide among female patients or patients aged 30-49 years in generalized random forest analyses. Patterns were similar in 30-day generalized random forest models. CONCLUSIONS: Emergency department personnel intend to hospitalize self-harm patients with high suicide risk; this study suggests that this goal is largely realized. Analyses that control for confounding by observable covariates did not find clear evidence that hospitalization reduces suicide risk and could not rule out the possibility of iatrogenic effects.

Scores on the suicide cognitions scale-revised (SCS-R) predict future suicide attempts among primary care patients denying suicide ideation and prior attempts.

BACKGROUND: Approximately half of patients who attempt or die by suicide screened negative for suicidal ideation during their most recent medical visit. Maladaptive beliefs and schemas can increase cognitive vulnerability to suicidal behavior, even among patients without recent or past suicidal thoughts and behaviors. Assessing these beliefs could improve the detection of patients who will engage in suicidal behavior after screening negative for elevated suicide risk. METHODS: Primary care patients who completed the Patient Health Questionnaire-9 and the Suicide Cognitions Scale-Revised (SCS-R) during routine clinic visits and denied suicidal ideation at baseline (N = 2417) were included in the study sample. Suicidal behaviors during the 12 months after baseline were assessed. Logistic regression analyses examined the association of baseline SCS-R scores with later suicidal behavior. RESULTS: In both univariate and multivariate analyses, SCS-R total scores were associated with significantly increased risk of suicidal behavior within 90, 180, and 365 days post-baseline. Results were unchanged when patients who reported prior suicidal behavior were excluded (N = 2178). In item-level analyses, all 16 SCS-R items significantly differentiated patients with and without follow-up suicidal behavior. LIMITATIONS: Study limitations included missing follow-up data, restriction of sample to U.S. military medical beneficiaries, and inability to assess representativeness of the sample relative to the full primary care population. CONCLUSIONS: SCS-R scores are elevated among patients who attempt suicide after denying both suicidal ideation and prior suicide attempts, suggesting the scale may reflect enduring suicide risk. The SCS-R could enhance suicide risk screening and assessment.

Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine.

BACKGROUND: There is a need for a rapid-acting, non-injection, acute treatment for agitation. AIMS: To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia. METHOD: This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression-Improvement scale (CGI-I) score 2 h after dose one. RESULTS: Inhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS-EC score was evident 10 min after dose one with both 5 and 10 mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications. CONCLUSIONS: Inhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.

Tailoring charge density and hydrogen bonding of imidazolium copolymers for efficient gene delivery.

Conventional free radical polymerization with subsequent postpolymerization modification afforded imidazolium copolymers with controlled charge density and side chain hydroxyl number. Novel imidazolium-containing copolymers where each permanent cation contained one or two adjacent hydroxyls allowed precise structure-transfection efficiency studies. The degree of polymerization was identical for all copolymers to eliminate the influence of molecular weight on transfection efficiency. DNA binding, cytotoxicity, and in vitro gene transfection in African green monkey COS-7 cells revealed structure-property-transfection relationships for the copolymers. DNA gel shift assays indicated that higher charge densities and hydroxyl concentrations increased DNA binding. As the charge density of the copolymers increased, toxicity of the copolymers also increased; however, as hydroxyl concentration increased, cytotoxicity remained constant. Changing both charge density and hydroxyl levels in a systematic fashion revealed a dramatic influence on transfection efficiency. Dynamic light scattering of the polyplexes, which were composed of copolymer concentrations required for the highest luciferase expression, showed an intermediate DNA-copolymer binding affinity. Our studies supported the conclusion that cationic copolymer binding affinity significantly impacts overall transfection efficiency of DNA delivery vehicles, and the incorporation of hydroxyl sites offers a less toxic and effective alternative to more conventional highly charged copolymers.

Effectiveness of adjunctive antidepressant treatment for bipolar depression.

BACKGROUND: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. METHODS: In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. RESULTS: Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

NIH Roundtable on Opportunities to Advance Research on Neurologic and Psychiatric Emergencies.

STUDY OBJECTIVE: The Institute of Medicine Committee on the Future of Emergency Care in the United States Health System (2003) identified a need to enhance the research base for emergency care. As a result, a National Institutes of Health (NIH) Task Force on Research in Emergency Medicine was formed to enhance NIH support for emergency care research. Members of the NIH Task Force and academic leaders in emergency care participated in 3 Roundtable discussions to prioritize current opportunities for enhancing and conducting emergency care research. We identify key research questions essential to advancing the science of emergency care and discuss the barriers and strategies to advance research by exploring the collaboration between NIH and the emergency care community. METHODS: Experts from emergency medicine, neurology, psychiatry, and public health assembled to review critical areas in need of investigation, current gaps in knowledge, barriers, and opportunities. Neurologic emergencies included cerebral resuscitation, pain, stroke, syncope, traumatic brain injury, and pregnancy. Mental health topics included suicide, agitation and delirium, substances, posttraumatic stress, violence, and bereavement. RESULTS: Presentations and group discussion firmly established the need for translational research to bring basic science concepts into the clinical arena. A coordinated continuum of the health care system that ensures rapid identification and stabilization and extends through discharge is necessary to maximize overall patient outcomes. There is a paucity of well-designed, focused research on diagnostic testing, clinical decisionmaking, and treatments in the emergency setting. Barriers include the limited number of experienced researchers in emergency medicine, limited dedicated research funding, and difficulties of conducting research in chaotic emergency environments stressed by crowding and limited resources. Several themes emerged during the course of the roundtable discussion, including the need for development of (1) a research infrastructure for the rapid identification, consent, and tracking of research subjects that incorporates innovative informatics technologies, essential for future research; (2) diagnostic strategies and tools necessary to understand key populations and the process of medical decisionmaking, including the investigation of the pathobiology of symptoms and symptom-oriented therapies; (3) collaborative research networks to provide unique opportunities to form partnerships, leverage patient cohorts and clinical and financial resources, and share data; (4) formal research training programs integral for creating new knowledge and advancing the science and practice of emergency medicine; and (5) recognition that emergency care is part of an integrated system from emergency medical services dispatch to discharge. The NIH Roundtable "Opportunities to Advance Research on Neurological and Psychiatric Emergencies" created a framework to guide future emergency medicine-based research initiatives. CONCLUSION: Emergency departments provide the portal of access to the health care system for most patients with acute neurologic and psychiatric illness. Emergency physicians and colleagues are primed to investigate neurologic and psychiatric emergencies that will directly improve the delivery of care and patient outcomes.

Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus.

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.