Discovery of Potent, Selective, and Short-Acting Peptidic V2 Receptor Agonists.

The vasopressin analogue desmopressin (desamino-d-arginine8 vasopressin, dDAVP, 1) is a potent vasopressin 2 (V2) receptor (V2R) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis, and hyponatremia. In search of novel, potent, selective, and short-acting peptidic V2R agonists, we synthesized a series of C-terminally truncated analogues of [Val4]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge. The peptides were evaluated for in vitro potency at the human V2 receptor, selectivity versus the related receptors (human vasopressin 1a receptor, human vasopressin 1b receptor, and human oxytocin receptor), and pharmacokinetic profiles in rodents and other higher species. The truncated analogues show excellent potency at the V2R, increased systemic clearance, and shorter half-life in rats. Two compounds 19 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-Agm) and 38 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-d-Arg-NEt2) have been selected for clinical development for nocturia.

Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis.

BACKGROUND: There is a significant need for novel, safe, and efficacious topical treatments for psoriasis. OBJECTIVE: We assessed the safety and efficacy of tapinarof in a new cream formulation at 2 concentrations and with 2 application frequencies in adults with psoriasis. METHODS: Double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in adults, with psoriasis with body surface involvement ≥1% and ≤15% and Physician Global Assessment (PGA) score ≥2 at baseline. Primary endpoint included PGA of 0 or 1 at week 12 and a 2-grade improvement from baseline. Additional analyses included assessment of ≥75% improvement of Psoriasis Area and Severity Index and mean percent change in Psoriasis Area and Severity Index and body surface area involvement. RESULTS: Treatment success defined by PGA 0 or 1 and a 2-grade improvement at week 12 was statistically significantly higher (at a .05 significance level) in the tapinarof groups (65% [1% twice daily], 56% [1% once daily], 46% [0.5% twice daily], and 36% [0.5% once daily]) than in the vehicle groups (11% [twice daily] and 5% [once daily]) and was maintained for 4 weeks posttreatment. Treatment-emergent adverse events were more frequent in patients treated with tapinarof (85/152, 56%) than vehicle (19/75, 25%) and mild-to-moderate in intensity. Severe treatment-emergent adverse events were reported in all tapinarof groups except the 0.5% once daily group. LIMITATIONS: Large confirmation trials are needed. CONCLUSIONS: Tapinarof cream is efficacious and well tolerated in adult patients with psoriasis.

A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis.

BACKGROUND: Safe and efficacious topical treatments are needed for atopic dermatitis (AD). OBJECTIVE: We assessed the safety and efficacy of tapinarof cream (2 concentrations and 2 application frequencies) in patients with AD. METHODS: A double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in patients age 12 to 65 years, with body surface area involvement of at least 5% to 35% and an Investigator's Global Assessment score of 3 or higher (moderate to severe) at baseline. Primary end points included an Investigator's Global Assessment score of clear or almost clear (0 or 1) and a minimum 2-grade improvement (treatment success) at week 12. Secondary analyses included a 75% or greater improvement in Eczema Area and Severity Index score, reduction of numeric rating scale (NRS) score for itch from baseline, and other prespecified end points. RESULTS: The rates of treatment success with tapinarof cream at week 12 were 53% (a concentration of 1% twice daily), 46% (a concentration of 1% once daily), 37% (a concentration of 0.5% twice daily), 34% (0.5% once daily), 24% (vehicle twice daily), and 28% (vehicle once daily). The rate with a concentration of 1% twice daily (53%) was statistically significantly higher than the rate with vehicle twice daily (24%). Treatment success was maintained for 4 weeks after the end of tapinarof treatment. The rate of treatment-emergent adverse events was higher with tapinarof (93 of 165 [56%]) than with vehicle (34 of 82 [41%]), and the events were mild to moderate in intensity. LIMITATIONS: Large confirmation trials are needed. CONCLUSIONS: Tapinarof cream is efficacious and well tolerated in adolescent and adult patients with AD.

A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy.

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance.

Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly(2),Nle(10),D-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NHEt), and 85 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH-((CH2)2O)4-(CH2)2-CONH2) displayed the desired profiles (EC50 (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound 73 (FE 203799) was selected as a candidate for clinical development.

Adjunctive Maintenance Lamotrigine for Pediatric Bipolar I Disorder: A Placebo-Controlled, Randomized Withdrawal Study.

OBJECTIVE: This study aimed to compare the efficacy of lamotrigine versus placebo in 10- to 17-year-olds with bipolar I disorder (BP-I) who were receiving conventional bipolar disorder treatment. METHOD: In this randomized withdrawal trial, patients with BP-I of at least moderate severity received lamotrigine during an ≤18-week open-label phase. Patients who maintained a stable lamotrigine dose for ≥2 weeks and Clinical Global Impression-Bipolar Severity of Illness (CGI-BP[S]) score of ≤3 for ≥6 consecutive weeks were randomized to double-blind lamotrigine or placebo for ≤36 weeks. RESULTS: Of 301 patients enrolled, 298 comprised the open-label intention-to-treat population, with 173 (58%) randomized. Of these patients, 41 (24%) completed the study. In the open-label phase, the mean (SD) baseline CGI-BP(S) rating was 4.4 (0.57), and the mean (standard error [SE]) time to stabilization was 101 (1.6) days. During the randomized phase, mean (SE) time to occurrence of a bipolar event (TOBE) for lamotrigine versus placebo (primary endpoint) was 155 (14.7) versus 50 (3.8), 163 (12.2) versus 120 (12.2), and 136 (15.4) versus 107 (13.8) days for the 3 index mood states (depressed, manic/hypomanic, mixed). The primary stratified log-rank analysis of TOBE was not statistically significant (hazard ratio [HR] = 0.63; p = .072); however, the prespecified Cox regression analysis favored lamotrigine (p = .047). In 13- to 17-year-olds, log-rank analysis of TOBE significantly favored lamotrigine (HR = 0.46; p = .015), but not in 10- to 12-year-olds (HR = 0.93; p = .877). Dermatologic events were reported in 4% (open-label phase) and 2% (randomized phase) of patients receiving lamotrigine. Suicidality-related adverse events were reported in 7% (open-label phase) and 7% (randomized phase) of patients receiving lamotrigine. CONCLUSION: Although the primary analysis failed to detect a benefit of add-on lamotrigine for BP-I in 10- to 17-year-olds, lamotrigine may be effective in a subset of older adolescents. Clinical trial registration information-Lamictal as Add-on Treatment for Bipolar I Disorder in Pediatric Patients; http://clinicaltrials.gov/; NCT00723450.

Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study.

BACKGROUND: Duchenne muscular dystrophy is caused by dystrophin deficiency and muscle deterioration and preferentially affects boys. Antisense-oligonucleotide-induced exon skipping allows synthesis of partially functional dystrophin. We investigated the efficacy and safety of drisapersen, a 2'-O-methyl-phosphorothioate antisense oligonucleotide, given for 48 weeks. METHODS: In this exploratory, double-blind, placebo-controlled study we recruited male patients (≥5 years of age; time to rise from floor ≤7 s) with Duchenne muscular dystrophy from 13 specialist centres in nine countries between Sept 1, 2010, and Sept 12, 2012. By use of a computer-generated randomisation sequence, we randomly allocated patients (2:2:1:1; block size of six; no stratification) to drisapersen 6 mg/kg or placebo, each given subcutaneously and either continuously (once weekly) or intermittently (nine doses over 10 weeks). The primary endpoint was change in 6-min walk distance (6MWD) at week 25 in patients in the intention-to-treat population for whom data were available. Safety assessments included renal, hepatic, and haematological monitoring and recording of adverse events. This trial is registered with ClinicalTrials.gov, number NCT01153932. FINDINGS: We recruited 53 patients: 18 were given continuous drisapersen, 17 were given intermittent drisapersen, and 18 were given placebo (continuous and intermittent groups combined). At week 25, mean 6MWD had increased by 31·5 m (SE 9·8) from baseline for continuous drisapersen, with a mean difference in change from baseline of 35·09 m (95% CI 7·59 to 62·60; p=0·014) versus placebo. We recorded no difference in 6MWD changes from baseline between intermittent drisapersen (mean change -0·1 [SE 10·3]) and placebo (mean difference 3·51 m [-24·34 to 31·35]) at week 25. The most common adverse events in drisapersen-treated patients were injection-site reactions (14 patients given continuous drisapersen, 15 patients given intermittent drisapersen, and six given placebo) and renal events (13 for continuous drisapersen, 12 for intermittent drisapersen, and seven for placebo), most of which were subclinical proteinuria. None of the serious adverse events reported (one for continuous, two for intermittent, and two for placebo) resulted in withdrawal from the study. INTERPRETATION: Continuous drisapersen resulted in some benefit in 6MWD versus placebo at week 25. The safety findings are similar to those from previous studies. Ambulation improvements in this young population with early-stage Duchenne muscular dystrophy are encouraging but need to be confirmed in larger studies. FUNDING: GlaxoSmithKline, Prosensa Therapeutics BV (a subsidiary of Prosensa Holding NV).

Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: results of a double-blind randomized clinical trial.

Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ⩾9years, in wheelchairs for ⩾1 to ⩽4years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12mg/kg), but study objectives were met with the 9mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3-9mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3-6mg/kg range. Single doses of drisapersen at 3 and 6mg/kg did not result in significant safety or tolerability concerns; however, at the 9mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population.

Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials.

OBJECTIVE: This meta-analysis of placebo-controlled paroxetine trials examines suicidality incidence in adults, focusing on disorder and age as potential risk factors. The findings are put in context with an efficacy meta-analysis of the same trial datasets. DATA SOURCES: GlaxoSmithKline paroxetine clinical trial database(s). STUDY SELECTION: All double-blind, randomized, placebo-controlled, parallel-group studies of paroxetine therapy in adults enrolling at least 30 patients total were included in the analysis. The dataset comprised 14,911 patients from 61 trials. DATA EXTRACTION: Possible cases of suicidality were identified and blindly categorized by an expert panel, using methodology previously used by the US Food and Drug Administration. Incidences of suicidal behavior (preparatory act, suicide attempt, or completed suicide) and any suicidality (suicidal behavior or ideation) were compared between paroxetine and placebo. Efficacy assessments were based on standard depression rating scales (eg, Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale) and Clinical Global Impressions Improvement scale (CGI-I) scores. RESULTS: In the primary dataset, ie, all disorders combined, there were no significant differences between paroxetine and placebo for overall suicidality (suicidal behavior or ideation: n/n = 83/8,958 [0.93%] vs n/n = 65/5,953 [1.09%], respectively; OR = 0.9 [95% CI, 0.7-1.3]; P = .649) or for suicidal behavior specifically (n/n = 50/8,958 [0.56%] vs n/n = 40/5,953 [0.67%], respectively; OR = 1.2 [95% CI, 0.8-1.9]; P = .483). However, in patients with major depressive disorder (MDD), a greater incidence of suicidal behavior occurred in paroxetine-treated patients than in placebo-treated patients (n/n = 11/3,455 [0.32%] vs n/n = 1/1,978 [0.05%], respectively; OR = 6.7 [95% CI, 1.1-149.4]; P = .058). Across all indications, a higher incidence of suicidal behavior occurred in paroxetine-treated versus placebo-treated adults aged 18 to 24 years (n/n = 17/776 [2.19%] vs n/n = 5/542 [0.92%], respectively; OR = 2.4 [95% CI, 0.9-7.3]). In older age groups, no increase in suicidality was observed. Efficacy was demonstrated in all disorders evaluated, including MDD. CONCLUSIONS: Across all disorders, overall suicidality incidence was similar between paroxetine and placebo. However, a higher frequency of suicidal behavior occurred with paroxetine in MDD, which was largely explained by the higher incidence in young adults. These data support the efficacy of paroxetine therapy; however, they also highlight the need for careful monitoring of suicidality during antidepressant therapy, particularly in younger adults.

Multimodal study of secondary interactions in Cp*Ir complexes of imidazolylphosphines bearing an NH group.

Hydrogen bonding phenomena are explored using a combination of X-ray diffraction, NMR and IR spectroscopy, and DFT calculations. Three imidazolylphosphines R(2)PImH (ImH = imidazol-2-yl, R = t-butyl, i-propyl, phenyl, 1a-1c) and control phosphine (i-Pr)(2)PhP (1d) lacking an imidazole were used to make a series of complexes of the form Cp*Ir(L(1))(L(2))(phosphine). In addition, in order to suppress intermolecular interactions with either imidazole nitrogen, 1e, a di(isopropyl)imidazolyl analogue of 1b was made along with its doubly (15)N-labeled isotopomer to explore bonding interactions at each imidazole nitrogen. A modest enhancement of transfer hydrogenation rate was seen when an imidazolylphosphine ligand 1b was used. Dichloro complexes (L(1) = L(2) = Cl, 2a-2c,2e) showed intramolecular hydrogen bonding as revealed by four X-ray structures and various NMR and IR data. Significantly, hydride chloride complexes [L(1) = H, L(2) = Cl, 3a-3c and 3e-((15)N)(2)] showed stronger hydrogen bonding to chloride than hydride, though the solid-state structure of 3b evinced intramolecular Ir-H...H-N bonding reinforced by intermolecular N...H-N bonding between unhindered imidazoles. These results are compared to literature examples, which show variations in preferred hydrogen bonding to hydride, halide, CO, and NO ligands. Surprising differences were seen between the dichloro complex 2b with isopropyl groups on phosphorus, which appeared to exist as a mixture of two conformers, and related complex 2a with tert-butyl groups on phosphorus, which exists in chlorinated solvents as a mixture of conformer 2a-endo and chelate 5a-Cl, the product of ionization of one chloride ligand. This difference became apparent only through a series of experiments, especially (15)N chemical shift data from 2D (1)H-(15)N correlation. The results highlight the difficulty of characterizing hemilabile, bifunctional complexes and the importance of innocent ligand substituents in determining structure and dynamics.

Clinical features of patients with treatment-emergent suicidal behavior following initiation of paroxetine therapy.

BACKGROUND: Understanding suicidal behavior is an important component of assessing suicidality in psychiatric patients. GlaxoSmithKline (GSK) conducted a meta-analysis of randomized, placebo-controlled trials to compare suicidality in adult patients treated with paroxetine vs. placebo. The goal was to identify emergent clinical characteristics of patients with definitive suicidal behavior (DSB: preparatory act, suicide attempt, completed suicide). METHODS: The dataset comprised 14,911 patients from 57 placebo-controlled paroxetine trials. Possible cases of suicidality were identified and were blindly reviewed by an expert panel, which categorized cases as suicidal or non-suicidal. DSB incidences were compared between paroxetine and placebo. Clinical narratives and case report forms for major depressive disorder (MDD) and anxiety disorder patients with DSB were reviewed. For MDD, rating scale items relating to suicidality, insomnia, agitation, and anxiety were examined. RESULTS: Overall (all indications) there were no differences between paroxetine and placebo for DSB (50/8958 [0.56%] vs. 40/5953 [0.67%], respectively; OR=1.2 [CI 0.8, 1.9]; p=0.483). However, in patients with major depressive disorder (MDD), the incidence of DSB was greater for paroxetine (11/3455 [0.32%] vs. 1/1978 [0.05%], OR=6.7 [CI 1.1, 149.4]; p=0.058). Review of the 11 paroxetine MDD cases revealed common clinical features: symptomatic improvement; younger age (18-30 years); psychosocial stressors; overdose as method; and absent/mild suicidal ideation at the visit prior to the event. There was no evidence for a consistent adverse event profile or onset of akathisia/agitation or a manic/mixed state. Anxiety disorder patients with DSB had a heterogeneous clinical picture. LIMITATIONS: Limitations to the study include the relatively small number of cases and the retrospective nature of the study. CONCLUSIONS: DSB incidence was similar between paroxetine and placebo overall, but a higher frequency of DSB was found for paroxetine in MDD patients, driven by young adults aged < or =30 years. Most MDD patients with DSB improved prior to the attempt and experienced a psychosocial stressor. Patients should receive careful monitoring for suicidality during paroxetine therapy.

Differences in medication adherence and healthcare resource utilization patterns: older versus newer antidepressant agents in patients with depression and/or anxiety disorders.

BACKGROUND: Given the number of antidepressants available and their rising costs, healthcare payers have initiated restrictive reimbursement policies for newer antidepressants, without consideration for differences in their effectiveness or tolerability. OBJECTIVE: The objective of this study was to comprehensively compare medication adherence rates and associated healthcare utilization costs for patients using later-generation versus earlier-generation antidepressants in a managed care setting. Antidepressants launched after 2002 were deemed third-generation antidepressants, while antidepressants available prior to 2002 were deemed first-generation (TCAs and MAOIs) and second-generation (serotonin and noradrenaline [norepinephrine]-dopamine reuptake inhibitors). STUDY DESIGN: Retrospective database analysis using medical and pharmacy data from over 75 managed care plans covering 55 million lives. SETTING/PATIENTS: All patients receiving an antidepressant between 1 January 2002 and 30 September 2004 were identified. The index date for patients was the date of their first antidepressant prescription within this time period. Patients had to (i) have a diagnosis of depression or anxiety disorder, or depression and anxiety disorder within 6 months prior to or 30 days after their index prescription; (ii) be at least 18 years of age, without having taken antidepressant therapy for 6 months prior to their index date; and (iii) be continuously eligible for 6 months prior to their index date and during their 6-month follow-up period. Patients were excluded if they had a diagnosis of psychosis-related disease, Alzheimer's or Parkinson's disease, or were initiated on psychosis-related medications. INTERVENTION/MAIN OUTCOME MEASURE: Patients meeting selection criteria were followed for 6 months to assess rates of antidepressant adherence, therapy change rates and medical healthcare costs. STUDY POPULATION: A total of 266 665 patients met the study criteria. Approximately 66% were female, with a mean age of 39 years. About 63% had a diagnosis of depression, 31% had an anxiety disorder diagnosis and 6% had diagnoses for both an anxiety disorder and depression. Therapy change: Therapy change within 6 months occurred in 18% of patients receiving third-generation agents compared with 21% and 40% for second- and first-generation agents, respectively. The odds of a therapy change were significantly lower with third-generation antidepressants compared with both older agent cohorts. Adherence: Of patients receiving third-generation antidepressants, 33.6% were adherent compared with 29.3% and 12.4% of patients receiving second- and first-generation antidepressants, respectively. Newer agents also had better adherence rates across all diagnostic cohorts. After adjusting for baseline differences, the odds of being adherent to therapy were significantly lower for those taking second- and first-generation agents versus newer antidepressants. Among the newer agents, the proportion of patients adherent to their therapy was: venlafaxine extended release 38%, paroxetine controlled release (CR) 35%, escitalopram 34%, duloxetine 32% and bupropion extended release (XL) 31%. Healthcare utilization: Of the patients taking older antidepressants, 13% (second generation) and 21% (first generation) were hospitalized at least once for any reason compared with 12% of patients taking newer agents. Overall, the odds of all-cause hospitalization within 6 months of therapy initiation were significantly higher for patients taking older antidepressants. Among the newer agents, hospitalization rates ranged from 15.9% for duloxetine to 12.5% for paroxetine CR and bupropion XL. The unadjusted 6-month total medical costs (not including pharmacy costs) per patient were $US 3514 for second-generation, $US 5744 for first-generation and $US 3284 for newer antidepressants. After controlling for baseline differences, patients receiving second- and first-generation antidepressants incurred 12% and 44% higher costs, respectively. The unadjusted 6-month medical costs for the newer agents ranged from $US 2715 for paroxetine CR to $US 6042 for duloxetine. CONCLUSION: The results of this study provide essential information for healthcare decision makers about the potential advantages of newer generation antidepressants versus older generation antidepressants, as well as the differences between the specific newer agents, with respect to improved rates of adherence and therapy change, reduced hospitalizations and healthcare costs.

Managing treatment resistant violent adolescents: a step forward by substituting seclusion for mechanical restraint?

Despite a growing consensus that seclusion or restraint should never be used with children or adolescents, there are a few patients who are resistant to treatment, and are persistently violent. The purpose of this study was to measure the efficacy of installing a padded seclusion room to decrease the use of mechanical restraints, a potentially more emotionally traumatic and dangerous intervention than seclusion. After padded room installation, the number of monthly mechanical restraint events per 1000 patient days decreased by 93.7%, from 21.2 to 1.3. A padded seclusion room may offer a safer, albeit a less than desirable alternative to mechanical restraint.

Use of public school immunization data to determine community-level immunization coverage.

OBJECTIVES: To evaluate whether immunization data collected on a child's entry into kindergarten, i.e., Chicago Public School Immunization Data (PSID), was comparable to coverage levels determined by the National Immunization Survey (NIS) and to use these data to identify community areas with consistently low immunization coverage. METHODS: The Chicago Department of Public Health obtained four years of PSID (2000-2003); these data included demographic information, home address, and immunization records. Coverage levels were determined in two ways: (1) one dose of measles-containing vaccine (MCV) and (2) four doses of diphtheria and tetanus toxoids and pertussis vaccine, three doses of poliovirus vaccine, and one dose of measles-containing vaccine (the 4:3:1 series), stratified by racial/ethnic group; these levels were compared to NIS estimates for the respective time periods. We used geographic information system software to illustrate variations in coverage levels between distinct community areas within Chicago. RESULTS: Year 2000 MCV coverage levels determined from PSID closely approximated NIS estimates (84.6% vs. 87.2% +/- 4.6%, respectively). MCV coverage levels determined by race/ethnicity from PSID were within the 95% confidence intervals (CI) for all racial categories (white, 89.5% vs. 92.2% +/- 6.4%; black, 79.0% vs. 83.5% +/- 9.4%; Hispanic, 89.5% vs. 87.5% +/- 5.8%). Comparison of PSID and NIS 4:3:1 coverage levels revealed similar findings. For each study year, PSID identified 12 community areas with consistently low MCV coverage levels, i.e., < 80%. CONCLUSIONS: PSID closely approximated NIS coverage estimates for MCV and 4:3:1 immunization. These methods can be used by state and city health departments to identify and direct resources to communities at greatest need.

Implementing a smoking ban in an acute psychiatric admissions unit.

In contrast to general medical hospitals, psychiatric hospitals often allow patients to smoke cigarettes. In addition to obvious health concerns, smoking can also interfere with clinical assessments and therapeutic activities, Implementation of a smoking ban on an acute male admissions unit did not result in any increase in aggressive behaviors. In addition, staff attitudes following the ban improved, and most staff members believed the ban was both ethical and beneficial to patients. Our research indicates that banning smoking on an acute admissions unit is feasible and well tolerated by patients and staff, although it may require extra vigilance for smoking-related contraband.

Clozapine reduces violent behavior in heterogeneous diagnostic groups.

Violent behavior is a significant problem in the psychiatric hospital setting. Persistently violent patients often require seclusion and/or restraints and typically receive high doses of medication and polypharmacy. Clozapine has been found to be effective in reducing aggression in patients with psychosis. Thus, we examined the effects of clozapine in a heterogeneous group of persistently violent patients. A chart review of the effect of clozapine in persistently violent patients was performed. Changes in the number of violent episodes and the need for seclusion and restraint were assessed for a 3-month period before and after receiving clozapine. In this group of five, carefully selected, persistently violent patients, clozapine treatment resulted in marked decreases in violent episodes and the use of seclusion and restraint. These data suggest a role for clozapine in the treatment of persistently violent patients irrespective of DSM-IV diagnosis.

Olanzapine versus risperidone in newly admitted acutely ill psychotic patients.

OBJECTIVE: Risperidone and olanzapine are the 2 most widely prescribed second-generation anti-psychotics. The purpose of this study was to compare the efficacy of risperidone and olanzapine using duration of hospitalization as the primary outcome measure. This outcome was selected as it is an indirect measure of how well patients are responding to the medication and represents a "real world" endpoint relevant to practicing hospital psychiatrists. METHOD: The study was done at a large state psychiatric hospital in North Carolina from 2001 to 2003. Subjects were eligible for inclusion if they required treatment with an antipsychotic (e.g., positive symptoms) and were able to provide informed consent. Eighty-five patients entered the study and were randomly assigned to risperidone (N = 40) or olanzapine (N = 45) as their initial antipsychotic. Treatment was naturalistic, and dosing was based on the discretion of the treating physician. RESULTS: There was no significant difference in the mean durations of hospitalization for the risperidone group (7.9 days) as compared to the olanzapine group (8.1 days). There were no significant differences in the demographics of either treatment group, but, during the study, risperidone-treated patients used more antihistamines (chi(2) = 4.0, p = .05). Eighty percent of each group (N = 36, olanzapine; N = 32, risperidone) remained on the study medication at discharge. CONCLUSIONS: Risperidone and olanzapine were equally efficacious, suggesting that measures other than "efficacy" (e.g., side effects, cost) should be considered when determining overall "effectiveness" of treatment.

Neurosyphilis in newly admitted psychiatric patients: three case reports.

BACKGROUND: Neurosyphilis, also known as "general paresis of the insane," at one time accounted for a large portion of admissions to state psychiatric facilities. With the introduction of antibiotics, neurosyphilis is now considered very rare. METHOD: Chart review was performed on patients diagnosed with neurosyphilis who were admitted to a state psychiatric hospital in Raleigh, N.C., during 2002. RESULTS: We identified 3 cases of confirmed neurosyphilis, representing 0.1% of adult admissions, diagnosed in newly admitted psychiatric patients. None of the patients were immunocompromised. Response to antibiotic treatment was poor. CONCLUSIONS: Given the increase in primary and secondary syphilis reported in the 1980s and early 1990s, routine screening of psychiatric patients for the presence of syphilis should be considered.