Phase 2 Results Indicate Evenamide, A Selective Modulator of Glutamate Release, Is Associated With Clinically Important Long-Term Efficacy When Added to an Antipsychotic in Patients With Treatment-Resistant Schizophrenia.

Results from a pilot, 6-week, randomized, open-label, rater-blinded study, with 46-week extension, indicate very good tolerability with exceptional, clinically important, increasing efficacy of evenamide (7.5, 15, and 30 mg bid), a glutamate modulator, as add-on treatment to antipsychotics in 161 treatment-resistant, schizophrenia patients. Ninety-five percent of patients completed 6 weeks (1 discontinued for adverse event), and 89% continued in the extension. Results from the first 100 patients enrolled showed very low attrition over 1 year (77 completers); data pooled from all dose groups showed the Positive and Negative Syndrome Scale total score improved significantly (P < .001; paired t test; last observation carried forward [LOCF]) from baseline at 6 weeks (-9.4), 6 months (-12.7), and 1 year (-14.7); similarly, the proportion of responders (≥20% improvement) increased over time from 6 weeks (16.5%) to 6 months (39%) to 1 year (47.4%). Noteworthy improvement was also observed at each timepoint on the Clinical Global Impression - Severity scale and Clinical Global Impression of Change, indicating progressively increasing efficacy of evenamide up to 1 year.

Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease.

In a 6-month double-blind, placebo-controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON-time without increasing dyskinesia. Further long-term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON-time over 24 months. Other efficacy endpoints included change in ON-time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2-year, controlled study of add-on safinamide in mid-to-late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON-time (without troublesome dyskinesia), OFF-time, activities of daily living, motor symptoms, quality of life, and symptoms of depression.

Implementing Grover's on AES-based AEAD schemes.

Extensive research is currently underway to determine the security of existing ciphers in light of the advancements in quantum computing. Against symmetric key cryptography, Grover's search algorithm is a prominent attack, capable of reducing search costs to the square root. For using Grover's algorithm, it is imperative to embed the target cipher into a quantum circuit. Even so, this area of research is relatively new; it has garnered significant attention from the research community. In this study, we provide the first estimation of the cost of Grover's key search attack against the AES-based AEAD schemes Rocca-S, AEGIS-128, and Tiaoxin-346. Our analysis considers circuit depth restrictions specified in NIST's PQC standardization process. Considering NIST's maximum depth constraints, We present the overall cost of these attacks using gate count and depth-times-width metrics. We observed that for MAXDEPTH = 2 40 , Rocca-S, AEGIS-128, and Tiaoxin-346 can be retrieved using Grover's search algorithm with gate count of 1.09 × 2253, 1.14 × 2124, and 1.22 × 2124 respectively. Concerning the current updated values by NIST, these ciphers are secure in terms of the cost of implementing Grover's attack for key recovery. The quantum circuits of these ciphers are implemented using QISKIT, an open-source software development kit (SDK) designed for working with quantum computers running on the IBM Quantum Experience platform.

A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients.

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of safinamide versus placebo was tested first; the success of safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received safinamide 100 mg (n = 90), safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for safinamide 200 mg, -6.0 for safinamide 100 mg and -3.60 for placebo. The difference between safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation.

Hyperglycemia Risk Evaluation of Hydrocortisone Intermittent Boluses versus Continuous Infusion in Septic Shock: A Prospective Randomized Trial.

Background: Hydrocortisone showed an important role in reversal of shock when added to standard therapy in managing septic shock. Hyperglycemia is one of the most common side effects associated with corticosteroid treatment. Aims: This study aimed to evaluate the risk of hyperglycemia of intermittent hydrocortisone boluses versus continuous infusion in septic shock patients. Settings and Design: This was a prospective randomized controlled study conducted in a tertiary care teaching hospital. Materials and Methods: One hundred and forty patients with septic shock and who received noradrenaline were enrolled in this randomized study. Group 1 was intermittent bolus hydrocortisone group (n = 70) and Group 2 was continuous infusion group (n = 70). All patients who were admitted with septic shock and who received noradrenaline and hydrocortisone were included in the study. Those patients who had exceeded 200 mg per day of hydrocortisone were excluded from the study. The primary outcome of the study was mean blood glucose. Statistical Analysis Used: Qualitative variables were compared between the two groups with the Chi-square of the Fisher's exact test and continuous variables were compared using the Student's t-test or the Wilcoxon rank-sum test. Results: Out of 112 patients, 54 patients received hydrocortisone as intermittent boluses (48.2%), and 58 patients (51.8%) received continuous infusion. For the primary outcome, no statistically or clinically significant difference was found in the blood glucose estimated marginal mean: 154.44 mg.dL-1 (95% confidence interval [CI]: 144.18-166.88) in the bolus group and 160.2 mg.dL-1 (95% CI: 143.82-176.76) in the infusion group with a mean difference of 05.76 mg.dL-1 (95% CI: -13.86-25.38). For the secondary outcomes of the study, no difference was found between the two groups in hyperglycemic or hypoglycemic events, mortality, length of stay in intensive care unit, and reversal of shock. Conclusions: The risk of hyperglycemia is almost equal in both intermittent and continuous infusions of hydrocortisone in septic shock patients.

Comparison of percutaneous tracheostomy methods in ICU patients: Conventional anatomical landmark method versus ultrasonography method - A randomised controlled trial.

Background and Aims: Percutaneous dilational tracheostomy (PDT) is a common procedure in intensive care unit (ICU) patients requiring long-term mechanical ventilation. PDT has gradually replaced surgical tracheostomy because it is associated with minimal invasiveness, reduced bleeding and simplicity in technique.This study was conducted to compare ultrasound-guided PDT versus conventional tracheostomy in terms of duration of the procedure, number of passes and immediate peri-procedural complications. Methods: A total of 72 patients with clinical indications of tracheostomy were recruited. A total of 12 patients met the exclusion criteria. The remaining were randomly assigned into two groups of 30 each: Group A (Landmark) with traditional anatomical landmark and Group B (USG) with real-time ultrasound guidance. Puncture positions were recorded with bronchoscopy. Midline deviation was captured on a bronchoscopy image using a protractor. Data on procedural safety and efficacy were also collected. Results: Group B had significantly fewer cases of midline deviation (11.33 ± 9.51) in comparison to Group A (16.60 ± 12.31). Trials > 2 were equal to 11 in Group A and 2 in Group B. However, the duration of the procedure was higher in Group B (20.07 ± 3.25 min) as compared to Group A (15.20 ± 3.71 min). Peri-procedural and post-procedural complications were also higher in the Landmark group. Conclusion: Ultrasound-guided PDT showed superiority over landmark PDT in terms of less number of trials, midline puncture and fewer complications. However, it took a little longer to perform USG-guided PDT.

Evidence for fungi and gold redox interaction under Earth surface conditions.

Microbial contribution to gold biogeochemical cycling has been proposed. However, studies have focused primarily on the influence of prokaryotes on gold reduction and precipitation through a detoxification-oriented mechanism. Here we show, fungi, a major driver of mineral bioweathering, can initiate gold oxidation under Earth surface conditions, which is of significance for dissolved gold species formation and distribution. Presence of the gold-oxidizing fungus TA_pink1, an isolate of Fusarium oxysporum, suggests fungi have the potential to substantially impact gold biogeochemical cycling. Our data further reveal that indigenous fungal diversity positively correlates with in situ gold concentrations. Hypocreales, the order of the gold-oxidizing fungus, show the highest centrality in the fungal microbiome of the auriferous environment. Therefore, we argue that the redox interaction between fungi and gold is critical and should be considered in gold biogeochemical cycling.

Publisher Correction: Natural gold particles in Eucalyptus leaves and their relevance to exploration for buried gold deposits.

This corrects the article DOI: 10.1038/ncomms3614.

A Study of the Pharmacokinetic Properties and the In Vivo Kinetics of Erythrocytes Loaded With Dexamethasone Sodium Phosphate in Healthy Volunteers.

The objectives of this 2-phase study were to elucidate pharmacokinetics (PK), in vivo 24-hour recovery, and red blood cell (RBC) survival properties of RBC-encapsulated dexamethasone sodium phosphate (DSP) prepared using the EryDex System (EDS). The 24-hour RBC recovery and T50 survival phase studied subjects were randomized to receive autologous RBCs loaded with either 15-20 mg DSP (Group 1A) or sham saline (Group 2A). Loaded RBCs were radiolabeled with 51-Cr, and the labeled RBCs were followed over time in vivo. The PK phase evaluated dose levels of 2.5-5 mg (Group 1B) and 15-20 mg (Group 2B) DSP encapsulated in RBCs infused into healthy randomized subjects. The mean ± SD 24-hour RBC recovery was 77.9% ± 3.3% and 72.7% ± 10.5% for Groups 1A and 2A, respectively. The mean ± SD RBC life span was 84.3 ± 8.3 days in Group 1A and 88.9 ± 6.2 days in Group 2A. The PK phase actual DSP loading doses (mean ± SEM) were 4.2 ± 0.27 mg and 16.9 ± 0.90 mg in Groups 1B and 2B, respectively. Release of dexamethasone from RBCs in vivo peaked at 1 hour, and a sustained release of dexamethasone could be detected until 35 days after the single intravenous infusion in Group 2B. The mean RBC in vivo recovery for DSP-loaded processed cells compares similarly to the 24-hour recovery of regulated RBC products intended for transfusion. There was a minimal but acceptable adverse impact on the survival of EDS-processed RBCs. DSP-loaded autologous RBCs, prepared using the EDS, delivered a sustained dose of dexamethasone in vivo.

Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers.

BACKGROUND: The FG loop peptide (FGL(L)), a novel mimetic of the neural cell adhesion molecule (NCAM), is in clinical development for neurodegenerative disorders such as Alzheimer's disease. Preclinical studies in rats, dogs and monkeys have demonstrated exposure in plasma and cerebrospinal fluid after parenteral or intranasal administration of FGL(L), with no systemic toxicity. This article reports on the results of the first administration of FGL(L) in humans. OBJECTIVE: To determine the tolerability, safety and pharmacokinetics of ascending, single intranasal doses of FGL(L) 25, 100 and 200mg in healthy subjects. METHODS: In an 8-day, open-label, phase I study, 24 healthy male volunteers (mean age 42 [range 24-55] years) received single intranasal doses of FGL(L) (25, 100 and 200mg) in accordance with an ascending dose, sequential-cohort design. RESULTS: All three intranasal doses of FGL(L) were well tolerated and there were no clinical notable abnormalities in ECG recordings, vital signs or laboratory tests. Three subjects (13%) reported five adverse events. A transient (<3 minutes) burning sensation in the nose was reported in two subjects at the 200mg dose level while runny eyes (<2 minutes) were experienced in one subject at 25mg. These events had an onset immediately following intranasal administration, and a relationship to FGL(L) was suspected. One of the latter subjects who had experienced a burning sensation in the nose also experienced dizziness, vomiting and headache with onset >2 days after single-dose administration of FGL(L); no relationship to the study drug was suspected. Quantifiable plasma concentrations of FGL(L) were observed up to 1 hour after intranasal administration of the 100mg dose and up to 4 hours after the 200mg dose (plasma FGL(L) concentrations were undetectable at all timepoints for the 25mg dose). Increasing doses of FGL(L) were associated with higher systemic exposures: mean C(max) 0.52 ng/mL and 1.38 ng/mL (100mg and 200mg, respectively); mean AUC(24) 1.27 ng x h/mL and 4.05 ng x h/mL (100mg and 200mg, respectively). CONCLUSIONS: Intranasal administration of FGL(L) (25, 100 and 200mg) was well tolerated in healthy male volunteers, with no safety concerns and a pharmacokinetic profile that was generally dose related. Further studies are currently being planned to evaluate the effects of FGL(L) in patients with Alzheimer's disease.

Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial.

IMPORTANCE: Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge. OBJECTIVE: To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with "off" time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient's regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group. INTERVENTIONS: Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was each treatment group's mean change from baseline to week 24 (or last "on" treatment value) in daily "on" time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data. RESULTS: At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]). CONCLUSIONS AND RELEVANCE: The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00627640.

Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT).

BACKGROUND: Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients. METHODS: A multicenter, randomized, international, 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder, 26.8% of whom were refractory to previous treatment, who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation. To equalize clinical contact across treatments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomization, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts. Suicidal behavior was assessed at each visit. Primary end points included suicide attempts (including those that led to death), hospitalizations to prevent suicide, and a rating of "much worsening of suicidality" from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved. RESULTS: Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P =.03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P =.03), required hospitalizations (82 vs 107; P =.05) or rescue interventions (118 vs 155; P =.01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P =.01) or anxiolytics or soporifics (301 vs 331; P =.03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P =.73). CONCLUSIONS: Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.

Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial.

BACKGROUND: Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide. METHODS: This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events. RESULTS: Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinson's, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present. CONCLUSIONS: This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography.

OBJECTIVE: Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophrenic subjects with predominantly negative symptoms (alogia, affective flattening, avolition, and attentional impairment) and in those with predominantly positive symptoms. METHOD: Fourteen right-handed male subjects with DSM-IV schizophrenia were assigned to groups with predominantly negative or predominantly positive symptoms on the basis of their post-drug-washout scores on the Positive and Negative Syndrome Scale. The patients were compared to seven age- and gender-matched normal volunteers. PET scans with [(18)F]fluorodeoxyglucose were obtained during a degraded Continuous Performance Task to measure absolute glucose metabolic rates. Statistical parametric mapping was used to estimate the regional metabolic differences between groups. RESULTS: The subjects with predominantly negative symptoms had significant differences in glucose metabolic rates, compared to both the subjects with predominantly positive symptoms and the normal subjects. Negative symptom subjects had a lower glucose metabolic rate in the right hemisphere, especially in the temporal and ventral prefrontal cortices, compared to the other groups, and higher metabolic rates in the cerebellar cortex and in the lower deep cerebellar nuclei. Negative symptom subscale scores were negatively correlated with glucose metabolic rates for most of the brain areas that differentiated subjects with predominantly negative symptoms from those with predominantly positive symptoms. CONCLUSIONS: Schizophrenic subjects with predominantly negative symptoms have greater metabolic abnormalities than subjects with predominantly positive symptoms, particularly in frontal, temporal, and cerebellar circuitry. These results are consistent with abnormalities in corticocortical, corticobasal ganglia, mesocortical dopamine, and cerebellar-thalamic-prefrontal circuits, which may underlie the negative symptoms of schizophrenia.

Neurocognitive performance does not correlate with suicidality in schizophrenic and schizoaffective patients at risk for suicide.

BACKGROUND: Almost 50% of schizophrenic persons attempt suicide at some time in their lives and 9-13% of patients ultimately commit suicide. While numerous studies have elucidated the relationship between psychiatric symptomatology and neurocognition in patients with schizophrenia, this is the first report, to our knowledge, to investigate the relationship between suicidal behavior and neurocognition in schizophrenia and schizoaffective disorder. METHODS: A subgroup of 188 patients participating in the InterSePT trial was assessed at baseline with an extensive neurocognitive battery and measures of suicidality and psychiatric symptomatology. RESULTS: Measures of suicidality did not significantly correlate with neurocognitive performance. Confirmatory analyses between patients currently judged to be at high and low risk for suicide also revealed no neurocognitive differences. Consistent with previous studies, poor neurocognitive performance tended to be modestly correlated with the Positive and Negative Syndrome Rating Scale (PANSS) negative symptom scale. The relationship between suicidality and neurocognitive performance was similar for schizoaffective and schizophrenic patients. CONCLUSIONS: The findings suggest that suicidality in patients with schizophrenia and schizoaffective disorder is not correlated with cognition and may, in fact, be a separate domain worthy of investigation and intervention.

The InterSePT scale for suicidal thinking reliability and validity.

BACKGROUND: The InterSePT Scale for Suicidal Thinking (ISST) is a 12-item instrument for the assessment of current suicidal ideation in patients with schizophrenia and schizoaffective disorders. We report the psychometric characteristics of this new scale based on two studies. METHOD: In Study 1, 22 inpatients with schizophrenia and schizoaffective disorders, who had recently attempted suicide or engaged in suicidal ideation, were rated by three trained independent raters to examine interrater reliability. In Study 2, a total of 980 patients with schizophrenia or schizoaffective disorder with a history of suicidal ideation in the past 36 months were enrolled in a 2-year industry-sponsored suicide prevention study. At baseline, these patients were administered the ISST and the Clinical Global Impression Scale for Severity of Suicidality (CGI-SS) by the Principal Investigator (PI) and by a blinded rater (BR), who also administered the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDS), and the Scale of Functioning (SOF). Indices of internal reliability, construct and discriminant validity were examined. RESULTS: The intraclass correlation coefficient (ICC) for the total ISST score for the 22 subjects in Study 1 was 0.90 and mean weighted item kappa coefficients ranged from 0.66 to 0.92. In Study 2, internal reliability (Cronbach alpha) was high, ranging from 0.86 to 0.89 for the individual items, and the overall Cronbach alpha coefficient for all items was 0.88. The ISST (PI) total score was highly correlated with the CGI-SS by the blind rater (r = 0.61, p < 0.0001). ISST total scores significantly differentiated the different levels of CGI-SS (F = 519.2; p < 0.0001). Results of construct and discriminant validity analyses are also presented. CONCLUSION: The ISST is a reliable and valid instrument for the assessment of current suicidal thinking in patients with schizophrenia and schizoaffective disorder by both clinicians and researchers.

Electrocardiographic effects of rivastigmine.

The electrocardiographic (ECG) effects of rivastigmine treatment were assessed in mild to moderately severe Alzheimer's disease (AD) by analysis of four 26-week, double-blind, multicenter, placebo-controlled, phase III clinical trials. Of an initial 2791 patients, 77% completed treatment. Seventy-one percent required at least one concomitant medication for conditions other than AD, with 34% requiring cardiovascular medications. Safety assessments included ECGs, adverse events, vital signs, and clinical laboratory parameters. Pooled 12-lead ECG data were analyzed by an independent cardiologist blinded to treatment group and clinical information. Heart rate, PR, QRS, and QTc intervals did not differ significantly between treatment and placebo groups. Percentage change from baseline for PR, QRS, and QTc intervals was also no different. In conclusion, rivastigmine appears not to produce adverse effects on cardiac function assessed by ECG.

The international suicide prevention trial (interSePT): rationale and design of a trial comparing the relative ability of clozapine and olanzapine to reduce suicidal behavior in schizophrenia and schizoaffective patients.

Suicidal behavior in patients with psychotic disorders represents a seriously undertreated life-threatening condition. The International Suicide Prevention Trial (InterSePT) is the first large-scale, prospective study designed to evaluate the potential of antipsychotic medications to reduce suicidal behaviors in patients with schizophrenia or schizoaffective disorder who are known to be at high risk for suicide. The unique challenges to study design and the solutions identified for the InterSePT study are described. These challenges included defining suicidal behavior in patients with psychosis, endpoint selection, determination of analytic strategy, and development of scales to assess suicidal behavior. Given the life-threatening nature of suicidal behavior, ethical considerations required that the design minimize suicide attempts and deaths. While the study focused primarily on treatment of suicide, opportunities were used to collect data in related areas of interest, including suicide risk factors, other efficacy measures (e.g., Positive and Negative Syndrome Scale, Covi Anxiety Scale, Calgary Depression Scale), adverse events, pharmacoeconomics, and pharmacogenetics. Because of the complexity of the design issues, a steering committee, suicide monitoring board, and publication committee were established to assist with their management.

Impact of Alzheimer's disease and rivastigmine treatment on activities of daily living over the course of mild to moderately severe disease.

OBJECTIVES: To investigate the relationship between activities of daily living (ADL) impairment and Alzheimer's disease (AD) severity in mild to moderately severe AD patients receiving the cholinesterase (ChE) inhibitor rivastigmine. METHODS: ADLs were evaluated using the Progressive Deterioration Scale (PDS). Disease severity was assessed with the Global Deterioration Scale (GDS). Patients were participants in one of three double-blind, placebo-controlled trials with rivastigmine. RESULTS: Baseline PDS scores differed significantly (P<.001) by disease severity. At Week 26, PDS declines from baseline for placebo patients were significantly different at all disease stages. Specific ADL affected were disease stage-dependent. Rivastigmine treatment (6-12 mg/day) resulted in total PDS scores being significantly improved compared with placebo at all disease stages, although the effect on individual items differed by severity. CONCLUSIONS: ADL impairment differs across the stages of AD. Greater impairment in total ADL scores is observed with increasing severity of illness. However, the stage of illness determines the type of ADLs lost. Treatment response to rivastigmine occurs with mild, moderate and moderately severe AD, with the largest effect in patients with advancing severity of disease.

Long-term effects of rivastigmine in moderately severe Alzheimer's disease: does early initiation of therapy offer sustained benefits?

Goals of the study included evaluating the long-term efficacy of rivastigmine in Alzheimer's disease (AD) patient categories stratified by baseline dementia severity, and post hoc investigation of particular benefits of early initiation of rivastigmine treatment in moderately severe AD. Both rivastigmine-treated groups (originally randomized to 1-4 or 6-12 mg/day) experienced significantly smaller declines in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores from baseline than the projected placebo group after 52 weeks. Patients receiving rivastigmine from Day 1 experienced significantly less decline compared with patients originally receiving placebo and then initiating rivastigmine treatment after a 6-month delay. Furthermore, cognitive benefits were more robust in patients with moderately severe disease compared with previous reports in mild to moderately severe AD. Findings suggest that early treatment with rivastigmine 6-12 mg/day is associated with sustained long-term cognitive benefits in patients with moderately severe AD. The results support the value of early treatment of AD patients, particularly those with moderately severe AD.