Risk for hypertension and heart failure linked to high normal serum sodium and tonicity in electronic medical records.

Background And Aims: Population aging is fueling an epidemic of age-related chronic diseases. Managing risk factors and lifestyle interventions have proven effective in disease prevention. Epidemiological studies have linked markers of poor hydration with higher risk of chronic diseases and premature mortality.

Consistency checks to improve measurement with the Young Mania Rating Scale (YMRS).

Background: Mitigating rating inconsistency can improve measurement fidelity and detection of treatment response.

Methods: The International Society for CNS Clinical Trials and Methodology convened an expert Working Group that developed logical consistency (LC) checks for ratings of the Young Mania Rating Scale (YMRS), which is widely used in studies of mood and bipolar disorders. LC and statistical outlier-response pattern checks (SC) were applied to 63,228 YMRS administrations from 14 clinical trials evaluating treatments for bipolar disorder.

Long-term effects of Roluperidone on negative symptoms of schizophrenia.

Roluperidone has antagonist properties for 5-HT, sigma, α- and α-adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40 weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis.

Consistency checks to improve measurement with the Hamilton Rating Scale for Anxiety (HAM-A).

Background: Mitigating rating inconsistency can improve measurement fidelity and detection of treatment response.

Methods: The International Society for CNS Clinical Trials and Methodology convened an expert Working Group that developed consistency checks for ratings of the Hamilton Anxiety Rating Scale (HAM-A) and Clinical Global Impression of Severity of anxiety (CGIS) that are widely used in studies of mood and anxiety disorders. Flags were applied to 40,349 HAM-A administrations from 15 clinical trials and to Monte Carlo-simulated data as a proxy for applying flags under conditions of inconsistency.

Consistency checks to improve measurement with the Hamilton Rating Scale for Depression (HAM-D).

Background: Symptom manifestations in mood disorders can be subtle. Cumulatively, small imprecisions in measurement can limit our ability to measure treatment response accurately. Logical and statistical consistency checks between item responses (i.

Outlier-response pattern checks to improve measurement with the Montgomery-Asberg depression rating scale (MADRS).

Symptom manifestations in affective disorders can be subtle. Small imprecisions in measurement can lead to incorrect estimation of change. Previously, expert-derived scoring inconsistency flags were developed for MADRS.

Outlier-response pattern checks to improve measurement with the Positive and Negative Syndrome Scale (PANSS).

We derived outlier-response pattern checks to flag possible careless PANSS (Positive and Negative Syndrome Scale) administrations based on analysis of 122,000 administrations from 29 registration trials of antipsychotics from NEWMEDS data repository. Flags identify outlier administrations based on frequency of endorsing a given response value, use of even or odd values, consecutive use of same value, variability of values, responses per specific item, and values on multiple items. Outlier flags were compared to published expert derived scoring inconsistency flags and tested in Monte Carlo simulated data, with known inconsistency, and appear to be useful at identifying administrations that require review.

Consistency checks to improve measurement with the Personal and Social Performance Scale (PSP).

International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Personal and Social Performance Scale (PSP). One hundred and forty seven flags were identified, 16 flag errors in deriving the PSP decile (i.e.

Early predictors of mental health in mid-adulthood.

Aim: Substantial research has focused on the examination of factors that contribute to the development of psychiatric problems. However, much less is known about factors early in life that may protect from poor mental health outcomes in midlife. This study aimed to identify the extent to which a set of key perinatal demographic variables and adolescent academic performance were associated with good mental health in mid-adulthood.

Low-dose ladostigil for mild cognitive impairment: A phase 2 placebo-controlled clinical trial.

Objective: Ladostigil reduces oxidative stress and microglial activation in aging rats. We assessed its safety and potential efficacy in a 3-year, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild cognitive impairment (MCI) and medial temporal lobe atrophy.

Methods: Patients 55 to 85 years of age with MCI, Clinical Dementia Rating (CDR) score of 0.

Model-Informed Approach to Assess the Treatment Effect Conditional to the Level of Placebo Response.

One of the most important reasons for failure of placebo-controlled randomized controlled clinical trials (RCTs) is the lack of appropriate methodologies for detecting treatment effect (TE; difference between placebo and active treatment response) in the presence of excessively low/high levels of placebo response. Although, the higher the level of placebo response in a trial, the lower the apparent detectable TE. TE is usually estimated in a conventional analysis of an RCT as an "apparent" TE value conditional to the level of placebo response in that RCT.

Consistency checks to improve measurement with the Montgomery-Asberg Depression Rating Scale (MADRS).

International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Montgomery-Asberg Depression Rating Scale (MADRS). Twenty-two flags were identified. Seven flags are believed to be strong flags that suggest that a thorough review of rating is warranted.

Psychiatric symptoms and related dysfunction in a general population sample.

Background: Along with the key clinical features of major psychiatric disorders such as psychosis, mania, and depression, these disorders are also associated with cognitive, social, and functional deficits. A growing body of evidence suggests that these disorders exist at the extreme end of a continuum of symptoms rather than as binary entities, so it is plausible that the associated cognitive, social, and functional deficits assume a similar pattern. Consistent with this approach, we sought to determine whether adults in the general population with psychiatric symptoms also demonstrate milder forms of the cognitive, social, and functional deficits that are often associated with the psychiatric disorders.

Determinants of antidepressant response: Implications for practice and future clinical trials.

Background: Response to antidepressants in major depressive disorder is variable and determinants are not well understood or used to design clinical trials. We aimed to understand these determinants.

Methods: Supported by Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from industry sponsored randomized placebo-controlled trials of antidepressant drugs in adults with MDD.

Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.

Objective: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia.

Method: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks.

Consistency checks to improve measurement with the Positive and Negative Syndrome Scale (PANSS).

International Society for CNS Clinical Trials and Methodology convened an expert working-group that assembled consistency/inconsistency flags for the Positive and Negative Syndrome Scale (PANSS). Twenty-four flags were identified and divided based on extent to which they represent error (Possibly, Probably, Very probably or definitely). The flags were applied to assessments derived from the NEWMEDS data repository and the CATIE clinical trial data.

Initial depression severity and response to antidepressants v. placebo: patient-level data analysis from 34 randomised controlled trials.

Several often-cited meta-analyses have reported that the efficacy of antidepressant medications depends on the severity of depression. They found that drug-placebo differences increased as a function of initial severity, which was attributed to decreased responsiveness to placebo among patients with severe depression rather than to increased responsiveness to medication. We retested this using patient-level data and also undertaking a meta-analysis of trial-level data from 34 randomised placebo controlled trials (n = 10 737) from the NEWMEDS registry.

Association of childhood and teen school performance and obesity in young adulthood in the US National Longitudinal Survey of Youth.

Background: The literature suggests an association between poor school performance and obesity. However, little is known about academic achievement and behavior as possible risk factors for future obesity.

Method: The analysis was based on data from 3172 participants aged 6 to 25years from the US National Longitudinal Survey conducted 1986 to 2010.

Study of resilience and environmental adversity in midlife health (STREAM).

Purpose: The Jerusalem study of resilience and environmental adversity in midlife health (STREAM) was established to examine the prevalence of common mental and physical health issues in mid-adulthood in the inner city of Jerusalem, and to examine their association with lifespan psychosocial factors of vulnerability and resilience.

Method: Participants were 811 randomly selected individuals from 7000 individuals who were born and grew up in inner-Jerusalem. Participants were 34-44 years old during first wave of STREAM assessment.

Biomarkers of treatment outcome in schizophrenia: Defining a benchmark for clinical significance.

Emerging data from on imaging and genetic studies have generated interest in "clinically significant" biomarkers to predict response and prognosis. What constitutes "clinical significance" and how a biomarker would reach that threshold are unclear. To develop a benchmark we reviewed different approaches for defining "clinical significance" applied in schizophrenia research and identified that an improvement of 15 points on the PANSS Total is considered meaningful in clinical settings.

Restrictive symptomatic inclusion criteria create barriers to clinical research in schizophrenia negative symptoms: an analysis of the CATIE dataset.

Background: Persistent negative symptoms are an important area of clinical research. However, there is limited consensus on how to define positive and negative symptom severity thresholds for inclusion in clinical trials. From the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset we evaluated the performance of varying baseline negative and positive symptom thresholds on baseline symptom severity, change from baseline, and negative symptom variance attributable to positive symptom change.

How antipsychotics impact the different dimensions of Schizophrenia: a test of competing hypotheses.

The clinical expression of schizophrenia is generally reported to be expressed by three to five different factors (i.e. positive, negative, disorganization, excitability, anxiety-depression symptoms).

Determinants of antipsychotic response in schizophrenia: implications for practice and future clinical trials.

Background: Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials.

Objective: We aimed to understand determinants of response to antipsychotic treatment.

Method: Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies.

Combining efficacy and completion rates with no data imputation: a composite approach with greater sensitivity for the statistical evaluation of active comparisons in antipsychotic trials.

Outcomes in RCT's of antipsychotic medications are often examined using last observation carried forward (LOCF) and mixed effect models (MMRM), these ignore meaning of non-completion and thus rely on questionable assumptions. We tested an approach that combines into a single statistic, the drug effect in those who complete trial and proportion of patients in each treatment group who complete trial. This approach offers a conceptually and clinically meaningful endpoint.