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

Roluperidone has antagonist properties for 5-HT2A, sigma2, α1A- and α1B-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. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32 mg/day or 64 mg/day for 24 weeks (trial 1) or 40 weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10 %. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia.

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. RESULTS: Thirty-three flags were derived these included logical consistency checks and statistical outlier-response pattern checks. Twenty-percent of the HAM-A administrations had at least one logical scoring inconsistency flag, 4 % had two or more. Twenty-six percent of the administrations had at least one statistical outlier flag and 11 % had two or more. Overall, 35 % of administrations had at least one flag of any type, 19 % had one and 16 % had 2 or more. Most of administrations in the Monte Carlo- simulated data raised multiple flags. LIMITATIONS: Flagged ratings may represent less-common presentations of administrations done correctly. Conclusions-Application of flags to clinical ratings may aid in detecting imprecise measurement. Flags can be used for monitoring of raters during an ongoing trial and as part of post-trial evaluation. Appling flags may improve reliability and validity of trial data.

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.e., cross-sectionally) and across administrations (i.e., longitudinally) can contribute to improving measurement fidelity. METHODS: The International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled flags indicating consistency/inconsistency ratings for the Hamilton Rating Scale for Depression (HAM-D17), a widely-used rating scale in studies of depression. Proposed flags were applied to assessments derived from the NEWMEDS data repository of 95,468 HAM-D administrations from 32 registration trials of antidepressant medications and to Monte Carlo-simulated data as a proxy for applying flags under conditions of known inconsistency. RESULTS: Two types of flags were derived: logical consistency checks and statistical outlier-response pattern checks. Almost thirty percent of the HAMD administrations had at least one logical scoring inconsistency flag. Seven percent had flags judged to suggest that a thorough review of rating is warranted. Almost 22% of the administrations had at least one statistical outlier flag and 7.9% had more than one. Most of the administrations in the Monte Carlo- simulated data raised multiple flags. LIMITATIONS: Flagged ratings may represent less-common presentations of administrations done correctly. CONCLUSIONS: Application of flags to clinical ratings may aid in detecting imprecise measurement. Reviewing and addressing these flags may improve reliability and validity of clinical trial data.

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. Currently, we derive empirically based outlier-pattern flags, to further detect imprecisions in ratings. NEWMEDS data repository of almost 25,000 MADRS administrations from 11 registration trials of antidepressants was used to identify outlier response patterns reflecting potentially careless responses. Coverage of these flags was compared to previously published expert derived flags. Both sets of flags were also further tested in Monte Carlo simulated data as a proxy to applying flags under conditions of known inconsistency. The outlier flags derived provide cutting points to identify: (1) under and overuse of values (e.g., Scoring "1″ on 6 or more items), (2) disproportionate use of even or odd response choices (e.g., 8 or more odd values), (3) longest consecutive use of value (e.g., more than 5 items in a row scored with same value), (4) high variability within administration (standard deviation greater than 1.8), (5) outlier responses on multiple items (i.e., multivariate outliers), and (6) outlier scoring (e.g., scoring 4,5 or 6 on item 1). Outlier response flags were raised in 26% of the MADRS administration and in 97% of the Monte Carlo data. Of administrations with no expert flag, 21.7% had an outlier flag and of administrations with at least one expert flag, 27.7% also had an outlier flag. Outlier-pattern flags appear to be a useful adjunct to expert derived flags in the quest to improve measurement in clinical trials.

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.

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. METHODS: In a sample of 525 individuals (aged 34-44, 55.4% male) born and raised in Jerusalem, Israel (STREAM study) we attempted to differentiate those who did and did not report psychiatric symptoms in mid-adulthood. Using χ2 and regression analysis, we explored birth factors (year of birth, sex, birth weight, and number of older siblings, data on parental immigration and socioeconomic status), academic achievement in eighth grade and contemporaneous measures of lifestyle factors, personality traits, and perceived resilience. RESULTS: Participants with good mental health were more often male (P = .005) and had better academic performance already at adolescence than participants who reported psychiatric symptoms in midlife (P < .001). They reported fewer physical complaints (P = .008), were less likely to smoke (P = .001) and considered themselves to be more "resilient" (P < .001). CONCLUSIONS: The results showed that better academic performance in adolescence may be associated with better stress-coping strategies, resulting in fewer psychiatric complaints, more perceived resilience, and less stress-related behaviours in mid-adulthood. Future studies confirming this hypothesis could inform public mental health interventions.

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., total) score from the four individual domain scores, 74 flag inconsistencies between domain scores relative to Positive and Negative Symptom Scale (PANSS) item ratings and 57 flag inconsistencies between PSP decile score and PANSS items ratings. The flags were applied to assessments from randomized clinical trial data of antipsychotics in schizophrenia from almost 18,000 ratings. Twenty-two flags were raised in at least 5 of 1000 ratings. Nearly 20% of the PSP ratings had at least one inconsistency flag raised. Application of flags to clinical ratings may improve the reliability of ratings and validity of trials.

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 0.5, Mini-Mental State Examination (MMSE) score >24, Wechsler Memory Scale-Revised Verbal Paired Associates I score ≤18, and Medial Temporal Lobe Atrophy Scale score >1 were stratified by APOE ε4 genotype and randomly assigned (1:1) to ladostigil 10 mg/d or placebo. Primary outcomes were safety and onset of Alzheimer disease dementia. Secondary endpoints were Neuropsychological Test Battery (NTB) composite, Disability Assessment in Dementia (DAD), and Geriatric Depression Scale (GDS) scores. Exploratory outcomes were NTB component, CDR, and MMSE scores. Biomarkers included MRI-derived whole-brain, hippocampus, and entorhinal cortex volumes. RESULTS: Two hundred ten patients from 15 sites in Austria, Germany, and Israel were randomly allocated to placebo (107 patients) or ladostigil (103 patients). After 36 months, 21 of 103 patients on placebo and 14 of 99 patients receiving ladostigil progressed to Alzheimer disease (log-rank test p = 0.162). There were no significant effects on the NTB composite, DAD, or GDS score. Whole-brain and hippocampus volumes decreased more in the placebo than in the ladostigil group (whole brain, p = 0.025, Cohen d = 0.43; hippocampus, p = 0.043, d = 0.43). Serious adverse events were reported by 28 of 107 patients treated with placebo and 26 of 103 with ladostigil. CONCLUSION: Ladostigil was safe and well tolerated but did not delay progression to dementia. Its association with reduced brain and hippocampus volume loss suggests a potential effect on atrophy. CLINICALTRIALSGOV IDENTIFIER: NCT01429623. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with MCI and medial temporal lobe atrophy, ladostigil did not significantly decrease the risk of the development of Alzheimer disease.

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. A model-informed methodology is proposed to establish a relationship between level of placebo response and TE. This relationship is used to estimate the "typical" TE associated with a "typical" level of placebo response, irrespective of the level of placebo response observed. The approach can be valuable for providing a reliable estimate of TE, for conducting risk/benefit analysis, and for determining dosage recommendations.

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. The flags were applied to assessments derived from the NEWMEDS data repository. Almost 65% of ratings had at least one inconsistency flag raised and 22% had two or more. Application of flags to clinical ratings may improve reliability of ratings and validity of trials.

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. METHODS: Using data from the Study of Resilience and Environmental Adversity in Midlife Health (STREAM), which includes survey responses of 811 individuals, we compared early academic achievement and self-reported social and functional outcomes between respondents who reported psychotic symptoms, manic symptoms, depressive symptoms, or no psychiatric symptoms (controls). RESULTS: Adults with psychotic symptoms had significantly poorer early academic performance (p = .04) and social and functional outcomes (self-reported marital status, p = .021, income, p = .001, and health, p < .001) than controls. Adults with depressive symptoms had significantly lower early academic performance and income and poorer health than controls (p's = 0.033, 0.037, 0.013 respectively), and adults with manic symptoms also reported significantly lower rates of marriage than controls (p = .006). CONCLUSIONS: The results are consistent with the continuum view of the etiology of psychiatric disorders in which psychiatric disorders are dimensional and experienced in varying degrees of severity across the general and clinical population. Importantly, the results highlight the potential impact of psychiatric symptomatology on functional outcomes in the population.

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. We examined patient and trial-design-related determinants of outcome as measured by change on Hamilton Depression Scale or Montgomery-Asberg Depression Rating Scale in 34 placebo-controlled trials (drug, n = 8260; placebo, n = 3957). RESULTS: While it is conventional for trials to be 6-8 weeks long, drug-placebo differences were nearly the same at week 4 as at week 6 and with lower dropout rates. At the multivariate level, having any of these attributes was significantly associated with greater drug vs. placebo differences on symptom improvement: female, increasing proportion of patients on placebo, centers located outside of North America, centers with low placebo response (regardless of active treatment response) and using randomized withdrawal designs. LIMITATIONS: Data on compounds that failed were not available to us. Findings may not be relevant for new mechanisms of action. CONCLUSIONS: Proof of concept trials can be shorter and efficiency improved by selecting enriched populations based on clinical and demographic variables, ensuring adequate balance of placebo patients, and carefully selecting and monitoring centers. In addition to improving drug discovery, patient exposure to placebo and experimental treatments can be reduced.

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-HT2A 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. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. RESULTS: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. CONCLUSIONS: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

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. Almost 40% of ratings had at least one inconsistency flag raised and 10% had two. Application of flags to clinical rating can improve reliability and validity of trials.

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. Although our trial-level data support prevous findings, patient-level data did not show any significant effect of initial depression severity on drug v. placebo difference.

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. Academic achievement, behavior problems and body mass index (BMI) were assessed at childhood (6-9) and teenhood (10-14). Height and weight were self-reported at pre-young adulthood (15-18) and young adulthood (19-25). RESULTS: Based on logistic regression stratified by sex and race/ethnicity, academic and behavioral deficiencies during childhood and teenhood were risk factors for young adult obesity with some sex and ethnic/racial differences. The highest prevalence rates of obesity by race/ethnicity and sex are as follows: black/Hispanic females, those in the lowest quartile of teen reading and math (32.8%); black/Hispanic males, those in lowest quartile of teen reading (26.1%); white males, those in the highest quartile of behavioral problems (21.9%); and white females, those in the lowest quartile teen math (23.2%). CONCLUSION: Poor school performance in childhood and teenhood is associated with an increased risk of adult obesity. Prospective studies should further examine the association of school performance and adult obesity and whether programs directed at improving school performance may have secondary gains in preventing obesity.

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. Initial telephone surveys took place in 2007-2008 and participants were followed-up for a second survey 1 year later. Upon funding, a new wave is planned for 2017-2018. Survey topics comprised common health problems (e.g., type 2 diabetes/migraine), health markers (e.g., BMI), and psychiatric vulnerabilities (e.g., anxiety, post-traumatic stress, depressive symptoms, psychosis). Other measures included socioeconomic status, creativity, life style behavior (e.g., smoking, exercise), social contact and adaptation to change. Survey data were retrospectively merged with data of national registry sources that included adverse psychosocial factors, psychiatric and social measures assessed across all developmental stages through midlife. This includes data available on birth factors, school achievement and adjustment, cognitive and behavioral functioning during young adulthood, psychiatric hospitalizations, immigration and socioeconomic status. RESULTS: Results on health outcomes of the first STREAM wave indicate that prevalence rates of health problems are comparable to recent World Mental Health Surveys. CONCLUSIONS: Apart from measures on adverse psychosocial factors, STREAM provides a cohort to examine resilience to developing health problems and having a poor health and functional outcome.

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. Using this benchmark and we simulated thousands of schizophrenia trials, using characteristics derived from the NEWMEDS database with over 8000 patients with schizophrenia, to the kind of imaging, genetic, and other biomarkers that could attain clinical significance. We plotted the interaction between frequency-of-occurrence, the effect size of biomarkers and their relationship to the clinical significance threshold. Results show that categorical biomarkers are likely to attain clinical significance when they occur in 20-50% of the clinical population, and can predict at least a 8-10 point PANSS scale difference. Genetic markers are likely to have clinical significance when they occur in 20-50% of the population and can predict 7-9 points on the PANSS scale. A marker with a lower frequency or lesser effect size would find it hard to meet clinical significance thresholds for schizophrenia. The assumptions and limitations of this approach are discussed. Compared with standards in the rest of medicine, biomarkers that can attain this benchmark will be cost-effective and are likely to be adopted by clinical systems.

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. METHODS: In CATIE, we first identified the group of subjects lacking an exacerbation prior to study enrollment. Six subsets with varying baseline positive and negative symptom thresholds were then identified. Baseline characteristics were summarized; negative and positive symptom change from baseline through month 3 was calculated both as crude change and change adjusted for corresponding baseline scores. Sensitivity analyses and correlations were calculated to assess the extent to which negative symptom variance was attributable to positive symptom change. RESULTS: More restrictive baseline symptom severity thresholds yielded a considerably smaller sample size and higher negative and lower positive symptoms at baseline. Unadjusted negative symptom change was greater with more restrictive criteria; when adjusted for baseline severity the magnitude of change was comparable across subsets. The amount of variance in negative symptom change attributed to positive symptom change was also comparable across subsets. CONCLUSIONS: The use of restrictive positive and negative symptom thresholds yields a marked decrease in eligible sample size with no clear improvement in adjusted negative symptom change or amount of variance associated with positive symptom change.