Schizophrenia Trial Research Articles

T129. PHARMACOLOGICAL INTERVENTIONS IN TRIALS OF PEOPLE WITH SCHIZOPHRENIA: A REGISTER-BASED CLASSIFICATION OF SEVENTY YEARS OF RESEARCH

BackgroundDrug development is a billion dollar business globally. It is crucial to stay up to date on drug developments all over the world any repetition will be irreversible waste of resources. The only way to keep up with all the development is to keep a living database of all trials running for each condition and covering all studies from every country in any language. An Information Specialist collects and classifies all pharmacological interventions from all schizophrenia trials.MethodsCochrane Schizophrenia’s Study-Based Register was developed and used as the source of trials, Emtree and MeSH for synonyms, AdisInsight and CT.gov for research drugs and WHO ATC for marketed drugs. This research took four years from 17 December 2014 and 6 January 2019 and involved 18,500 randomized controlled trial from 90 countries in 23 languages.ResultsOne third of tested interventions on patients with schizophrenia are pharmacological (816; belonging to 106 clinical classes) with antipsychotic drugs being the most researched (15.1%). Only 528 of these medications are listed in WHO ATC. Around one third of these drug interventions are seen only in research (236; from 21 pharmacological/biochemical classes). Within the pharmacological evaluations we identified 28 ‘qualifiers’ including dose, route, and timing of drug delivery. Using Data Science approaches, this research revealed unique antipsychotic drugs that are being prescribed only in certain countries such as Japan but the West is not aware of them. This research is also revealed all the research drugs and current trends in developing drugs in pharmaceutical companies.DiscussionClassification of medication interventions from trials requires use of many sources of information none of which are inclusive of all drugs. Without a global search in all languages the pharmaceutical companies and researchers are missing important successful developments from non-English speaking world. The cycle of developing research/withdrawn drugs does not stop and may end in veterinary medicine, doping agents in sports, and illicit drug market.

M42. INDEPENDENT REVIEW & MONITORING IMPROVES QUALITY OF PANSS DATA IN GLOBAL CLINICAL TRIALS

BackgroundThe Positive and Negative Syndrome Scale (PANSS) (1) is the most widely used endpoint for measuring change in schizophrenia clinical trials. A set of flags have been developed by ISCTM expert working group to identify potential scoring errors in PANSS assessments (2). Measures have been taken by sponsors (pharmaceutical industry) with the goal of increasing scoring reliability and data quality, such as the use of Independent Review (IRev). We evaluated changes in data quality when site raters stop being recorded and monitored via IRev by comparing two studies with the same cohort of raters, one with independent review and one without.MethodsData from PANSS assessments in two global multisite schizophrenia clinical trials were analyzed. We selected data from raters participating in both studies (which run concurrently for a significant period of time). Raters were rigorously trained on administration and scoring conventions and certified prior to the study through demonstration of adequate interrater reliability. In addition to these steps, raters in study A were required to audio record all PANSS assessments with a selected subset of visits being subject to IRev. PANSS assessments in study B were neither recorded nor monitored via IRev. Data quality after study completion was examined by calculating the frequency of anomalous data patterns identified as “high” (very probable or definite error) by the ISCTM Working Group in both studies. Additionally, we examined the percentage of assessments with lower than expected PANSS interview duration as captured via an eCOA platform.ResultsThere were 9441 eCOA PANSS assessments in study A and 6178 in study B included in this analysis. The proportions of flags that represented highly probable/definite error differed significantly between the studies (9% vs 18% for Study A and B, respectively, p<.01). The most significant differences in ISCTM flags were related to overly consistent scoring patterns (27 or more items scored identically to the prior visit) occurring with higher frequency in study B. Additionally, study B also had a significantly higher frequency of assessments flagged for low interview duration (< 15 minutes) (1% vs 4% for Study A and B, respectively, p<.01).DiscussionInitial rater training is necessary but not sufficient to ensure adequate data quality in schizophrenia trials. Implementation of additional in-study oversight through Independent Review or similar methods reduces the probability of data error in PANSS assessments, including the appearance of improbable rating patterns and decreased time spent interviewing study subjects. One potential limitation is that study A is a double-blind study whereas study B is an open label extension of study A.

Clinical Validity of Subjective Clinical Prognosis in First Episode Psychosis Schizophrenia Patients: An Analysis of Data from the European First Episode Schizophrenia Trial (EUFEST) Study.

PurposeThis study examined the validity of subjective clinical prognosis (SCP), a commonly used clinical tool, in first episode psychosis patients included in the European First Episode Schizophrenia Trial (EUFEST) study.Patients and MethodsThe study comprised 455 patients from the EUFEST trial (mean age 25.92, SD=5.45; 188 (41.31%) women, 267 (58.69%) men). SCP was classified into three mutually exclusive groups: “good prognosis” (GP) (n=265), “average prognosis” (AP) (n=131), and “poor prognosis” (PP) (n=59). The validity of the SCP was assessed by investigating the differences between the SCP groups and completer or responder status of the patients, during 1 year of the trial.ResultsThe proportion of completers was significantly higher in the GP group (64.4%) compared to the AP group (25.6%) (OR=1.62, 95% CI=1.062–2.476, p<0.031) and the PP group (10%) (OR=2.17, 95% CI=1.226–3.853, p<0.009) throughout the whole duration of the trial. In what concerns responsiveness, a significantly higher number of responders were registered in the GP group compared to the AP and the PP groups in the first three months of treatment, but this outcome did not persist afterwards.ConclusionIn terms of its predictive value at first episode schizophrenic patients, SCP seems to be reliable for treatment completion, but has a limited utility in what concerns responsiveness to treatment. This finding suggests the necessity of creating a prediction model potentially including, besides SCP, other measurement-based variables.

The Trend of Increasing Placebo Response and Decreasing Treatment Effect in Schizophrenia Trials Continues: An Update From the US Food and Drug Administration.

Concerns of increasing placebo response and declining treatment effect in acute schizophrenia trials have been reported for new drug applications (NDAs) submitted to the US Food and Drug Administration (FDA) during an 18-year period from 1991 through January 2009 (ie, the pre-2009 period). Current exploratory analyses provide an update in the trends observed in placebo response, treatment effect, and dropout rates for NDAs submitted from February 2009 to 2015 (ie, the post-2009 period). Clinical trial data from all acute schizophrenia trials that were submitted as part of NDAs to the US FDA during a 24-year period from 1991 to 2015. Aggregate trial-level efficacy data from multicenter, multiregional, randomized, placebo-controlled, 4- to 8-week, fixed- and flexible-dose trials in adult schizophrenia patients were compiled. There were 12 NDAs pre-2009 (32 trials, N = 11,567) and 3 NDAs post-2009 (14 trials, N = 6,434). Baseline demographic and disease variables and scores on the Positive and Negative Syndrome Scale (PANSS) were summarized and compared for the two time periods (pre-2009 and post-2009). The primary efficacy measure was mean change from baseline to endpoint in total PANSS score obtained by last-observation-carried-forward analysis. Regional differences in placebo response and treatment effect were explored for the two time periods based on baseline patient characteristics, sample size, and dropout rates. Trials were predominantly multiregional (10/14; 71%) during the post-2009 period compared to the pre-2009 period (11/32; 34%). The overall trial success rates were 57% (8/14) and 78% (25/32) during the post-2009 and pre-2009 periods, respectively. Comparing the pre-2009 and post-2009 periods, the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5 and the mean treatment effect (drug response - placebo response) declined from -8.6 to -5.8 , with substantial differences observed especially in North American trials. In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009). The difference in placebo response (pre- and post-2009: -10.0 and -11.3 ) and treatment effect (pre and post-2009: -8.1 and -6.4 ) in multiregional trials for the two time periods remained minimal. Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100. Trials with higher mean baseline PANSS scores tended to show higher treatment effect irrespective of the time period and region. Post-2009, dropout rates were higher (55%) in North American trials compared with 33% in multiregional trials, similar to the pre-2009 trend. The continuing trend of increasing placebo responses and decreasing treatment effects in schizophrenia trials over the 24-year period does remain of great concern, especially with respect to North American trials. However, given the current global nature of drug development, close attention to trial conduct and reexamination of design elements for future trials may be warranted.

Double blind, two dose, randomized, placebo-controlled, cross-over clinical trial of the positive allosteric modulator at the alpha7 nicotinic cholinergic receptor AVL-3288 in schizophrenia patients.

Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα7) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα7 positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thustheoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placeboacross three separate treatment weeks. The primary outcome measurewas the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with non-significant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα7 target.

Add-on spironolactone as antagonist of the NRG1-ERBB4 signaling pathway for the treatment of schizophrenia: Study design and methodology of a multicenter randomized, placebo-controlled trial

BackgroundPreclinical studies recently showed that the mineralocorticoid antagonist spironolactone acts also as an antagonist of the NRG1-ERBB4 signaling pathway and improves schizophrenia-like behaviour in Nrg1 transgenic mouse model. As this signaling pathway is critically linked to the pathophysiology of schizophrenia, especially in the context of working-memory dysfunction, spironolactone may be a novel treatment option for patients with schizophrenia targeting cognitive impairments. AimsTo evaluate whether spironolactone added to an ongoing antipsychotic treatment improves cognitive functioning in schizophrenia. MethodsThe add-on spironolactone for the treatment of schizophrenia trial (SPIRO-TREAT) is a multicenter randomized, placebo-controlled trial with three arms (spironolactone 100 mg, spironolactone 200 mg and placebo). Schizophrenia patients are treated for three weeks and then followed-up for additional nine weeks. As primary outcome, we investigate changes in working memory before and at the end of the intervention phase. We will randomize 90 patients. Eighty-one patients are intended to reach the primary endpoint measure at the end of the three-week intervention period. Secondary endpoints include other measures of cognition, psychopathology, safety measures and biological measures. ConclusionsSPIRO-TREAT is the first study evaluating the efficacy of the mineralocorticoid receptor antagonist spironolactone to improve cognitive impairments in schizophrenia patients targeting the NRG1-ERBB4 signaling pathway. With SPIRO-TREAT, we intend to investigate a novel treatment option for cognitive impairments in schizophrenia that goes beyond the established concepts of interfering with dopaminergic neurotransmission as key pathway in schizophrenia treatment. Clinical trial registrationInternational Clinical Trials Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE

Individual Alpha Peak Frequency Moderates Transfer of Learning in Cognitive Remediation of Schizophrenia.

Meta-analyses report moderate effects across cognitive remediation (CR) trials in schizophrenia. However, individual responses are variable, with some participants showing no appreciable gain in cognitive performance. Furthermore, reasons for heterogeneous outcome are undetermined. We examine the extent to which CR outcome is attributable to near learning-direct gains in trained cognitive tasks-while also exploring factors influencing far transfer of gains during training to external cognitive measures. Thirty-seven schizophrenia outpatients were classified as CR responders and non-responders according to change in MATRICS Consensus Cognitive Battery composite score following 20 sessions of computer-based training. Metrics of near learning during training, as well as baseline demographic, clinical, cognitive, and electroencephalographic (EEG) measures, were examined as predictors of responder status. Significant post-training improvement in cognitive composite score (Cohen's d = .41) was observed across the sample, with n = 21 and n = 16 classified as responders and non-responders, respectively. Near learning was evidenced by significant improvement on each training exercise with practice; however, learning did not directly predict responder status. Group-wise comparison of responders and non-responders identified two factors favoring responders: higher EEG individual alpha frequency (IAF) and lower antipsychotic dosing. Tested in moderation analyses, IAF interacted with learning to predict improvement in cognitive outcome. CR outcome in schizophrenia is not directly explained by learning during training and appears to depend on latent factors influencing far transfer of trained abilities. Further understanding of factors influencing transfer of learning is needed to optimize CR efficacy.

Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

BackgroundUp to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly.MethodsEight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed).FindingsOne implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators’ knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively).InterpretationThese preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects.

Cochrane Schizophrenia Group’s Study-Based Register of Randomized Controlled Trials: Development and Content Analysis

AbstractBackgroundStudy-based registers facilitate systematic reviews through shortening the process for review team and reducing considerable waste during the review process. Such a register also provides new insights about trends of trials in a sub-specialty. This paper reports development and content analysis of Cochrane Schizophrenia Group’s Study-Based Register.MethodsThe randomized controlled trials were collected through systematic searches of major information sources. Data points were extracted, curated and classified in the register. We report trends using regression analyses in Microsoft Excel and we used GIS mapping (GunnMap 2) to visualize the geographical distribution of the origin of schizophrenia trials.ResultsAlthough only 17% of trials were registered, the number of reports form registered trials is steadily increasing and registered trials produce more reports. Clinical trial registers are main source of trial reports followed by sub-specialty journals. Schizophrenia trials have been published in 23 languages from 90 countries while 105 nations do not have any reported schizophrenia trials. Only 9.7% of trials were included in at least one Cochrane review. Pharmacotherapy is the main target of trials while trials targeting psychotherapy are increasing in a continuous rate. The number of people randomized in trials is on average 114 with 60 being the most frequent sample size.ConclusionsCurated datasets within the register uncover new patterns in data that have implications for research, policy, and practice for testing new interventions in trials or systematic reviews.

Varenicline for cognitive impairment in people with schizophrenia: systematic review and meta-analysis.

People with schizophrenia frequently have cognitive dysfunction, which does not respond to pharmacological interventions. Varenicline has been identified as a potential treatment option for nicotinic receptor dysfunction with a potential to treat cognitive impairment in schizophrenia. We conducted a systematic review of Pubmed, Embase, Psycinfo, CINAHL and the Cochrane Schizophrenia Trial Registry for randomised controlled trials of varenicline in people with schizophrenia for cognitive dysfunction. We excluded trials among people with dementia. We then undertook a meta-analysis with the primary outcome of difference in change of cognitive measures between varenicline and placebo as well as secondary outcomes of difference in rates of adverse events. We conducted a sensitivity analysis on smoking status and study duration. We included four papers in the meta-analysis (n = 339). Varenicline was not superior to placebo for overall cognition (SMD = -0.022, 95% CI -0.154-0.110; Z = -0.333; p = 0.739), attention (SMD = -0.047, 95% CI -0.199-0.104; Z = -0.613; p = 0.540), executive function (SMD = -0.060, 95% CI -0.469-0.348; Z =- 0.290; p = 0.772) or processing speed (SMD = 0.038, 95% CI -0.232-0.308; Z = 0.279; p = 0.780). There was no difference in psychotic symptoms, but varenicline was associated with higher rates of nausea. Sensitivity analyses for smoking status and study duration did not alter the results. Within the present literature, varenicline does not appear to be a useful target compound for improving cognitive impairment in schizophrenia. Based on these results, a trial would need over 2500 participants to be powered to show statistically significant findings.

P.382 Circadian rhythm of hallucinatory experiences in patients with schizophrenia

The metabolic syndrome is highly prevalent in patients with schizophrenia. We previously found that blood C-reactive protein (CRP), interleukin-6 (IL-6), and leptin levels were predictors of current metabolic syndrome in schizophrenia. In the present study, we investigated whether baseline levels of total and differential white blood cell (WBC) counts, inflammatory markers, and adipokines predicted incident metabolic syndrome in schizophrenia.For subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial who did not have metabolic syndrome at baseline (n = 726), WBC counts, inflammatory markers, and adipokines were investigated as predictors of incident metabolic syndrome over 12 months of antipsychotic treatment. Cox proportional hazards regression models, controlling for multiple potential confounding factors, were used to investigate these associations.39% of subjects (n = 280) had incident metabolic syndrome over 12 months. After controlling for potential confounders, baseline blood IL-6 (HR = 1.12, 95% CI 1.01–1.24, p = 0.031) and leptin (HR = 1.12, 95% CI 1.01–1.24, p = 0.038) were significant predictors of incident metabolic syndrome, and there was a trend-level association with CRP (HR = 1.09, 95% CI 1.00–1.19, p = 0.059).Our findings provide additional evidence that measurement of inflammatory markers and adipokines are germane to the clinical care of patients with schizophrenia. Specifically, these markers may identify—prior to treatment—patients with schizophrenia at heightened risk for incident adverse cardiometabolic effects of antipsychotics. Given the tremendous burden of cardiovascular disease morbidity and mortality in schizophrenia, vigilant screening for and treatment of metabolic risk factors in this patient population are warranted.

P.739 Use of cannabis, alcohol and other substances in mentally ill offenders-data from Northern Greece

Studies and meta-analyses investigating the influence of substance use disorder (SUD) (substance abuse or dependence) on psychopathology and neurocognitive function in schizophrenia patients have revealed controversial results. Most studies did only have small samples and did not focus exclusively on first-episode schizophrenia patients.In a post-hoc analysis of the European First Episode Schizophrenia Trial (EUFEST) psychopathology and cognitive performances of patients with (FE-SUD, N = 119, consisting of N = 88 patients with persisting SUD at baseline and N = 31 patients with previous SUD) and without SUD (FE-non-SUD, N = 204) were compared at baseline and 6 months follow-up. Neurocognitive assessment included the Rey Auditory Verbal Learning Test (RAVLT); Trail Making Tests A and B (TMT), Purdue Pegboard and Digit-Symbol Coding.In total 31.1% of patients reported SUD, and 22.2% of patients used cannabis. There were no significant differences between patients with and without SUD concerning PANSS scores, extrapyramidal motor symptoms or neurocognitive measures except better performance in psychomotor speed (TMT-A, p = 0.033, Cohen's d = 0.26) in patients with SUD at 6 months follow-up. Interestingly, SUD patients with ongoing substance use at follow-up showed elevated positive symptoms (PANSS positive score, p = 0.008, Cohen's d = 0.84) compared to those who abstained. PANSS scores at baseline were increased in patients with an onset of SUD before the age of 16 years. In addition we found a correlation between longer duration of cannabis use and higher cognitive performance as well as reduced symptom improvement and more extrapyramidal motor symptoms in patients with higher frequency of cannabis consumption.FE-SUD and FE-non-SUD show similar psychopathology and neuropsychological performances at baseline and during the first 6 months of antipsychotic treatment.

P.370 Impact of full versus partial response on signal detection in placebo-controlled schizophrenia trials

P.370 Impact of full versus partial response on signal detection in placebo-controlled schizophrenia trials

Antipsychotic drugs v. barbiturates or benzodiazepines used as active placebos for schizophrenia: a systematic review and meta-analysis.

Comparisons of antipsychotics with placebo can be biased by unblinding due to side effects. Therefore, this meta-analysis compared the efficacy of antipsychotics for acute schizophrenia in trials using barbiturates or benzodiazepines as active placebos. Randomized controlled trials (RCTs) in acute schizophrenia with at least 3 weeks duration and comparing any antipsychotic with barbiturates or benzodiazepines were eligible. ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, PubMed, WHO-ICTRP as well as previous reviews were searched up to 9 January 2018. Two separate meta-analyses, one for barbiturates and one for benzodiazepines, were conducted using random-effects models. The primary outcome was response to treatment, and mean values of schizophrenia rating scales and dropouts were analyzed as secondary outcomes. This study is registered with PROSPERO (CRD42018086263). Seven barbiturate-RCTs (number of participants n = 1736), and two benzodiazepine-RCTs (n = 76) were included in the analysis. The studies were published between 1960 and 1968 and involved mainly chronically ill patients. More patients on antipsychotics in comparison to barbiturates achieved a 'good' response (36.2% v. 16.8%; RR 2.15; 95% CI 1.36-3.41; I2 = 48.9) and 'any' response (57.4% v. 27.8%; RR 2.07; 95% CI 1.35-3.18; I2 = 68.2). In a single small trial (n = 60), there was no difference between antipsychotics and benzodiazepines on 'any' response (74.7% v. 65%; RR 1.15; 95% CI 0.82-1.62). Antipsychotic drugs were more efficacious than barbiturates, based on a large sample size. Response ratios were similar to those observed in placebo-controlled trials. The results on benzodiazepines were inconclusive due to the small number of studies and participants.

Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis.

Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342).

Evaluation of Differences in Individual Treatment Response in Schizophrenia Spectrum Disorders

An assumption among clinicians and researchers is that patients with schizophrenia vary considerably in their response to antipsychotic drugs in randomized clinical trials (RCTs). To evaluate the overall variation in individual treatment response from random variation by comparing the variability between treatment and control groups. Cochrane Schizophrenia, MEDLINE/PubMed, Embase, PsycINFO, Cochrane CENTRAL, BIOSIS Previews, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform from January 1, 1955, to December 31, 2016. Double-blind, placebo-controlled, RCTs of adults with a diagnosis of schizophrenia spectrum disorders and prescription for licensed antipsychotic drugs. Means and SDs of the Positive and Negative Syndrome Scale pretreatment and posttreatment outcome difference scores were extracted. Data quality and validity were ensured by following the PRISMA guidelines. The outcome measure was the overall variability ratio of treatment to control in a meta-analysis across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. A personal element of response was hypothesized to be reflected by a substantial overall increase in variability in the treatment group compared with the control group. An RCT was simulated, comprising 30 patients with schizophrenia randomized to either the treatment or the control group. The different components of variation in RCTs were illustrated with simulated data. In addition, we assessed the variability ratio in 52 RCTs involving 15 360 patients with a schizophrenia or schizoaffective diagnosis. The variability was slightly lower in the treatment compared with the control group (variability ratio = 0.97; 95% CI, 0.95-0.99; P = .01). In this study, no evidence was found in RCTs that antipsychotic drugs increased the outcome variance, suggesting no personal element of response to treatment but instead indicating that the variance was slightly lower in the treatment group than in the control group; although the study cannot rule out that subsets of patients respond differently to treatment, it suggests that the average treatment effect is a reasonable assumption for the individual patient.

Total and differential white blood cell counts, inflammatory markers, adipokines, and incident metabolic syndrome in phase 1 of the clinical antipsychotic trials of intervention effectiveness study

ObjectiveThe metabolic syndrome is highly prevalent in patients with schizophrenia. We previously found that blood C-reactive protein (CRP), interleukin-6 (IL-6), and leptin levels were predictors of current metabolic syndrome in schizophrenia. In the present study, we investigated whether baseline levels of total and differential white blood cell (WBC) counts, inflammatory markers, and adipokines predicted incident metabolic syndrome in schizophrenia. MethodFor subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial who did not have metabolic syndrome at baseline (n = 726), WBC counts, inflammatory markers, and adipokines were investigated as predictors of incident metabolic syndrome over 12 months of antipsychotic treatment. Cox proportional hazards regression models, controlling for multiple potential confounding factors, were used to investigate these associations. Results39% of subjects (n = 280) had incident metabolic syndrome over 12 months. After controlling for potential confounders, baseline blood IL-6 (HR = 1.12, 95% CI 1.01–1.24, p = 0.031) and leptin (HR = 1.12, 95% CI 1.01–1.24, p = 0.038) were significant predictors of incident metabolic syndrome, and there was a trend-level association with CRP (HR = 1.09, 95% CI 1.00–1.19, p = 0.059). ConclusionsOur findings provide additional evidence that measurement of inflammatory markers and adipokines are germane to the clinical care of patients with schizophrenia. Specifically, these markers may identify—prior to treatment—patients with schizophrenia at heightened risk for incident adverse cardiometabolic effects of antipsychotics. Given the tremendous burden of cardiovascular disease morbidity and mortality in schizophrenia, vigilant screening for and treatment of metabolic risk factors in this patient population are warranted.

Off-Label Use of Bumetanide for Brain Disorders: An Overview.

Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl− gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl− importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl− levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.

Analysis of covariance in randomized trials: More precision and valid confidence intervals, without model assumptions.

"Covariate adjustment" in the randomized trial context refers to an estimator of the average treatment effect that adjusts for chance imbalances between study arms in baseline variables (called "covariates"). The baseline variables could include, for example, age, sex, disease severity, and biomarkers. According to two surveys of clinical trial reports, there is confusion about the statistical properties of covariate adjustment. We focus on the analysis of covariance (ANCOVA) estimator, which involves fitting a linear model for the outcome given the treatment arm and baseline variables, and trials that use simple randomization with equal probability of assignment to treatment and control. We prove the following new (to the best of our knowledge) robustness property of ANCOVA to arbitrary model misspecification: Not only is the ANCOVA point estimate consistent (as proved by Yang and Tsiatis, 2001) but so is its standard error. This implies that confidence intervals and hypothesis tests conducted as if the linear model were correct are still asymptotically valid even when the linear model is arbitrarily misspecified, for example, when the baseline variables are nonlinearly related to the outcome or there is treatment effect heterogeneity. We also give a simple, robust formula for the variance reduction (equivalently, sample size reduction) from using ANCOVA. By reanalyzing completed randomized trials for mild cognitive impairment, schizophrenia, and depression, we demonstrate how ANCOVA can achieve variance reductions of 4 to 32%.

T26. CLINICAL OUTCOME ASSESSMENTS FOR TRIALS IN COGNITIVE IMPAIRMENT ASSOCIATED WITH SCHIZOPHRENIA

AbstractBackgroundFor clinical development programs in cognitive impairment associated with schizophrenia (CIAS), it has been stated that significant improvement on a cognitive performance endpoint would be necessary, but not sufficient, for drug approval. In addition, regulators require improvement on a functionally meaningful co-primary. A co-primary approach may require a more conservative criterion be set for statistical significance: first a modest impact of correlation between the endpoints is observed on required sample size for a given effect size and power; second a more important impact of effect size is observed. If the standardized effect size for one endpoint is smaller, the sample size is determined by this. In the recent draft guidance for treatment of early AD, the FDA acknowledge the entity of cognition as meaningful and they outline circumstances in which integrated cognition-function, or cognition only outcomes would be acceptable as single primary endpoints. In addition, it is stated that when measured using conventional assessments, the meaningfulness of cognition may not be apparent.MethodsA review was conducted of Phase 2 and 3 industry clinical trials for schizophrenia listed on clinicaltrials.gov, and which studied potential for cognitive improvement. Fifty-two trials were identified and the most commonly reported outcomes for cognition and function identified.ResultsThe most commonly used and reported outcomes have been the MCCB for cognition and the UPSA for function. The other cognitive outcomes used most frequently (≥7 trials) have been the Cogstate, and BACS batteries, whilst the other most frequently used functional outcomes (≥5 trials) have been the SCoRS and PSP. Furthermore, several versions of the UPSA have been employed (e.g. UPSA-B, UPA-2, UPSA-VIM). These clinical outcome assessments (COAs) fall into groups of cognitive performance-based outcome (PerfO), functional capacity assessments, and clinician-reported outcome (ClinRO) assessments. Whilst no treatment is yet approved for CIAS, several trials have shown encouraging data in early clinical development and certain antipsychotic trials have also shown evidence for improvement.DiscussionCognition as measured by conventional cognitive PerfO assessments is most commonly an indirect measure of meaningful health outcomes (i.e. the test activities are not a part of a person’s usual normal life). Consequently, the meaning of any change in a cognitive score is not intrinsically known. This lack of direct measurement of meaningful health outcomes drives the requirement for the use of co-primary endpoints. There may be alternate approaches such as establishing cognitive only outcomes as intermediate or surrogate endpoints or creating integrated cognition-function endpoints with greater statistical power. Sufficient data likely exist across completed industry trials to facilitate the development and validation of such endpoints. Furthermore, novel cognitive PerfO may be developed that are more direct measures of health outcomes and could also form single primary endpoints.