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.

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.

Adjunctive Brexpiprazole in Patients With Major Depressive Disorder and Irritability: An Exploratory Study.

OBJECTIVE: To evaluate the effects of adjunctive brexpiprazole on symptoms of irritability in patients with major depressive disorder (MDD). METHODS: Patients diagnosed with MDD according to DSM-IV-TR criteria who had inadequate response to antidepressant treatment continued treatment with their current antidepressant for 2 weeks. Patients still having inadequate response, and with irritability, received 6 weeks of open-label treatment with their current antidepressant at the same dose and adjunctive brexpiprazole (target dose: 3 mg/d). Brexpiprazole was discontinued at week 6, and the patients continued with their antidepressant until week 10. Changes from baseline to week 6 and week 6 to week 10 were analyzed. RESULTS: This study was conducted between October 7, 2013, and July 30, 2014. Fifty-four patients were treated with adjunctive brexpiprazole. At week 6, clinically relevant improvements were observed in Sheehan Irritability Scale total (-21.1) and item 1 (irritable mood) (-3.5) scores, Kellner Symptom Questionnaire total (-24.4) and anger-hostility subscale (-7.7) scores, and 30-item Inventory of Depressive Symptomatology, clinician version (IDS-C30), item 6 (irritable mood) score (-1.2). More (15 patients) stopped than developed (5 patients) anger attacks during treatment, as measured by the Anger Attacks Questionnaire. The Clinical Global Impressions-Severity of Illness score improved (-1.4), as did the depressive symptoms (IDS-C30 total score, -17.8; Kellner Symptom Questionnaire depression subscale score, -7.7; and Montgomery-Asberg Depression Rating Scale total score, -14.2). Irritability symptoms worsened after brexpiprazole discontinuation, assessed at week 10. Adjunctive brexpiprazole was well tolerated. CONCLUSIONS: Adjunctive treatment with brexpiprazole may represent a strategy for patients with MDD and inadequate response to antidepressant treatment who have symptoms of irritability. TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT01942785.

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.

Fast-moving features in the debris disk around AU Microscopii.

In the 1980s, excess infrared emission was discovered around main-sequence stars; subsequent direct-imaging observations revealed orbiting disks of cold dust to be the source. These 'debris disks' were thought to be by-products of planet formation because they often exhibited morphological and brightness asymmetries that may result from gravitational perturbation by planets. This was proved to be true for the ß Pictoris system, in which the known planet generates an observable warp in the disk. The nearby, young, unusually active late-type star AU Microscopii hosts a well-studied edge-on debris disk; earlier observations in the visible and near-infrared found asymmetric localized structures in the form of intensity variations along the midplane of the disk beyond a distance of 20 astronomical units. Here we report high-contrast imaging that reveals a series of five large-scale features in the southeast side of the disk, at projected separations of 10-60 astronomical units, persisting over intervals of 1-4 years. All these features appear to move away from the star at projected speeds of 4-10 kilometres per second, suggesting highly eccentric or unbound trajectories if they are associated with physical entities. The origin, localization, morphology and rapid evolution of these features are difficult to reconcile with current theories.

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. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo-controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580). RESULTS: While it is conventional for trials to be 6 weeks long, drug-placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P ≤ .04), being a young adult patient who is a few years beyond the first episode (P ≤ .03), having prominent positive and negative symptoms (P ≤ .03), and living in Eastern Europe versus North America (P ≤ .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented. CONCLUSIONS: Proof-of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments.

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. Composite approach was compared to LOCF (ANCOVA) and MMRM in 59 industry sponsored RCT's. For within study comparisons we computed effect size (z-score) and p values for (a) rates of completion, (b) symptom change for complete cases, which were combined into composite statistic, and (c) symptom change for all cases using last observation forward (LOCF). In the 30 active comparator studies, composite approach detected larger differences in effect size than LOCF (ES=.05) and MMRM (ES=.076). In 10 of the 49 comparisons composite lead to significant differences (p ≤ .05) where LOCF and MMRM did not. In 3 comparisons LOCF was significant, in 2 MMRM lead to significant differences whereas composite did not. In placebo controlled trials, there was no meaningful difference in effect size between composite and LOCF and MMRM when comparing placebo to active treatment, however composite detected greater differences than other approaches when comparing between active treatments. Composite was more sensitive to effects of experimental treatment vs. active controls (but not placebo) than LOCF and MMRM thereby increasing study power while answering a more relevant question.

Negative symptoms in schizophrenia--the remarkable impact of inclusion definitions in clinical trials and their consequences.

BACKGROUND: Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus. OBJECTIVES: We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms. METHOD: Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome. RESULTS: Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from "typical" trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics. CONCLUSIONS: Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow.

Flows of gas through a protoplanetary gap.

The formation of gaseous giant planets is thought to occur in the first few million years after stellar birth. Models predict that the process produces a deep gap in the dust component (shallower in the gas). Infrared observations of the disk around the young star HD 142527 (at a distance of about 140 parsecs from Earth) found an inner disk about 10 astronomical units (AU) in radius (1 AU is the Earth-Sun distance), surrounded by a particularly large gap and a disrupted outer disk beyond 140 AU. This disruption is indicative of a perturbing planetary-mass body at about 90 AU. Radio observations indicate that the bulk mass is molecular and lies in the outer disk, whose continuum emission has a horseshoe morphology. The high stellar accretion rate would deplete the inner disk in less than one year, and to sustain the observed accretion matter must therefore flow from the outer disk and cross the gap. In dynamical models, the putative protoplanets channel outer-disk material into gap-crossing bridges that feed stellar accretion through the inner disk. Here we report observations of diffuse CO gas inside the gap, with denser HCO(+) gas along gap-crossing filaments. The estimated flow rate of the gas is in the range of 7 × 10(-9) to 2 × 10(-7) solar masses per year, which is sufficient to maintain accretion onto the star at the present rate.

A prospective study of escitalopram in the treatment of major depressive episodes in the presence or absence of anxiety.

This open, multicenter, prospective study in France assessed the efficacy and tolerability of escitalopram in patients with depression, with or without comorbid anxiety. Escitalopram was administered over a 12-week treatment period to 790 depressed patients, including 482 patients with at least one concomitant anxiety disorder. The study was completed by 649 patients. At baseline, the mean Montgomery-Asberg Depression Rating Scale (MADRS) total score was 31.5 and decreased to 12.4 at end point (last observation carried forward [LOCF]). The MADRS score decreased by 20.5 points in patients with no anxiety disorder and by 18.3 points in patients with at least one concomitant anxiety disorder. The mean Hamilton Anxiety Rating Scale (HAM-A) total score at baseline was 25.6, which decreased to 10.8 at end point (LOCF). The HAM-A score decreased by 13.8 points in patients with no anxiety disorder and by 15.5 points in patients with at least one anxiety disorder. Adverse events were reported by 246 patients (31%). The most frequent adverse events were nausea in 65 patients (8%) and headache in 38 patients (5%); 61 patients (8%) discontinued treatment due to adverse events. Escitalopram was well tolerated and efficacious in reducing symptoms of depression in patients with or without comorbid anxiety over a 12-week treatment period.

Anatomy of a flaring proto-planetary disk around a young intermediate-mass star.

Although planets are being discovered around stars more massive than the Sun, information about the proto-planetary disks where such planets have built up is sparse. We have imaged mid-infrared emission from polycyclic aromatic hydrocarbons at the surface of the disk surrounding the young intermediate-mass star HD 97048 and characterized the disk. The disk is in an early stage of evolution, as indicated by its large content of dust and its hydrostatic flared geometry, indicative of the presence of a large amount of gas that is well mixed with dust and gravitationally stable. The disk is a precursor of debris disks found around more-evolved A stars such as beta-Pictoris and provides the rare opportunity to witness the conditions prevailing before (or during) planet formation.

A proteomic analysis of penicillin resistance in Streptococcus pneumoniae reveals a novel role for PstS, a subunit of the phosphate ABC transporter.

Resistance to penicillin is widespread in the Gram-positive bacterium Streptococcus pneumoniae, and while several mutations are known to be implicated in resistance other mechanisms are likely to occur. We used a proteomic screen of two independent mutants in which resistance was selected in vitro. We found a number of differentially expressed proteins including PstS, a subunit of the phosphate ABC transporter of S. pneumoniae. This protein was increased in both mutants, a phenotype correlated to increased RNA expression of the entire phosphate ABC transporter operon. Inactivation of the pstS gene led to increased susceptibility to penicillin in the wild-type strain. To further link the expression of the ABC phosphate transporter with penicillin resistance, we looked at pstS mRNA levels in 12 independent clinical isolates sensitive and resistant to penicillin and found an excellent correlation between resistance and increased expression of pstS. Inactivation of pstS in one of the clinical isolates significantly reduced penicillin resistance. Global approaches are ideally suited for the discovery of novel factors in the biology of resistance.

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis.

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.