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.

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.

Post hoc analysis of nutritional status in patients with transthyretin familial amyloid polyneuropathy: impact of tafamidis.

Introduction: Gastrointestinal symptoms are common among patients with transthyretin familial amyloid polyneuropathy (TTR-FAP). This post hoc analysis evaluated the nutritional status of TTR-FAP patients treated with tafamidis while enrolled in clinical trials.

Methods: Nutritional status was measured by the modified body mass index (mBMI = BMI × albumin level).

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 effect of ziprasidone on metabolic syndrome risk factors in subjects with schizophrenia: a 1 year, open-label, prospective study.

Objective: Metabolic syndrome (MetS) is prevalent in subjects with schizophrenia-related psychotic disorders and contributes to increased rates of premature death due to cardiovascular disease. This study examined the impact of switching from another antipsychotic to ziprasidone on the distribution of the number of risk factors for MetS in subjects with schizophrenia or related psychotic disorders.

Research Design And Methods: In this 1 year, open-label, prospective study, all subjects received ziprasidone 40-160 mg/day.

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.

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.

Achieving and sustaining remission in bipolar I disorder with ziprasidone : a post hoc analysis of a 24-week, double-blind, placebo-controlled study.

Background And Objective: A number of operational definitions have been proposed to describe outcomes in bipolar disorders; the criteria used to define terms such as recurrence, relapse, response, remission and recovery have varied both in observational studies and in clinical trials. We carried out a post hoc analysis of rates of symptomatic point remission and sustained remission using four different remission criteria that had been evaluated in a previously published 24-week, double-blind, placebo-controlled study.

Methods: After stabilization for 8 consecutive weeks on open-label ziprasidone plus lithium or valproate, stabilized subjects were randomized to two groups, ziprasidone with lithium or valproate (ziprasidone group), or placebo with lithium or valproate (placebo group) for 16 weeks.

Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial.

To evaluate the efficacy of pregabalin in facilitating taper off chronic benzodiazepines, outpatients (N = 106) with a lifetime diagnosis of generalized anxiety disorder (current diagnosis could be subthreshold) who had been treated with a benzodiazepine for 8-52 weeks were stabilized for 2-4 weeks on alprazolam in the range of 1-4 mg/day. Patients were then randomized to 12 weeks of double-blind treatment with either pregabalin 300-600 mg/day or placebo while undergoing a gradual benzodiazepine taper at a rate of 25% per week, followed by a 6-week benzodiazepine-free phase during which they continued double-blind study treatment. Outcome measures included ability to remain benzodiazepine-free (primary) as well as changes in Hamilton Anxiety Rating Scale (HAM)-A and Physician Withdrawal Checklist (PWC).

Impact of geographical and cultural factors on clinical trials in acute mania: lessons from a ziprasidone and haloperidol placebo-controlled study.

Clinical trials today are conducted in multiple countries to enhance patient recruitment and improve efficiency of trials. However, the demographic and cultural diversity may contribute to variations in study outcomes. Here we conducted post-hoc analyses for a placebo-controlled study with ziprasidone and haloperidol for the treatment of acute mania to address the demographic, dosing, and outcome disparities in India, Russia and the USA.

Clinical Global Impression of Improvement (CGI-I) as a valid proxy measure for remission in schizophrenia: analyses of ziprasidone clinical study data.

Objective: To determine the degree to which a proxy measure of remission in schizophrenia correlates with the criteria identified by the Remission in Schizophrenia Working Group, and how well early treatment response to ziprasidone predicts remission.

Methods: Data from 10 ziprasidone studies were analyzed to determine rates of remission achieved with ziprasidone using a remission definition of Clinical Global Impression of Improvement (CGI-I) of 1, and compared with rates of remission achieved using the remission working group criteria. Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scores were then investigated as predictors of remission.

The efficacy of pregabalin and benzodiazepines in generalized anxiety disorder presenting with high levels of insomnia.

The objective of this study was to assess the impact of high levels of insomnia on response to pregabalin (PGB) in patients with generalized anxiety disorder (GAD). Pooled data were analyzed from six double-blind, placebo-controlled, 4- to 6-week trials of outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria for GAD with a minimum Hamilton Rating Scale for Anxiety (HAM-A) score = 18. Response was evaluated for three fixed-dose PGB groups (150, 300-450, 600 mg/day), and for a benzodiazepine group (alprazolam or lorazepam).

Impact of gastrointestinal symptoms on response to pregabalin in generalized anxiety disorder: results of a six-study combined analysis.

The objective of the study was to evaluate the response of generalized anxiety disorder (GAD) patients with prominent gastrointestinal (GI) symptoms to pregabalin (PGB) treatment. Data were pooled from six double-blind, placebo (PBO)-controlled, 4-6 week trials in outpatients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for GAD with a minimum Hamilton Anxiety Rating Scale (HAM-A) total score of 20. Treatment response was evaluated for three PGB fixed-dosage groups: 150, 300-450, and 600 mg/day, and for fixed doses of a benzodiazepine (alprazolam, 1.

Efficacy of pregabalin and venlafaxine-XR in generalized anxiety disorder: results of a double-blind, placebo-controlled 8-week trial.

The objective of this study was to evaluate the anxiolytic efficacy, and speed of onset of efficacy, of pregabalin (PGB) and venlafaxine-XR (VXR) in patients with generalized anxiety disorder (GAD). In this double-blind trial, outpatients, ages 18-65 years, who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for GAD were randomized to 8 weeks of flexible-dose treatment with PGB (300-600 mg/day), VXR (75-225 mg/day), or placebo (PBO). The intent-to-treat sample consisted of 121 patients on PGB [least square (LS) mean ± SE baseline Hamilton Anxiety Rating Scale (HAM-A), 27.

A comparison of ziprasidone and risperidone in the long-term treatment of schizophrenia: a 44-week, double-blind, continuation study.

Objective: This randomized, double-blind, multicentre extension study compared the efficacy, tolerability, and safety of ziprasidone and risperidone for schizophrenia or schizoaffective disorder.

Methods: Patients who had responded to treatment for an acute exacerbation of illness in an 8-week study received ziprasidone, 80 to 160 mg/day (n = 62), or risperidone, 6 to 10 mg/day (n = 77), for up to 44 additional weeks. Primary efficacy variables included changes in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impression Severity (CGI-S) score.

Efficacy of ziprasidone against hostility in schizophrenia: Post hoc analysis of randomized, open-label study data.

Objective: The objective was to determine the effects of sequential intramuscular/oral ziprasi-done on hostility.

Method: A total of 572 inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were the subjects in a randomized, rater-blinded, 6-week, open-label study comparing sequential intramuscular and oral ziprasidone with haloperidol. The Brief Psychiatric Rating Scale (BPRS) was the principal outcome measure.

High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a multicenter double-blind trial.

Objective: To evaluate the efficacy and safety of high-dose sertraline for patients with obsessive-compulsive disorder (OCD) who failed to respond to standard sertraline acute treatment.

Method: Sixty-six nonresponders to 16 weeks of sertraline treatment who met DSM-III-R criteria for current OCD were randomly assigned, in a double-blind continuation phase of a multicenter trial, either to continue on 200 mg/day of sertraline or to increase their dose to between 250 and 400 mg/day for 12 additional weeks. Efficacy measures included the Yale-Brown Obsessive Compulsive Scale (YBOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH Global OC Scale), and the Clinical Global Impressions-Severity of Illness and -Improvement (CGI-I) scales.

Efficacy, safety, and tolerability of sertraline in patients with late-life depression and comorbid medical illness.

Objectives: To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres-sed patients with and without comorbid medical illness.

Setting: Multicenter.

Design: Randomized, double-blind, placebo-controlled study.

Interactional effects of marital status and physical abuse on adolescent psychopathology.

Objective: The purpose of this study was to explore the interactional effects of parental marital disruption and physical abuse on risk for adolescent psychopathology in a nonclinical sample with a randomly selected control group.

Method: The sample was drawn from 99 community-based adolescents indicated as physically abused by Child Protective Services and 99 randomly selected controls. Nonabused adolescents whose parents were married, abused adolescents whose parents were married, nonabused adolescents with a parental marital disruption, and abused adolescents with a parental marital disruption were compared.