Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.

Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis.

Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia.

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues.

Randomized, Double-Blind, Placebo-Controlled Study of Encenicline, an α7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive Impairment in Schizophrenia.

Encenicline is a novel, selective α7 nicotinic acetylcholine receptor agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease. A phase 2, double-blind, randomized, placebo-controlled, parallel-design, multinational study was conducted. Patients with schizophrenia on chronic stable atypical antipsychotics were randomized to encenicline 0.

Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.

Background: Transthyretin (TTR) amyloidosis is a progressive systemic disorder caused by misfolded TTR monomers that cumulatively deposit in the heart and systemically as amyloid.

Methods And Results: This phase 2 open-label trial evaluated the stabilization of TTR tetramers using 20 mg of tafamidis daily at week 6 (primary end point), month 6, and month 12, as well as safety of tafamidis treatment and efficacy with respect to progression of TTR amyloid cardiomyopathy. Thirty-one wild-type patients (median age, 76.

Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: did baseline characteristics impact trial outcome?

Two randomized, double-blind, placebo-controlled, 6-week studies comparing ziprasidone versus placebo for treatment of bipolar depression (BPD) failed to meet their primary study objectives, indicating that either ziprasidone is ineffective in the treatment of BPD or the study failed. Adult outpatients with bipolar I depression with 17-item Hamilton Rating Scale for Depression total score more than 20 at screening and baseline received either ziprasidone 40 to 80 mg/d, 120 to 160 mg/d, or placebo (study 1), or ziprasidone 40 to 160 mg/d or placebo (study 2). Primary efficacy measure in both studies was change from baseline in Montgomery-Åsberg Depression Rating Scale total scores at week 6 (end of the study).

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.

Measurement of the serotonin 1A receptor availability in patients with schizophrenia during treatment with the antipsychotic medication ziprasidone.

The aim of this study was to compare 5-HT(1A) availability in vivo in individuals with schizophrenia before and during treatment with the atypical antipsychotic ziprasidone. Six individuals with schizophrenia underwent two PET scans with [(11)C]WAY 100635; the first while medication-free (baseline) and the second while taking the atypical antipsychotic ziprasidone (on-medication). Regional volumes of distribution (V(T), mL g(-1)) were derived using a two-tissue compartment kinetic model.

Findings of a U.S. national cardiometabolic screening program among 10,084 psychiatric outpatients.

Objective: A national cardiometabolic screening program for patients in a variety of public mental health facilities, group practices, and community behavioral health clinics was funded by Pfizer Inc. between 2005 and 2008.

Methods: A one-day, voluntary metabolic health fair in the United States offered patients attending public mental health clinics free cardiometabolic screening and same-day feedback to physicians from a biometrics testing third party that was compliant with the Health Insurance Portability and Accountability Act.

Understanding the relationship between baseline BMI and subsequent weight change in antipsychotic trials: effect modification or regression to the mean?

The purpose of this study was to examine whether prior evidence of an inverse relationship between initial body weight and subsequent antipsychotic-induced weight change represents true effect modification or a statistical artifact, regression to the mean (RTM). We conducted a post-hoc analysis after pooling seven randomized, placebo- or active-controlled trials of ziprasidone and other antipsychotic agents. ANCOVA was applied to evaluate treatment-by-baseline body mass index (BMI) range interaction effect on weight change.

Reduction of functional disability with atypical antipsychotic treatment: a randomized long term comparison of ziprasidone and haloperidol.

Background: Recent interest has focused on the definition and measurement of clinical remission in people with schizophrenia. This study examined the process of development of "functional remission" in a long-term comparative double-blind study of haloperidol and the atypical antipsychotic medication ziprasidone.

Methods: Community dwelling patients with schizophrenia were randomized to treatment with haloperidol (n=47) or ziprasidone dosed either once or twice daily (n=139).

Metabolic risk status and second-generation antipsychotic drug selection: a retrospective study of commercially insured patients.

Background: Routine metabolic screening and consideration of patient metabolic status in the choice of a second-generation antipsychotic (SGA) medication are recommended. This study evaluated the association between abnormal blood glucose and lipid values and SGA prescribing patterns.

Materials And Methods: A retrospective cohort study using administrative data from 2 managed care plans in the United States evaluated 7904 adults initiating SGA therapy between 2001 and 2004.

The impact of calories and fat content of meals on oral ziprasidone absorption: a randomized, open-label, crossover trial.

Background: Food is known to increase the bioavailability of ziprasidone. Therefore, we evaluated the effects of meals of differing caloric and fat content on steady-state ziprasidone exposure in a stable, treated group of subjects with DSM-IV diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, or psychotic disorder (not otherwise specified) who were already receiving oral ziprasidone as their standard therapy.

Method: Patients took ziprasidone under 6 meal conditions in randomized sequences (fasted, low calorie/low fat, low calorie/high fat, medium calorie/high fat, high calorie/low fat, and high calorie/high fat); each crossover period was separated by at least 3 days for washout of the previous meal condition.

Ziprasidone for the treatment of acute manic or mixed episodes associated with bipolar disorder.

Ziprasidone, a benzisothiazolyl piperazine-type atypical antipsychotic agent, has a unique receptor-binding profile. A potent antagonist of serotonin 5-HT(2A) and dopamine D(2) receptors, ziprasidone has an affinity for 5-HT(2A) receptors >10-fold higher than its affinity for D(2) receptors. Ziprasidone has been shown to be effective in the treatment of bipolar disorder in patients experiencing manic or mixed episodes.

Serotonin 1A receptor availability in patients with schizophrenia and schizo-affective disorder: a positron emission tomography imaging study with [11C]WAY 100635.

Background: Postmortem and positron emission tomography (PET) studies have reported several alterations in serotonin 1A receptor (5-HT(1A)) binding parameters in patients with schizophrenia. This study examines 5-HT(1A) availability in vivo in individuals with schizophrenia and schizo-affective disorder.

Materials And Methods: Twenty-two medication-free individuals with schizophrenia or schizo-affective disorder and 18 healthy subjects underwent PET scans with [(11)C]WAY 100635.

Serotonin transporter availability in patients with schizophrenia: a positron emission tomography imaging study with [11C]DASB.

Background: Postmortem studies have reported several alterations in serotonin transporter (SERT) binding parameters in patients with schizophrenia. The aim of this study was to compare SERT availability in vivo in patients with schizophrenia and matched control subjects.

Methods: Ten medication-free patients with schizophrenia and 10 healthy subjects underwent positron emission tomography (PET) scans for 90 min after 11C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([11C]DASB) injection.

Brain serotonin transporter distribution in subjects with impulsive aggressivity: a positron emission study with [11C]McN 5652.

Objective: The serotonin system is believed to play a role in modulating impulsivity and violence. Previous imaging studies have implicated the anterior cingulate and orbitofrontal cortex in impulsive aggression. This study evaluated regional serotonin transporter distribution in the brain of individuals with impulsive aggression by using positron emission tomography (PET) with the serotonin transporter PET radiotracer [(11)C]McN 5652.

Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [(11)C]McN 5652.

Background: Serotonergic abnormalities have been hypothesized to contribute to obsessive-compulsive disorder (OCD). This study examined whether brain serotonin transporter (SERT) availability is altered in OCD using positron emission tomography (PET) and the SERT PET radiotracer [(11)C]McN 5652.

Methods: Eleven OCD subjects, free of psychiatric medications and comorbid depression, and 11 matched healthy control subjects underwent PET scans following injection of [(11)C]McN 5652 and magnetic resonance imaging (MRI) scans.

Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with 11C McN 5652.

Rationale: Although selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of anxiety and depressive disorders, the occupancy of the serotonin reuptake transporter (SERT) achieved in humans at typical clinical doses by these agents remains poorly characterized.

Objective: The purpose of this study was to determine the occupancy of the SERT achieved in vivo by the SSRI paroxetine in social phobia patients at typical antianxiety doses.

Methods: Measures of SERT availability were obtained with positron emission tomography and the SERT radiotracer [(11)C](+)-McN 5652 in five patients with social phobia before and during treatment with paroxetine at usual therapeutic doses (20-40 mg per day).

Prefrontal dopamine D1 receptors and working memory in schizophrenia.

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function.