A multilevel structural equation model for assessing a drug effect on a patient-reported outcome measure in on-demand medication data.

We analyze data from a clinical trial investigating the effect of an on-demand drug for women with low sexual desire. These data consist of a varying number of measurements/events across patients of when the drug was taken, including data on a patient-reported outcome consisting of five items measuring an unobserved construct (latent variable). Traditionally, these data are aggregated prior to analysis by composing one sum score per event and averaging this sum score over all observed events.

A survival of the fittest strategy for the selection of genotypes by which drug responders and non-responders can be predicted in small groups.

Phenotype Prediction Scores (PPS) might be powerful tools to predict traits or the efficacy of treatments based on combinations of Single-Nucleotide Polymorphism (SNPs) in large samples. We developed a novel method to produce PPS models for small samples sizes. The set of SNPs is first filtered on those known to be relevant in biological pathways involved in a clinical condition, and then further filtered repeatedly in a survival strategy to select stabile positive/negative risk alleles.

The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects.

Introduction: A new combination tablet containing sublingual testosterone and oral buspirone (T+B) was developed to benefit a subgroup of women suffering from female sexual interest/arousal disorder, caused by dysfunctionally overactive sexual inhibition.

Aim: The aim of this study was to compare the effect of food intake on the pharmacokinetics of buspirone, administered as a dual-route, dual-release combination tablet containing 0.5 mg testosterone (T) and 10 mg buspirone (B).

The Effect of Food on the Pharmacokinetics of Sildenafil after Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects.

Introduction: Female sexual interest/arousal disorder (FSIAD) affects many women worldwide, but pharmacological treatment options are scarce. A new medicine being developed for FSIAD is an on-demand, dual-route, dual-release drug combination product containing 0.5 mg testosterone (T) and 50 mg sildenafil (S), referred to here as T+S.

Multilevel analyses of on-demand medication data, with an application to the treatment of Female Sexual Interest/Arousal Disorder.

Data from clinical trials investigating on-demand medication often consist of an intentionally varying number of measurements per patient. These measurements are often observations of discrete events of when the medication was taken, including for example data on symptom severity. In addition to the varying number of observations between patients, the data have another important feature: they are characterized by a hierarchical structure in which the events are nested within patients.

Genotype scores predict drug efficacy in subtypes of female sexual interest/arousal disorder: A double-blind, randomized, placebo-controlled cross-over trial.

Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of 'one size fits all', and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response.

Differential Resting-State Connectivity Patterns of the Right Anterior and Posterior Dorsolateral Prefrontal Cortices (DLPFC) in Schizophrenia.

In schizophrenia (SCZ), dysfunction of the dorsolateral prefrontal cortex (DLPFC) has been linked to the deficits in executive functions and attention. It has been suggested that, instead of considering the right DLPFC as a cohesive functional entity, it can be divided into two parts (anterior and posterior) based on its whole-brain connectivity patterns. Given these two subregions' differential association with cognitive processes, we investigated the functional connectivity (FC) profile of both subregions through resting-state data to determine whether they are differentially affected in SCZ.

Psychometric Properties of the Sexual Event Diary in a Sample of Dutch Women With Female Sexual Interest/Arousal Disorder.

Background: Efficacy of on-demand drugs for women with hypoactive sexual desire disorder or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken, because this type of assessment is more proximate to an on-demand drug's efficacy compared to instruments that assess sexual function over longer periods of time.

Aim: The aim of this study was to assess the psychometric properties of the Dutch translation of the previously validated 11-item Sexual Event Diary (SED) for measuring sexual satisfaction and sexual functioning during discrete sexual events.

Methods: Psychometric assessment was performed on data of 1,840 SEDs from 139 women with hypoactive sexual desire disorder/FSIAD, collected during a randomized clinical cross-over trial conducted in the Netherlands.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

Background: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available.

Aim: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups.

Methods for assessing and controlling placebo effects.

The placebo serves as an indispensable control in many randomized trials. When analyzing the benefit of a new treatment, researchers are often confronted with large placebo effects that diminish the treatment effect. Various alternative methods have been proposed for analyzing placebo and treatment effects in studies where large placebo effects are expected or have already occurred.

The Sexual Event Diary (SED): Development and Validation of a Standardized Questionnaire for Assessing Female Sexual Functioning During Discrete Sexual Events.

Background: The efficacy of on-demand drugs for hypoactive sexual desire disorder (HSDD) or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken.

Aim: To develop and validate an event log for measuring sexual satisfaction and sexual functioning of discrete sexual events.

Methods: Psychometric assessment was carried out on data of 10,959 Sexual Event Diaries (SEDs) collected during three clinical trials in a total of 421 women with HSDD.

Restrictions and satisfaction with participation in patients who are ADL-independent after an aneurysmal subarachnoid hemorrhage.

Background: Most survivors of an aneurysmal subarachnoid hemorrhage (aSAH) are ADL-independent, but they often experience restrictions in (social) activities and, therefore, cannot regain their pre-morbid level of participation.

Objective: In this study, participation restrictions and participation satisfaction experienced after aSAH were assessed. Moreover, possible predictors of participation after aSAH were examined to identify goals for rehabilitation.

Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison.

Aim: The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.

Systematic review of cardiopulmonary exercise testing post stroke: Are we adhering to practice recommendations?

Objective: To systematically review the use of cardiopulmonary exercise testing in people who have survived a stroke. The following questions are addressed: (i) What are the testing procedures used? (ii) What are the patient, safety and outcomes characteristics in the cardiopulmonary exercise testing procedures? (iii) Which criteria are used to determine maximum oxygen uptake (VO2peak/max) in the cardiopulmonary exercise testing procedures?

Methods: Systematic review of studies of cardiopulmonary exercise testing in stroke survivors. PubMed, EMBASE, and CINAHL were searched from inception until January 2014.

The 5-HT₁A receptor C(1019)G polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation.

Introduction: Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 min, and has been postulated as a neurobiological dysfunction related to diminished serotonergic neurotransmission with 5-HT₁A receptor hyperfunction and 5-HT₂C hypofunction.

Aim: To investigate the relationship between 5-HT₁A receptor gene (HTR₁A)-C(1019)G promoter polymorphism and IELT in men with LPE. This polymorphism is known to increase 5-HT1A receptor expression.

Serotonin 1A receptors and sexual behavior in a genetic model of depression.

The Flinder Sensitive Line (FSL) is a rat strain that displays distinct behavioral and neurochemical features of major depression. Chronic selective serotonin reuptake inhibitors (SSRIs) are able to reverse these symptoms in FSL rats. It is well known that several abnormalities in the serotonergic system have been found in FSL rats, including increased 5-HT brain tissue levels and reduced 5-HT synthesis.

Review of the efficacy of transcranial magnetic stimulation for auditory verbal hallucinations.

With an increase of the number of studies exploring repetitive transcranial magnetic stimulation (rTMS) for the treatment of auditory verbal hallucinations (AVH), an update is provided on the efficacy of different paradigms. A literature search was performed from 1966 through April 2013. Twenty-five randomized controlled trials using the severity of AVH or psychosis as outcome measures were included.

Serotonin 1A receptors and sexual behavior in female rats: a review.

This review focuses on the role of serotonin and especially 5-HT₁A receptors in female rat sexual behavior. In addition, the differences and/or similarities with male rats are discussed. Overall, in both males and females 5-HT₁A receptors do not appear to be involved in sexual behavior under normal circumstances, but become very important under conditions of elevated serotonin levels.

Serotonin 1A receptors and sexual behavior in male rats: a review.

Serotonin plays an important role in male sexual behavior. Many studies have been performed on the pivotal role of 5-HT₁A receptors in sexual behavior. Overall, 5-HT₁A receptors do not appear to be involved under normal circumstances, but become very important under conditions of elevated serotonin levels in sexual behavior.

Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test.

The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val¹⁵⁸Met polymorphism.

Background: Cannabis use and childhood maltreatment are independent risk factors for the development of psychotic symptoms. These factors have been found to interact in some but not all studies. One of the reasons may be that childhood maltreatment and cannabis primarily induce psychotic symptoms in genetically susceptible individuals.

The effect of stress on core and peripheral body temperature in humans.

Even though there are indications that stress influences body temperature in humans, no study has systematically investigated the effects of stress on core and peripheral body temperature. The present study therefore aimed to investigate the effects of acute psychosocial stress on body temperature using different readout measurements. In two independent studies, male and female participants were exposed to a standardized laboratory stress task (the Trier Social Stress Test, TSST) or a non-stressful control task.

Wheelchair exercise capacity in spinal cord injury up to five years after discharge from inpatient rehabilitation.

Objective: To elucidate the course and determinants of wheelchair exercise capacity in spinal cord injury up to 5 years after discharge from inpatient rehabilitation, and to describe loss to follow-up.

Design: Prospective cohort study, with measurements at the start and discharge from inpatient rehabilitation, 1 and 5 years after discharge.

Subjects: A total of 225 wheelchair-dependent persons with spinal cord injury.