Thomas D. Meyer

Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes

Recent withdrawals of prescription drugs from clinical use because of unexpected side effects on the heart have highlighted the need for more reliable cardiac safety pharmacology assays. Block of the human Ether-a-go go Related Gene (hERG) ion channel in particular is associated with life-threatening arrhythmias, such as Torsade de Pointes (TdP). Here we investigated human cardiomyocytes derived from pluripotent (embryonic) stem cells (hESC) as a renewable, scalable, and reproducible system on which to base cardiac safety pharmacology assays. Analyses of extracellular field potentials in hESC-derived cardiomyocytes (hESC-CM) and generation of derivative field potential duration (FPD) values showed dose-dependent responses for 12 cardiac and noncardiac drugs. Serum levels in patients of drugs with known effects on QT interval overlapped with prolonged FPD values derived from hESC-CM, as predicted. We thus propose hESC-CM FPD prolongation as a safety criterion for preclinical evaluation of new drugs in development. This is the first study in which dose responses of such a wide range of compounds on hESC-CM have been generated and shown to be predictive of clinical effects. We propose that assays based on hESC-CM could complement or potentially replace some of the preclinical cardiac toxicity screening tests currently used for lead optimization and further development of new drugs.

Cardiotoxicity testing using pluripotent stem cell-derived human cardiomyocytes and state-of-the-art bioanalytics: a review.

In this article, recent progress in cardiotoxicity testing based on the use of immortalized cell lines or human embryonic stem cell (hESC) derived cardiomyocytes in combination with state‐of‐the‐art bioanalytical methods and sensors is reviewed. The focus is on hESC‐derived cells and their refinement into competent testing cells, but the access and utility of other relevant cell types are also discussed. Recent developments in sensor techniques and bioanalytical approaches for measuring critical cardiotoxicity parameters are highlighted, together with aspects of data evaluation and validation. Finally, recommendations for further research are given. Copyright

The Hypomanic Personality Scale, the Big Five, and their relationship to depression and mania

The present study investigates (1) if the Hypomanic Personality Scale [Hyp; Eckblad, M., & Chapman, L.J., (1986). Development and validation of a scale for hypomanic personality. Journal of Abnormal Psychology, 95, 214–222.] correlates with other personality traits and (2) whether the Hyp scales or other measures such as Neuroticism and Extraversion are more strongly associated with affective symptoms. The participants (n=224) completed questionnaires including the Hyp scale, the NEO-FFI, and the CES-D and were independently interviewed with the CIDI to assess depression and mania. The results showed that the Hyp scale correlated only with the NEO-FFI dimensions Extraversion and Openness. In contrast to Extraversion, the Hyp scale was significantly associated with symptoms of depression and mania, and was more strongly related to manic symptoms than Neuroticism was. Decile scores of the Hyp scale were not associated with depressive symptoms, but were associated with manic symptoms. Discussion focuses on the question of whether the Hyp scale represents a possible risk factor for bipolar disorder. The possibility of a “manic defense” against depression is also discussed.

Hypomania : a transcultural perspective

This study examined the transcultural robustness of a screening instrument for hypomania, the Hypomania Checklist-32, first revised version (HCL-32 R1). It was carried out in 2606 patients from twelve countries in five geographic regions (Northern, Southern and Eastern Europe, South America and East Asia). In addition, GAMIAN Europe contributed data from its members. Exploratory and confirmatory factor analyses were used to examine the transregional stability of the measurement properties of the HCL-32 R1, including the influence of sex and age as covariates. Across cultures, a two-factor structure was confirmed: the first factor (F1) reflected the more positive aspects of hypomania (being more active, elated, self-confident, and cogni-tively enhanced); the second factor (F2) reflected the more negative aspects (being irritable, impulsive, careless, more substance use). The measurement properties of the HCL-32 R1 were largely invariant across cultures. Only few items showed transcultural differences in their relation to hypomania as measured by the test. F2 was higher among men and in more severe manic syndromes; F1 was highest in North and East Europe and lowest in South America. The scores decreased slightly with age. The frequency of the 32 items showed remarkable similarities across geographic areas, with two excep-tions: South Europeans had lower symptom frequencies in general and East Europeans higher rates of substance use. These findings support the interna-tional applicability of the HCL-32 R1 as a screening instrument for hypomania.

The misdiagnosis of bipolar disorder as a psychotic disorder: some of its causes and their influence on therapy.

OBJECTIVES Looking at chart records bipolar disorder is often misdiagnosed as a psychotic disorder but no study has ever systematically looked into the reasons. One reason for misdiagnoses could be that clinicians use heuristics like the prototype approach in routine practice instead of strictly adhering to the diagnostic criteria. Using an experimental approach we investigated if the use of heuristics can explain when a diagnosis of psychotic disorder is given instead of bipolar disorder. We systematically varied information about the presence or absence of specific symptoms, i.e. hallucinations and decreased need for sleep during a manic episode. METHODS Experimentally varied case vignettes were randomly sent to psychiatrists in Southern Germany. The four versions of the case vignette all described the same person in a manic state and differed only in two aspects: the presence or absence of auditory hallucinations and of decreased need for sleep. The psychiatrists were asked to make a diagnosis, to rate their confidence in their diagnosis, and to recommend treatments. RESULTS Almost half of the 142 psychiatrists (45%) did not diagnose bipolar disorder. Mentioning hallucinations decreased the likelihood of diagnosing bipolar disorder. The information about decreased need for sleep only affected the diagnosis significantly, if schizoaffective disorder was considered a bipolar disorder. CONCLUSIONS Our results suggest that clinicians indeed use heuristics when making diagnostic decisions instead of strictly adhering to diagnostic criteria. More research is needed to better understand diagnostic decision making, especially under real life settings, and this might also be of interest when revising diagnostic manuals such as DSM.

Cognitive behaviour therapy and supportive therapy for bipolar disorders: relapse rates for treatment period and 2-year follow-up.

BACKGROUND The efficacy of adjunctive psychosocial interventions such as cognitive behaviour therapy (CBT) for bipolar disorder (BD) has been demonstrated in several uncontrolled and controlled studies. However, these studies compared CBT to either a waiting list control group, brief psycho-education or treatment as usual (TAU). Our primary aim was to determine whether CBT is superior to supportive therapy (ST) of equal intensity and frequency in preventing relapse and improving outcome at post-treatment. A secondary aim was to look at predictors of survival time. METHOD We conducted a randomized controlled trial (RCT) at the Department of Psychology, University of Tübingen, Germany (n=76 patients with BD). Both CBT and ST consisted of 20 sessions over 9 months. Patients were followed up for a further 24 months. RESULTS Although changes over time were observed in some variables, they were not differentially associated with CBT or ST. CBT showed a non-significant trend for preventing any affective, specifically depressive episode during the time of therapy. Kaplan-Meier survival analyses revealed that 64.5% of patients experienced a relapse during the 33 months. The number of prior episodes, the number of therapy sessions and the type of BD predicted survival time. CONCLUSIONS No differences in relapse rates between treatment conditions were observed, suggesting that certain shared characteristics (e.g. information, systematic mood monitoring) might explain the effects of psychosocial treatment for BD. Our results also suggest that a higher number of prior episodes, a lower number of therapy sessions and a diagnosis of bipolar II disorder are associated with a shorter time before relapse.

Assessing the dysregulation of the Behavioral Activation System: the Hypomanic Personality Scale and the BIS-BAS scales.

We discuss the Hypomanic Personality Scale (Hyp; Eckblad & Chapman, 1986) and the Behavioral Inhibition System (BIS–BAS; Carver & White, 1994) and Behavioral Activation System (BAS; Gray, 1991) Scales as risk factors for bipolar disorders. The dysregulation of the BAS is considered to be central and results in higher variability in mood. Therefore, we examined how those scales are associated with mood fluctuations. A total of 59 participants completed a diary for at least 17 days. It included a modified Center for Epidemiologic Studies–Depression Scale (Meyer & Hautzinger, 2001) assessing depression and mania and the Positive and Negative Affect Schedule (Watson, Clark, & Tellegen, 1988). Hyp and BAS predicted levels of mania and of positive affect but also fluctuations of mania. Hyp also predicted instability of negative affect. Our data also suggest that mood variability is a trait-like feature. Both scales seem not to be perfect measures of the dysregulation factor. Future research should assess this dysregulation more directly.

Academic performance and expectations for the future in relation to a vulnerability marker for bipolar disorders: the hypomanic temperament

Abstract Several studies show an association between the Hypomanic Personality Scale (Eckblad & Chapman, 1986) and variables that are related to bipolar disorders. Prior research reports that people with such a temperament tend to provide very high estimates of their own future success regardless of their current performance. Therefore we wanted to know if they differ from others in school performance and predictions of future performance. The participants ( n =2562) were students between the age of 14 and 16 years who completed the questionnaire including the Hyp Scale, the CES-D to assess current symptoms of depression, and questions about performance in school and future success. Regression analyses were used to see if the current and expected performance was predicted by the Hyp Scale and current depression symptoms. High scores on the Hyp Scale were not associated with a superior performance in school. The Hyp Scale furthermore was not associated with exaggerating the expected performance in a specific class for the near future. On the other hand, the Hyp Scale was predictive of overly optimistic estimations of the probability of achievements and performances that are heavily delayed in time (e.g. getting the job of their dreams) while the current performance was not. The results are integrated with a more general model of a dysregulation of the Behavioral Activation System, and the limitations of the study are discussed.

New cell models and assays in cardiac safety profiling.

Drug-induced prolongation of the QT interval in the electrocardiogram has been associated with life-threatening ventricular tachycardia of the Torsades de Pointes type. To prevent this risk to patients, all new drug entities must undergo thorough in vitro and preclinical in vivo testing. Because a hERG channel block is the primary reason for ventricular repolarisation, disturbances causing a QT interval prolongation, established in vitro test systems focus on the analysis of drug action on hERG channel function. More sophisticated assays study ventricular repolarisation directly with cardiac tissue preparations. In addition, in the future, novel biological models, such as stem-cell-derived cardiomyocytes and cardiac tissue slices, may allow the design of innovative assay systems to address relevant cardiac safety pharmacology parameters. In this review, established as well as innovative assays and cell models used in these assays are discussed.

Cardiac safety pharmacology: from human ether-a-gogo related gene channel block towards induced pluripotent stem cell based disease models.

Introduction: The field of cardiac safety pharmacology has been experiencing exciting changes over the recent years. Drug induced arrhythmia of the torsade des pointes types has been the reason for the denial of approval of novel drug candidates. The aim of cardiac safety pharmacology is to detect undesirable pharmacodynamic drug effects within and above the therapeutic range. A special focus is on the identification of potential arrhythmogenic effects within the drug discovery chain. Areas covered: Here, the authors discuss the relevance of induced pluripotent stem (iPS) cell derived cardiomyocytes for safety pharmacology. The technology of obtaining functional cardiomyocytes from somatic cells of healthy donors and patients with inherited diseases is the basis for diverse disease models in multi-level safety pharmacology screening. The reader will gain an overview of stem cell based technologies in cardiac safety pharmacology in cardiac and disease modeling by iPS cell derived cardiomyocytes from patients with an inherited cardiac syndrome. Expert opinion: iPS cell derived cardiomyocytes – especially from patients with increased risk of cardiac arrhythmia – are on the verge of offering new options for drug testing. More reliable assays can be expected to predict the arrhythmogenic risk of drug candidates in humans. However, this technology is still new and extensive validation studies are due.