Pharmacogenetic guided drug therapy - how to deal with phenoconversion in polypharmacy.

Introduction: The prevalence of polypharmacy and the increasing availability of pharmacogenetic information in clinical practice have raised the prospect of data-driven clinical decision-making when addressing the issues of drug-drug interactions and genetic polymorphisms in metabolizing enzymes. Inhibition of metabolizing enzymes in drug interactions can lead to genotype-phenotype discrepancies (phenoconversion) that reduce the relevance of individual pharmacogenetic information.

Areas Covered: The aim of this review is to provide an overview of existing models of phenoconversion, and we discuss how phenoconversion models may be developed to estimate joint drug-interactions and genetic effects.

Dealing with adverse drug reactions in the context of polypharmacy using regression models.

Polypharmacy in older adults increases the risk of adverse drug reactions (ADRs), but studying this relationship is complex. In real-world data, the high number of medications, coupled with rare drug combinations, results in high-dimensional datasets that are difficult to analyze using conventional statistical methods. This study applies horseshoe and lasso regression for analyzing rare events in polypharmacy contexts, focusing on severe ADRs such as falls and bleedings.

Cognitions in antisocial personality and their association with "dark" traits.

Unlike the cognitions associated with depressive symptoms, little is known about those associated with antisocial personality and with its related traits ("dark traits"). Using the scrambled sentences task, an instrument from depression research, we investigated cognitions such as justifications (external blaming for one's behavior) and harm to others (based on the notion that some of these individuals enjoy harming or humiliating others) that we hypothesized may be prevalent in those high in antisocial personality traits. Confirming our hypothesis, these cognitions were associated with ratings on different antisocial personality scales and with antisocial and detachment scores in the alternative model of personality disorders of the DSM-5 (AMPD) in three non-clinical samples, but not with depressive symptoms or neuroticism.

When alienated from society, conspiracy theory belief gives meaning to life.

Background: Conspiracy theory belief - explaining the ultimate causes of social and political events with claims of secret conspiracies - is assumed to arise from a desire to make sense of uncertainty, especially in times of crisis. However, there is no compelling evidence that conspiracy theory belief actually fulfils this function, particularly in terms of evaluating one's life as meaningful. We posit that the adoption of conspiracy theory belief can be explained as a when a more proximal source of meaning, a sense of belonging to society, is threatened.

The fMRI global signal and its association with the signal from cranial bone.

The nature of the global signal, i.e. the average signal from sequential functional imaging scans of the brain or the cortex, is not well understood, but is thought to include vascular and neural components.

The dark side of personality functioning: associations between antisocial cognitions, personality functioning (AMPD), empathy and mentalisation.

Introduction: With the introduction of the new psychiatric diagnostic manuals, personality functioning has gained new prominence. Several studies have reported consistent findings that individual showing high levels of antisocial features are associated with alterations in interpersonal functioning domains such as empathy and mentalisation. The focus of the current study ( = 198) is to examine antisocial cognitions, as measured by the Scrambled Sentences Task (SST), and to what extent this approach can help to better understand the relationship between antisocial traits and personality functioning/empathy.

Phenotypic Models of Drug-Drug-Gene Interactions Mediated by Cytochrome Drug-Metabolizing Enzymes.

Genetic polymorphisms in drug metabolizing enzymes and drug-drug interactions are major sources of inadequate drug exposure and ensuing adverse effects or insufficient responses. The current challenge in assessing drug-drug gene interactions (DDGIs) for the development of precise dose adjustment recommendation systems is to take into account both simultaneously. Here, we analyze the static models of DDGI from in vivo data and focus on the concept of phenoconversion to model inhibition and genetic polymorphisms jointly.

Novel Insight into Pickering Emulsion and Colloidal Particle Network Construction of Basil Extract for Enhancing Antioxidant and UV-B-Induced Antiaging Activities.

We developed a facile preparation method of oil-in-water (O/W) Pickering emulsion in an emollient formulation using basil extract ( L.) as a solid particle stabilizer by fine-tuning the concentration and mixing steps of common cosmetic formulas, such as humectants (hexylene glycol and glycerol), surfactant (Tween 20), and moisturizer (urea). The hydrophobicity of the main phenolic compounds of basil extract (BE), namely, salvigenin, eupatorin, rosmarinic acid, and lariciresinol, supported high interfacial coverage to prevent coalescence of globules.

Pharmacogenetic Dose Modeling Based on CYP2C19 Allelic Phenotypes.

Pharmacogenetic variability in drug metabolism leads to patient vulnerability to side effects and to therapeutic failure. Our purpose was to introduce a systematic statistical methodology to estimate quantitative dose adjustments based on pharmacokinetic differences in pharmacogenetic subgroups, addressing the concerns of sparse data, incomplete information on phenotypic groups, and heterogeneity of study design. Data on psychotropic drugs metabolized by the cytochrome P450 enzyme CYP2C19 were used as a case study.

The gradient model of brain organization in decisions involving "empathy for pain".

Influential models of cortical organization propose a close relationship between heteromodal association areas and highly connected hubs in the default mode network. The "gradient model" of cortical organization proposes a close relationship between these areas and highly connected hubs in the default mode network, a set of cortical areas deactivated by demanding tasks. Here, we used a decision-making task and representational similarity analysis with classic "empathy for pain" stimuli to probe the relationship between high-level representations of imminent pain in others and these areas.

The interplay of Criterion A of the Alternative Model for Personality Disorders, mentalization and resilience during the COVID-19 pandemic.

Background And Aims: The COVID-19 pandemic has been accompanied by a worsening of mental health levels in some, while others manage to adapt or recover relatively quickly. Transdiagnostic factors such as personality functioning are thought to be involved in determining mental health outcomes. The present study focused on two constructs of personality functioning, Criterion A of the Alternative Model for Personality Disorders (AMPD, DSM-5) and mentalization, as predictors of depressive symptoms and life satisfaction during the COVID-19 pandemic.

A Short Functional Neuroimaging Assay Using Attachment Scenes to Recruit Neural Correlates of Social Cognition-A Replication Study.

Attachment theory provides a conceptual framework to understand the impact of early child-caregiver experiences, such as loss or separation, on adult functioning and psychopathology. In the current study, scenes from the Adult Attachment Projective Picture System (AAP), a validated, commonly used standardized diagnostic instrument to assess adult attachment representations, were used to develop a short fMRI assay eliciting the neural correlates of encoding of potentially hurtful and threatening social situations such as social losses, rejections or loneliness. Data from healthy participants (N = 19) showed activations in brain areas associated with social cognition and semantic knowledge during exposure to attachment-related scenes compared to control scenes.

Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain.

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids.

Effort-Reward-Imbalance, Burnout, and Depression Among Psychiatrists 2006 and 2016-Changes After a Legislative Intervention.

Physicians, especially psychiatrists, have a high risk of job-related stress, and mental impairment. In our study we examined changes in private and occupational stress factors and mental health within a decade. The legislative reduction of physicians' working hours in Germany during this period made it possible to investigate the impact of working hours in particular.

Neurobiological models of emotion regulation: a meta-analysis of neuroimaging studies of acceptance as an emotion regulation strategy.

Emotional acceptance is an important emotion regulation strategy promoted by most psychotherapy approaches. We adopted the Activation Likelihood Estimation technique to obtain a quantitative summary of previous fMRI (functional Magnetic Resonance Imaging) studies of acceptance and test different hypotheses on its mechanisms of action. The main meta-analysis included 13 experiments contrasting acceptance to control conditions, yielding a total of 422 subjects and 170 foci of brain activity.

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity.

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied.

Segregation, connectivity, and gradients of deactivation in neural correlates of evidence in social decision making.

Functional imaging studies of sensory decision making have detected a signal associated with evidence for decisions that is consistent with data from single-cell recordings in laboratory animals. However, the generality of this finding and its implications on our understanding of the organization of the fMRI signal are not clear. In the present functional imaging study, we investigated decisions in an elementary social cognition domain to identify the neural correlates of evidence, their segregation, connectivity, and their relationship to task deactivations.

Altered subcortical emotional salience processing differentiates Parkinson's patients with and without psychotic symptoms.

Objective: Current research does not provide a clear explanation for why some patients with Parkinson's Disease (PD) develop psychotic symptoms. The 'aberrant salience hypothesis' of psychosis has been influential and proposes that dopaminergic dysregulation leads to inappropriate attribution of salience to irrelevant/non-informative stimuli, facilitating the formation of hallucinations and delusions. The aim of this study is to investigate whether non-motivational salience is altered in PD patients and possibly linked to the development of psychotic symptoms.

Signals of anticipation of reward and of mean reward rates in the human brain.

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors.

Interferon-beta-induced changes in neuroimaging phenotypes of appetitive motivation and reactivity to emotional salience.

Treatment with interferon (IFN) has been associated with depressive side effects. Previous neuroimaging studies have provided information about changes in brain activation patterns in patients under treatment with IFN-alpha, but the effect of other IFNs, or the role of the underlying disease, has yet to be clarified. In the present fMRI study, we looked at brain changes after 8 days of IFN-beta treatment in N = =17 healthy volunteers, thus avoiding the possible confound of the effects of underlying pathology in studies of IFN-treated patients with neurological or other medical disorders.

Mirror neuron activations in encoding of psychic pain in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by pronounced emotional instability in interpersonal relations. Previous studies have shown increased activity in the amygdala, an imaging phenotype of negative affect. However, clinical accounts of BPD have drawn attention to deficits in social cognition and their likely role in engendering emotional instability.

Adaptation of the Scrambled-Sentences Task to Assess "Shattered Assumptions:" Construction of the Test and Investigation of Neural Substrates in an fMRI Study.

Background: Increasing recognition is being given to the importance of cognitions observed in posttraumatic conditions. These cognitions may reflect the activation of negative schemas. The aim of this work was to evaluate the feasibility of the scrambled-sentences task (SST) to assess individual differences in attributions commonly observed after traumas.

Repeated fMRI in measuring the activation of the amygdala without habituation when viewing faces displaying negative emotions.

Functional imaging studies of affective disorders have demonstrated abnormal activity in the amygdala in response to emotionally salient stimuli. Since in other studies this response has been shown to habituate during the scanning session, it is not clear if it may be of use in monitoring disease progression or remission, or in monitoring the effects of therapy, as habituation may confound normalisation of response. We investigated here amygdala activation in healthy participants exposed to displays of emotional facial expressions in a sample of N = 31 individuals assessed twice in an interval of three weeks.

Accelerated 3D-GRASE imaging improves quantitative multiple post labeling delay arterial spin labeling.

Purpose: To investigate the impact of accelerated, single-shot 3D-GRASE acquisition on quantitative arterial spin labeling (ASL) with multiple and single post-labeling delay (PLD) in terms of perfusion-weighted SNR per unit scan time (TSNR ) and quantification accuracy.

Methods: Five subjects were scanned on a 3T MRI scanner using the pseudo-continuous arterial spin labeling (PCASL) technique with a 3D-GRASE imaging sequence capable of parallel imaging acceleration. A 3-inversion pulse background suppression was simulated and implemented in the sequence.