Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). METHODS: The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. ETHICS AND DISSEMINATION: The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.

Drug safety in older patients with alcohol use disorder: a retrospective cohort study.

Background: Older patients with alcohol use disorder are at particular risk of developing adverse drug reactions due to multimorbidity, polypharmacy, and altered organ function. Objectives: In this study, we investigated the frequency and characteristics of potentially serious alcohol-medication interactions, potentially inappropriate medications (PIMs) for older adults, and potential drug-drug interactions (pDDIs) in a population of older patients with alcohol use disorder over a 10-year period. Design: Retrospective monocentric cohort study. Methods: Prescribed medications were screened for potentially serious alcohol-medication interactions, PIMs, and pDDIs using the POSAMINO (POtentially Serious Alcohol-Medication INteractions in Older adults) criteria, the PRISCUS 2.0 list, the FORTA (Fit fOR The Aged) classification, and the drug interaction program AiDKlinik®. Results: We enrolled 114 patients aged ⩾65 years with alcohol use disorder, who were treated in an addiction unit of a university hospital in Germany. About 80.7% of the study population had at least one potentially serious alcohol-medication interaction. Potentially serious alcohol-medication interactions most commonly affected the cardiovascular (57.7%) and the central nervous system (32.3%). A total of 71.1% of the study population received at least one prescription of a FORTA C or D drug, compared with 42.1% who received at least one PIM prescription according to the PRISCUS 2.0 list. A total of 113 moderate and 72 severe pDDIs were identified in the study population. Conclusion: Older patients with alcohol use disorders are frequently exposed to potentially serious alcohol-medication interactions, PIMs, and pDDIs. Improvements in the quality of prescribing should primarily target the use of cardiovascular and psychotropic drugs.

Edema related to treatment with psychotropic drugs.

Edema as an adverse drug reaction is a commonly underestimated yet potentially debilitating condition. This study analyzes the incidence of severe psychotropic drug-induced edema (e.g., edema affecting the face, legs, or multiple body parts and lasting for more than 1 week, or in any case necessitating subsequent diuretic use) among psychiatric inpatients. The cases under examination are derived from an observational pharmacovigilance program conducted in German-speaking countries ("Arzneimittelsicherheit in der Psychiatrie", AMSP) from 1993 to 2016. Among the 462,661 inpatients monitored, severe edema was reported in 231 cases, resulting in an incidence of 0.05%. Edema occurred more frequently in women (80% of all cases) and older patients (mean age 51.8 years). Pregabalin had the highest incidence of severe edema, affecting 1.46‰ of patients treated with pregabalin, followed by mirtazapine (0.8‰). The majority of edema cases showed a positive response to appropriate countermeasures, such as dose reduction and drug discontinuation, and resolved by the end of the observation period. While most instances of drug-induced edema are reversible, they can have a significant impact on patient well-being and potentially result in decreased treatment adherence. It is, therefore, crucial to remain vigilant regarding risk-increasing circumstances during treatment with psychotropic drugs.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation.

INTRODUCTION: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. METHODS: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). RESULTS: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. DISCUSSION: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

The significance of cerebrospinal fluid analysis in the differential diagnosis of 564 psychiatric patients: Multiple sclerosis is more common than autoimmune-encephalitis.

The analysis of cerebrospinal fluid (CSF) is an essential tool for the differential diagnosis of psychiatric disorders caused by autoimmune inflammation or infections. Clear guidelines for CSF analysis are limited and mainly available for schizophrenia and dementia. Thus, insights into CSF changes in psychiatric patients largely derive from research. We analyzed the clinical and CSF data of 564 psychiatric patients without pre-existing neurological diagnoses from March 1998 to April 2020. Primary aim was to detect previously undiagnosed neurological conditions as underlying cause for the psychiatric disorder. Following CSF analysis, 8 % of patients (47/564) were diagnosed with a neurological disorder. This was the case in 12.0 % (23/193) of patients with affective disorders, 7.2 % (19/262) of patients with schizophrenia, and 4.0 % (23/193) of patients with anxiety disorders. The predominant new diagnoses were multiple sclerosis (19/47) and autoimmune encephalitis (10/47). Abnormal CSF findings without any implications for further treatment were detected in 17.0 % (94/564) of patients. Our data indicates that CSF analysis in patients suffering from psychiatric disorders may uncover underlying organic causes, most commonly multiple sclerosis and autoimmune encephalitis. Our findings imply that the incorporation of CSF analysis in routine psychiatric assessments is potentially beneficial.

Clinical and sociodemographic predictors of inpatient admission after presentation in a psychiatric emergency room: an observational study.

BACKGROUND: The admission decision after presentation in the psychiatric emergency room (PER) has potentially far-reaching consequences for the patient and the community. In a short amount of time, information must be collected and evaluated for a well-founded admission decision. The present study aimed to identify risk factors associated with inpatient psychiatric admission (IPA) after previous emergency presentation to the PER. METHODS: Electronic patient records for all patients presenting in the PER of Hannover Medical School (MHH) in the year 2022 were retrospectively examined (n = 2580). Out of these, 2387 were included in this study. Two multivariate binary logistic regression analyses were performed to identify risk factors for IPA within sociodemographic, circumstantial and clinical variables. RESULTS: 1300 (54.5%) consultations resulted in IPA. The most significant sociodemographic and circumstantial risk factors for IPA were found to be suicide attempt (depending on method: OR 9.1-17.4), aggressive behavior towards people prior to presentation (OR 2.9, 95% CI 1.7-4.8), previous psychiatric treatment (OR 1.8, 95% CI 1.4-2.3) and transfer from another hospital or medical discipline of MHH as means of presentation (OR 6.3, 95% CI 3.0-13.0). Among psychopathological aspects, suicidal ideation (OR 3.8, 95% CI 2.9-4.9), suicidal intent (OR 116.0, 95% CI 15.9-844.8), disturbance of orientation (OR 3.7, 95% CI 2.5-5.3), delusions (OR 2.3, 95% CI 1.6-3.1), visual hallucinations (OR 2.9, 95% CI 1.6-5.1), hopelessness/despair (OR 2.4, 95% CI 1.7-3.2) and inhibition of drive (OR 1.6, 95% CI 1.3-2.1) were significantly associated with IPA. CONCLUSIONS: The admission decision is a complex process influenced by a multitude of sociodemographic, circumstantial and clinical factors. A deeper understanding of the decision-making process can be used to improve patient care and facilitate the evaluation process in the PER.

A targeted long-read sequencing approach questions the association of OXTR methylation with high-functioning autism.

BACKGROUND: DNA sequence variation and altered epigenetic regulation of the oxytocin receptor gene (OXTR) have been implicated in autism and autistic-like behaviors. While previous studies have examined subsegments of OXTR, nanopore Cas9-targeted sequencing (nCATS) allows deep characterization of entire genes with simultaneous assessment of epigenetic 5-methylcytosine (5mC) modification and without the need for prior DNA amplification or bisulfite conversion. This pilot study uses an nCATS approach to sequence the entire OXTR gene and its regulatory construct and screen for 5mC modification to compare results between individuals with high-functioning autism (HFA) and neurotypical controls (NC). METHODS: Using DNA extracted from peripheral blood, OXTR (Hg38, chr3: 8750381-8770434, 20,054 base pairs) was analyzed by nCATS. 5mC modification probabilities were calculated and visualized across the gene and differential methylation analysis was performed. RESULTS: Twenty adults with HFA (10 males, 10 females) and 20 age- and sex-matched NC (± 5 years) were included. There were no apparent group differences in the entire OXTR gene sequence, except for the intron variant rs918316, which was clustered in the HFA group. However, differential methylation analysis did not reveal a single significant group-dependent differentially methylated site among the 412 CpG sites captured. LIMITATIONS: Limitations of this study include the small number of samples due to the pilot nature of the study, which particularly limits the relevance of the sequence variants found. It should also be noted that the use of peripheral blood material limits the ability to draw conclusions about central processes. CONCLUSIONS: Previous findings of autism-associated OXTR epigenetic alterations were not reproducible with our method. In our opinion, this may lead to a reconsideration of the relevance of altered methylation at individual OXTR CpG positions in autism research. However, given the pilot nature of the study, these results need to be replicated in independent cohorts and with larger sample sizes.

The effect of multisensory semantic congruency on unisensory object recognition in schizophrenia.

Multisensory, as opposed to unisensory processing of stimuli, has been found to enhance the performance (e.g., reaction time, accuracy, and discrimination) of healthy individuals across various tasks. However, this enhancement is not as pronounced in patients with schizophrenia (SZ), indicating impaired multisensory integration (MSI) in these individuals. To the best of our knowledge, no study has yet investigated the impact of MSI deficits in the context of working memory, a domain highly reliant on multisensory processing and substantially impaired in schizophrenia. To address this research gap, we employed two adopted versions of the continuous object recognition task to investigate the effect of single-trail multisensory encoding on subsequent object recognition in 21 schizophrenia patients and 21 healthy controls (HC). Participants were tasked with discriminating between initial and repeated presentations. For the initial presentations, half of the stimuli were audiovisual pairings, while the other half were presented unimodal. The task-relevant stimuli were then presented a second time in a unisensory manner (either auditory stimuli in the auditory task or visual stimuli in the visual task). To explore the impact of semantic context on multisensory encoding, half of the audiovisual pairings were selected to be semantically congruent, while the remaining pairs were not semantically related to each other. Consistent with prior studies, our findings demonstrated that the impact of single-trial multisensory presentation during encoding remains discernible during subsequent object recognition. This influence could be distinguished based on the semantic congruity between the auditory and visual stimuli presented during the encoding. This effect was more robust in the auditory task. In the auditory task, when congruent multisensory pairings were encoded, both participant groups demonstrated a multisensory facilitation effect. This effect resulted in improved accuracy and RT performance. Regarding incongruent audiovisual encoding, as expected, HC did not demonstrate an evident multisensory facilitation effect on memory performance. In contrast, SZs exhibited an atypically accelerated reaction time during the subsequent auditory object recognition. Based on the predictive coding model we propose that this observed deviations indicate a reduced semantic modulatory effect and anomalous predictive errors signaling, particularly in the context of conflicting cross-modal sensory inputs in SZ.

Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data.

BACKGROUND: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). METHODS: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. RESULTS: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. CONCLUSIONS: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives.

Cognitive control in adults with high-functioning autism spectrum disorder: a study with event-related potentials.

Introduction: Little is known about cognitive control in adults with high-functioning forms of autism spectrum disorder because previous research focused on children and adolescents. Cognitive control is crucial to monitor and readjust behavior after errors to select contextually appropriate reactions. The congruency effect and conflict adaptation are measures of cognitive control. Post-error slowing, error-related negativity and error positivity provide insight into behavioral and electrophysiological correlates of error processing. In children and adolescent with autism spectrum disorder deficits in cognitive control and error processing have been shown by changes in post-error slowing, error-related negativity and error positivity in the flanker task. Methods: We performed a modified Eriksen flanker task in 17 adults with high-functioning autism spectrum disorder and 17 healthy controls. As behavioral measures of cognitive control and error processing, we included reaction times and error rates to calculate congruency effects, conflict adaptation, and post-error slowing. Event-related potentials namely error-related negativity and error positivity were measured to assess error-related brain activity. Results: Both groups of participants showed the expected congruency effects demonstrated by faster and more accurate responses in congruent compared to incongruent trials. Healthy controls exhibited conflict adaptation as they obtained performance benefits after incongruent trials whereas patients with autism spectrum disorder did not. The expected slowing in reaction times after errors was observed in both groups of participants. Individuals with autism spectrum disorder demonstrated enhanced electrophysiological error-processing compared to healthy controls indicated by increased error-related negativity and error positivity difference amplitudes. Discussion: Our findings show that adults with high-functioning autism spectrum disorder do not show the expected upregulation of cognitive control in response to conflicts. This finding implies that previous experiences may have a reduced influence on current behavior in these patients which possibly contributes to less flexible behavior. Nevertheless, we observed intact behavioral reactions after errors indicating that adults with high-functioning autism spectrum disorder can flexibly adjust behavior in response to changed environmental demands when necessary. The enhancement of electrophysiological error-processing indicates that adults with high-functioning autism spectrum disorder demonstrate an extraordinary reactivity toward errors reflecting increased performance monitoring in this subpopulation of autism spectrum disorder patients.

Psychometric properties of the German Penn Alcohol Craving Scale.

Craving for alcohol is an important diagnostic criterion in alcohol use disorder (AUD) and an established predictor of future relapse. The 5-item Penn Alcohol Craving Scale (PACS) is one of the most widely used questionnaires to quantify craving and has been translated into different languages. It is assumed that the PACS constitutes one factor, although theoretical considerations suggest an additional second factor. We conducted stability and factor analyses (principal component and confirmatory factor analyses) of the German PACS (PACS-G) in samples of patients with AUD from the following three German study sites: Erlangen, N = 188 (mean age: 47.1 years, 43.5% female); Mannheim, N = 440 (45.5 years, 28.6% female); Hannover, N = 107 (48.1 years, 48.6% female). In our samples, the 2-factor solution of the PACS-G version is more stable than the internationally assumed 1-factor solution. The resulting two PACS-G subscores 'difficulty to resist' (items 4 and 5) and 'thoughts about alcohol' (items 1, 2, and 3) have an internal consistency (Cronbach's alpha) of 0.80 ≤ α ≤ 0.90, m = 0.86 and 0.86 ≤ α ≤ 0.91, m = 0.89 with an overlap of R2 = 62%. We found good convergent validity assessed via the Craving Automatized Scale-Alcohol and the Obsessive-Compulsive Drinking Scale, but also correlations with depression and anxiety assessed via the Beck's Depression and Anxiety Inventories. This study is the first to provide evidence for a 2-factor solution ('difficulty to resist' and 'thoughts about alcohol') underlying the PACS-G version.

Alzheimer's disease biomarkers in cerebrospinal fluid are stable with the Elecsys immunoassay to most pre-analytical influencing factors except freezing at -80 °C.

BACKGROUND: Alzheimer´s disease is considered a neurodegenerative disease and is diagnosed by exclusion, while the detection of specific cerebrospinal fluid (CSF) biomarkers, namely amyloid-beta (Aß) peptides Aß1-42 (Aß42), phospho-tau (181P; P-tau), and total-tau (T-tau), has been shown to improve diagnostic accuracy. Recently, a new generation of sample tubes (Sarstedt false-bottom tubes) for the Elecsys CSF immunoassay for the determination of Alzheimer´s disease biomarkers in CSF was introduced, promising better measurability. However, the pre-analytic influencing factors have not yet been sufficiently investigated. METHODS: In 29 patients without Alzheimer's disease diagnosis, CSF concentrations of Aß42, P-tau and T-tau were examined in native CSF and after different influencing interventions using the Elecsys immunoassay test method. The following influencing factors were analyzed: contamination with blood (10,000 and 20,000 erythrocytes/µl CSF), 14-day storage at 4 °C, blood contamination of CSF and 14-day storage at 4 °C, 14-day freezing at -80 °C in Sarstedt tubes or glass vials, 3-month intermediate storage at -80 °C in glass vials. RESULTS: Both storage at -80 °C for 14 days in Sarstedt false-bottom tubes and in glass vials and storage at -80 °C for 3 months in glass vials resulted in significant decreases in Aß42 (13% after 14 days in Sarstedt and 22% in glass vials, 42% after 3 months in glass vials), P-tau (9% after 14 days in Sarstedt and 13% in glass vials, 12% after 3 months in glass vials) and T-tau (12% after 14 days in Sarstedt and 19% in glass vials, 20% after 3 months in glass vials) concentrations in CSF. No significant differences were found for the other pre-analytical influencing factors. CONCLUSIONS: Measurements of the concentrations of Aß42, P-tau, and T-tau in CSF with use of the Elecsys immunoassay are robust to the pre-analytical influencing factors of blood contamination and duration of storage. Freezing at -80 °C results in significant reduction of biomarker concentrations regardless of the storage tube and must be considered in retrospective analysis.

[Understanding and assessing the antidepressant drug-associated risk of bleeding]. / Das Blutungsrisiko unter Antidepressiva verstehen und einschätzen.

Antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are the most commonly prescribed psychopharmacological drug group. Thus, a precise knowledge of the expected adverse drug reactions is indispensable. The increased risk of bleeding events is well documented, especially in patients treated with SSRIs. However, many other antidepressant drug groups have also been implicated in increasing the risk of bleeding. In the following review, the thrombocytic serotonin system and the respective targets of the different antidepressants are explained. Subsequently, the available literature on bleeding under the respective antidepressant classes or individual substances is presented, using data from meta-analyses whenever possible. In addition to the risk of bleeding in general, individual bleeding entities are also considered, such as gastrointestinal and cerebral hemorrhages. Finally, the effects of other drugs that increase the risk of bleeding (i. e., nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors and anticoagulants) in combination with antidepressant drugs are discussed. The information presented here is meant to guide practitioner's decision making regarding an appropriate antidepressant pharmacotherapy based on the patient's individual risk constellation.

Deficient Audiovisual Speech Perception in Schizophrenia: An ERP Study.

In everyday verbal communication, auditory speech perception is often disturbed by background noise. Especially in disadvantageous hearing conditions, additional visual articulatory information (e.g., lip movement) can positively contribute to speech comprehension. Patients with schizophrenia (SZs) demonstrate an aberrant ability to integrate visual and auditory sensory input during speech perception. Current findings about underlying neural mechanisms of this deficit are inconsistent. Particularly and despite the importance of early sensory processing in speech perception, very few studies have addressed these processes in SZs. Thus, in the present study, we examined 20 adult subjects with SZ and 21 healthy controls (HCs) while presenting audiovisual spoken words (disyllabic nouns) either superimposed by white noise (-12 dB signal-to-noise ratio) or not. In addition to behavioral data, event-related brain potentials (ERPs) were recorded. Our results demonstrate reduced speech comprehension for SZs compared to HCs under noisy conditions. Moreover, we found altered N1 amplitudes in SZ during speech perception, while P2 amplitudes and the N1-P2 complex were similar to HCs, indicating that there may be disturbances in multimodal speech perception at an early stage of processing, which may be due to deficits in auditory speech perception. Moreover, a positive relationship between fronto-central N1 amplitudes and the positive subscale of the Positive and Negative Syndrome Scale (PANSS) has been observed.

Generation of an induced pluripotent stem cell line, ZIPi021-A, from fibroblasts of a Prader-Willi syndrome patient with maternal uniparental disomy (mUPD).

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of paternal expression of imprinted genes on chromosome 15q11-q13. We established a human induced pluripotent stem cell line (hiPSC), ZIPi021-A, from fibroblasts of a 4-year-old female PWS patient with the subtype of maternal uniparental disomy (mUPD). The generated hiPSC line was transgene-free, expressed pluripotency markers and showed the ability to differentiate into all three germ layers in vitro. The ZIPi021-A hiPSC line could be used as a cellular model for PWS in humans.

Hypomethylation of the dopamine transporter (DAT) gene promoter is associated with hyperphagia-related behavior in Prader-Willi syndrome: A case-control study.

Prader-Willi syndrome (PWS), a neurodevelopmental disorder based on the loss of paternally derived but maternally imprinted genes on chromosome 15q11-13, is typically associated with hyperphagia-related behavior leading to massive obesity. Recently, there has been increasing evidence for dysregulated expression patterns of genes outside the PWS locus that influence the behavioral phenotype and for alterations in the dopaminergic system associated with weight regulation in PWS. In this study, we investigated the epigenetic regulation of the promoter regions of the dopamine transporter (DAT) and dopamine receptor D2 (DRD2) genes and their association with hyperphagia-related behavior in PWS. Methylation of the DAT and DRD2 promoter regions was examined by DNA bisulfite sequencing in 32 individuals with PWS and compared with a control group matched for sex, age, and body mass index (BMI). Hyperphagia-related behavior was assessed using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Analysis by linear mixed models revealed a significant effect of factor group on mean DAT promoter methylation rate with decreased mean methylation in PWS (7.3 ± 0.4%) compared to controls (18.8 ± 0.6%), p < 0.001. In the PWS group, we further identified effects of HQ-CT score and BMI on DAT promoter methylation. Although also statistically significantly different (8.4 ± 0.2 in PWS, 10.5 ± 0.3 in controls, p < 0.001), DRD2 promoter methylation visually appeared to be evenly distributed between groups, raising concerns regarding a biological effect. Here, we provide evidence for altered epigenetic regulation of the DAT gene in PWS, which is associated with PWS-typical hyperphagia-related behaviors.

Characteristics of clinical-pharmacological recommendations in psychiatry.

OBJECTIVE: Psychiatric patients in general, and elderly psychiatric patients in particular, are at risk of adverse drug reactions due to comorbidities and inappropriate polypharmacy. Interdisciplinary and clinical-pharmacologist-led medication reviews may contribute to medication safety in the field of psychiatry. In this study, we reported the frequency and characteristics of clinical-pharmacological recommendations in psychiatry, with a particular focus on geriatric psychiatry. METHOD: A clinical pharmacologist, in collaboration with the attending psychiatrists and a consulting neurologist, conducted interdisciplinary medication reviews in a general psychiatric ward with a geropsychiatric focus at a university hospital over a 25-week period. All clinical and pharmacological recommendations were recorded and evaluated. RESULTS: A total of 316 recommendations were made during 374 medication reviews. Indications/contraindications of drugs were the most frequently discussed topics (59/316; 18.7 %), followed by dose reductions (37/316; 11.7 %), and temporary or permanent discontinuation of medications (36/316; 11.4 %). The most frequent recommendations for dose reduction involvedbenzodiazepines (9/37; 24.3 %). An unclear or absent indication was the most common reason for recommending temporary or permanent discontinuation of the medication (6/36; 16.7 %). CONCLUSION: Interdisciplinary clinical pharmacologist-led medication reviews represented a valuable contribution to medication management in psychiatric patients, particularly the elderly ones.

Bifrontal electroconvulsive therapy leads to improvement of cerebral glucose hypometabolism in frontotemporal dementia with comorbid psychotic depression - a case report.

BACKGROUND: Differentiating depression and dementia in elderly patients represents a major clinical challenge for psychiatrists. Pharmacological and non-pharmacological treatment options for both conditions are often used cautiously due to fear of adverse effects. If a clinically indicated therapy is not initiated due to fear of adverse effects, the quality of life of affected patients may significantly be reduced. CASE PRESENTATION: Here, we describe the case of a 65-year-old woman who presented to the department of psychiatry of a university hospital with depressed mood, pronounced anxiety, and nihilistic thoughts. While several pharmacological treatments remained without clinical response, further behavioral observation in conjunction with 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed the diagnosis of frontotemporal dementia (FTD). To counter the pharmacological treatment resistance of psychotic depression, we decided to perform electroconvulsive therapy (ECT). Remarkably, ten sessions of ECT yielded an almost complete remission of depressive symptoms. In addition, the patient's delusional ideas disappeared. A follow-up 18F-FDG PET/CT after the ECT series still showed a frontally and parieto-temporally accentuated hypometabolism, albeit with a clear regression compared to the previous image. The follow-up 18F-FDG PET/CT thus corroborated the diagnosis of FTD, while on the other hand it demonstrated the success of ECT. CONCLUSIONS: In this case, ECT was a beneficial treatment option for depressive symptoms in FTD. Also, 18F-FDG PET/CT should be discussed as a valuable tool in differentiating depression and dementia and as an indicator of treatment response.

Determinants of severe QTc prolongation in a real-world gerontopsychiatric setting.

Introduction: QTc prolongation carries the risk of ventricular tachyarrhythmia (Torsades de Pointes) and sudden cardiac death. Psychotropic drugs can affect ventricular repolarization and thus prolong the QTc interval. The present study sought to investigate the risk factors (pharmacological and non-pharmacological) of severe QTc prolongation in gerontopsychiatric patients. Methods: Electrocardiograms of patients on a gerontopsychiatric ward were screened for QTc prolongation. Medication lists were examined utilizing the AzCERT classification. Potential drug interactions were identified with the electronic drug interaction program mediQ. Results: The overall prevalence of QTc prolongation was 13.6%, with 1.9% displaying severe QTc prolongation (≥ 500 ms). No statistically significant differences between patients with moderate and severe QTc prolongation were identified; however, patients with severe QTc prolongation tended to take more drugs (p = 0.063). 92.7% of patients with QTc prolongation took at least one AzCERT-listed drug, most frequently risperidone and pantoprazole. Risperidone and pantoprazole, along with pipamperone, were also most frequently involved in potential drug interactions. All patients displayed additional risk factors for QTc prolongation, particularly cardiac diseases. Conclusion: In addition to the use of potentially QTc-prolonging drugs, other risk factors, especially cardiac diseases, appear to be relevant for the development of QTc prolongation in gerontopsychiatric patients. Pantoprazole was frequently involved in potential drug interactions and should generally not be used for more than 8 weeks in geriatric populations. As clinical consequences of QTc prolongation were rare, potentially QTc-prolonging drugs should not be used overcautiously; their therapeutic benefit should be considered as well. It is paramount to perform diligent benefit-risk analyses prior to the initiation of potentially QTc-prolonging drugs and to closely monitor their clinical (side) effects.

DNA Methylation of POMC and NR3C1-1F and Its Implication in Major Depressive Disorder and Electroconvulsive Therapy.

INTRODUCTION: Precision medicine in psychiatry is still in its infancy. To establish patient-tailored treatment, adequate indicators predicting treatment response are required. Electroconvulsive therapy (ECT) is considered one of the most effective options for pharmacoresistant major depressive disorder (MDD), yet remission rates were reported to be below 50%. METHODS: Since epigenetics of the stress response system seem to play a role in MDD, we analyzed the DNA methylation (DNAm) of genes encoding the glucocorticoid receptor (NR3C1) and proopiomelanocortin (POMC) through Sanger Sequencing. For analysis, blood was taken before and after the first and last ECT from MDD patients (n=31), unmedicated depressed controls (UDC; n=19, baseline), and healthy controls (HC; n=20, baseline). RESULTS: Baseline DNAm in NR3C1 was significantly lower in UDCs compared to both other groups (UDC: 0.014(±0.002), ECT: 0.031(±0.001), HC: 0.024(±0.002); p<0.001), whereas regarding POMC, ECT patients had the highest DNAm levels (ECT: 0.252(±0.013), UDC: 0.156(±0.015), HC: 0.162(±0.014); p<0.001). NR3C1m and POMCm decreased after the first ECT (NR3C1: p<0.001; POMC: p=0.001), and responders were less methylated compared to non-responders in NR3C1(p<0.001). DISCUSSION: Our findings indicate that both genes might play a role in the chronification of depression and NR3C1 may be relevant for ECT response prediction.