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.

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.

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.

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.

Drug Safety Profiles of Geriatric Patients Referred to Consultation Psychiatry in the Emergency Department-A Retrospective Cohort Study.

OBJECTIVE: Geriatric patients account for a significant proportion of the collective treated by psychiatric consultation service in hospitals. In the Emergency Department (ED), psychotropic drugs are frequently recommended, notwithstanding their extensive side-effect profiles. This study sought to investigate medication safety of geriatric patients referred to psychiatric consultation service in the ED. METHODS: Medication lists of 60 patients from the general internal medicine and trauma surgery EDs referred to psychiatric consultation service were analyzed. Utilizing PRISCUS list and Fit fOR The Aged (FORTA) classification, prescriptions of potentially inappropriate medications (PIMs) were assessed. RESULTS: 84 drugs were newly prescribed following psychiatric consultations. The total number of drugs per patient was 5.4 ± 4.2 before psychiatric consultation and 6.5 ± 4.2 thereafter (p < .001). 22.6 % of the newly recommended drugs were PIMs according to the PRISCUS list, while 54.8 % were designated as therapeutic alternatives to PIMs. 54.8 % and 20.2 % of the newly recommended drugs were FORTA category C and D drugs, respectively. An average of 1.2 ± 1.7 drug-drug interactions (DDIs) existed before psychiatric consultation and 1.3 ± 1.9 DDIs thereafter (p = .08). CONCLUSION: The majority of newly recommended drugs by psychiatric consultation service in the ED were designated as suitable therapeutic alternatives to PIMs according to the PRISCUS list, but had comparatively unfavorable ratings according to the FORTA classification, demonstrating discrepancies between these two PIM classification systems. Physicians delivering psychiatric consultation services in the ED should not solely rely on one PIM classification system.

Potentially inappropriate prescriptions of antibiotics in geriatric psychiatry-a retrospective cohort study.

Introduction: Older patients are frequently affected by infectious diseases and adverse drug reactions (ADRs) of consecutively prescribed antibiotics. Particularly within geriatric psychiatry, high rates of potentially inappropriate prescriptions (PIPs) have been described, significantly complicating pharmacological treatment. Therefore, this study aimed to investigate the frequency and characteristics of antibiotic PIPs in geriatric psychiatry. Methods: Medication charts of 139 patient cases (mean age 78.8 years; 69.8% female) receiving antibiotic treatment on a geriatric psychiatric ward were analyzed. Utilizing previously published definitions of antibiotic PIPs, adequacy of the antibiotic prescriptions was subsequently assessed. Results: 16.3% of all screened patient cases (139/851) received an antibiotic treatment during their inpatient stay. 59.5% of antibiotic prescriptions were due to urinary tract infections, followed by pulmonary (13.3%) and skin and soft tissue infections (11.3%). 46.7% of all antibiotic prescriptions fulfilled at least one PIP criterium, with the prescription of an antibiotic course for more than seven days as the most common PIP (15.3%). Discussion: Antibiotic PIPs can be considered as a frequent phenomenon in geriatric psychiatry. Especially the use of fluoroquinolones and cephalosporins should be discussed critically due to their extensive side effect profiles. Due to the special characteristics of geriatric psychiatric patients, international guidelines on the use of antibiotics should consider frailty and psychotropic polypharmacy of this patient population more closely.

White Blood Cell and Platelet Counts Are Not Suitable as Biomarkers in the Differential Diagnostics of Dementia.

Apart from Alzheimer's disease (AD), no biomarkers for the differential diagnosis of dementia have been established to date. Inflammatory processes contribute to the pathogenesis of dementia subtypes, e.g., AD or frontotemporal dementia (FTD). In the context of cancer or cardiovascular diseases, white blood cell (WBC) populations and platelet counts, as well as C-reactive protein (CRP), have emerged as biomarkers. Their clinical relevance in dementia, however, is currently only insufficiently investigated. In the present study, hematological and inflammatory parameters were measured in the peripheral blood of 97 patients admitted to the gerontopsychiatric ward of Hannover Medical School, a university hospital in Germany, for dementia assessment. The study population comprised 20 non-demented, depressed patients (control group) and 77 demented patients who were assigned to five different groups based on their underlying dementia etiology: AD, n = 33; vascular dementia, n = 12; mixed dementia, n = 21; FTD, n = 5; and Korsakoff syndrome, n = 6. We observed neither statistically significant differences regarding total WBC populations, platelet counts, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, nor CRP levels between the control group and the five dementia groups. CRP levels tended to be higher in patients with Korsakoff syndrome than in the control group and in AD patients. Thus, CRP could possibly play a role in the differential diagnosis of dementia. This should be investigated further in future prospective studies with larger sample sizes. WBC and platelet counts, by contrast, do not appear to be suitable biomarkers in the differential diagnosis of dementia.

Decision Conflicts in Clinical Care during COVID-19: A Multi-Perspective Inquiry.

Background: The early COVID-19-pandemic was characterized by changes in decision making, decision-relevant value systems and the related perception of decisional uncertainties and conflicts resulting in decisional burden and stress. The vulnerability of clinical care professionals to these decisional dilemmas has not been characterized yet. Methods: A cross-sectional questionnaire study (540 patients, 322 physicians and 369 nurses in 11 institutions throughout Germany) was carried out. The inclusion criterion was active involvement in clinical treatment or decision making in oncology or psychiatry during the first year of COVID-19. The questionnaires covered five decision dimensions (conflicts and uncertainty, resources, risk perception, perception of consequences for clinical processes, and the perception of consequences for patients). Data analysis was performed using ANOVA, Pearson rank correlations, and the Chi²-test, and for inferential analysis, nominal logistic regression and tree classification were conducted. Results: Professionals reported changes in clinical management (27.5%) and a higher workload (29.2%), resulting in decisional uncertainty (19.2%) and decisional conflicts (22.7%), with significant differences between professional groups (p < 0.005), including anxiety, depression, loneliness and stress in professional subgroups (p < 0.001). Nominal regression analysis targeting "Decisional Uncertainty" provided a highly significant prediction model (LQ p < 0.001) containing eight variables, and the analysis for "Decisional Conflicts" included six items. The classification rates were 64.4% and 92.7%, respectively. Tree analysis confirmed three levels of determinants. Conclusions: Decisional uncertainty and conflicts during the COVID-19 pandemic were independent of the actual pandemic load. Vulnerable professional groups for the perception of a high number of decisional dilemmas were characterized by individual perception and the psychological framework. Coping and management strategies should target vulnerability, enable the handling of the individual perception of decisional dilemmas and ensure information availability and specific support for younger professionals.

Differences in Stakeholders' Perception of the Impact of COVID-19 on Clinical Care and Decision-Making.

Background: Pandemics are related to changes in clinical management. Factors that are associated with individual perceptions of related risks and decision-making processes focused on prevention and vaccination, but perceptions of other healthcare consequences are less investigated. Different perceptions of patients, nurses, and physicians on consequences regarding clinical management, decisional criteria, and burden were compared. Study Design: Cross-sectional OnCoVID questionnaire studies. Methods: Data that involved 1231 patients, physicians, and nurses from 11 German institutions that were actively involved in clinical treatment or decision-making in oncology or psychiatry were collected. Multivariate statistical approaches were used to analyze the stakeholder comparisons. Results: A total of 29.2% of professionals reported extensive changes in workload. Professionals in psychiatry returned severe impact of pandemic on all major aspects of their clinical care, but less changes were reported in oncology (p < 0.001). Both patient groups reported much lower recognition of treatment modifications and consequences for their own care. Decisional and pandemic burden was intensively attributed from professionals towards patients, but less in the opposite direction. Conclusions: All of the groups share concerns about the impact of the COVID-19 pandemic on healthcare management and clinical processes, but to very different extent. The perception of changes is dissociated in projection towards other stakeholders. Specific awareness should avoid the dissociated impact perception between patients and professionals potentially resulting in impaired shared decision-making.

Medication-related problems in geriatric psychiatry-a retrospective cohort study.

OBJECTIVES: Information on medication-related problems (MRPs) in elderly psychiatric patients is scarce. In the present study, we analyzed the frequency and characteristics of MRPs in patients ≥60 years treated on the gerontopsychiatric ward of Hannover Medical School in 2019. METHODS: Taking advantage of an interdisciplinary approach, two independent investigators screened hospital discharge letters of 230 psychiatric inpatients for clinically relevant MRPs, followed by validation through an interdisciplinary expert panel. Drug interactions as a subset of MRPs were analyzed with the aid of two different drug interaction programs. RESULTS: 230 patients (63.0% female, mean age 73.7 ± 8.4 years, median length of stay 18 days) were prescribed a median of 6 drugs. In total, 2180 MRPs were detected in the study population and 94.3% of the patients exhibited at least one MRP. Patients displayed a median of 7 MRPs (interquartile range 3-15). Pharmacodynamic interactions accounted for almost half of all MRPs (48.1%; 1048/2180). The number of drugs prescribed and the number of MRPs per patient showed a strong linear relationship (adjusted R2  = 0.747). CONCLUSION: An exceedingly high proportion of elderly psychiatric inpatients displayed clinically relevant MRPs in the present study, which may be explained by the multimorbidity prevalent in the study population and the associated polypharmacy. The number of drug interactions was largely in accordance with previous studies. As a novel finding, we detected that a considerable proportion of elderly psychiatric inpatients were affected by potential prescribing omissions, potentially inappropriate duplicate prescriptions, and insufficient documentation.

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. PWS individuals typically show insatiable appetite with subsequent obesity representing the major mortality factor unless food intake is inhibited. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, a region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and DNA methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter DNA methylation was assessed by bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated significantly with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to sex-, age- and BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror those seen in non-syndromic obesity.

Dysregulated Methylation Patterns in Exon IV of the Brain-Derived Neurotrophic Factor (BDNF) Gene in Nicotine Dependence and Changes in BDNF Plasma Levels During Smoking Cessation.

Introduction: Several studies reported dysregulated protein levels of brain-derived neurotrophic factor (BDNF) in smokers and during cessation. However, the epigenetic regulation of the BDNF gene has not yet been investigated. We measured the plasma levels of BDNF and the epigenetic regulation of exon IV of the BDNF gene in smokers compared to healthy controls over a cessation period of 14 days. Method: We measured BDNF plasma levels and BDNF promoter methylation in 49 smokers and 51 non-smokers at baseline, day 7, and day 14 of smoking cessation. Mean methylation levels of 11 Cytosine Guanosine dinucleotides of exon IV of the BDNF gene were determined via bisulfite sequencing. Results: BDNF plasma and methylation levels were significantly lower in healthy controls when compared with smokers across all time points. BDNF levels for smokers decreased significantly during the cessation period. Comparing the sexes, female smokers showed significantly lower plasma BDNF levels than healthy controls at baseline and over 14 days of cessation. Male and female smokers showed significantly higher mean methylation rates than non-smokers at baseline. In male smokers, mean methylation levels decreased significantly during the cessation period. Conclusion: Our findings replicate the findings of previous studies that BDNF plasma levels are altered in smokers. Furthermore, BDNF expression and gene methylation are altered during the first 14 days of cessation. Our novel findings of dysregulated methylation patterns in exon IV of the BDNF gene further support the thesis that BDNF plays a role in nicotine dependence.

Decision Conflicts in Clinical Care during COVID-19: A Patient Perspective.

(1) Background: Uncertainty is typical for a pandemic or similar healthcare crisis. This affects patients with resulting decisional conflicts and disturbed shared decision making during their treatment occurring to a very different extent. Sociodemographic factors and the individual perception of pandemic-related problems likely determine this decisional dilemma for patients and can characterize vulnerable groups with special susceptibility for decisional problems and related consequences. (2) Methods: Cross-sectional data from the OnCoVID questionnaire study were used involving 540 patients from 11 participating institutions covering all major regions in Germany. Participants were actively involved in clinical treatment in oncology or psychiatry during the COVID-19 pandemic. Questionnaires covered five decision dimensions (conflicts and uncertainty, resources, risk perception, perception of consequences for clinical processes, perception of consequences for patients) and very basic demographic data (age, gender, stage of treatment and educational background). Decision uncertainties and distress were operationalized using equidistant five-point scales. Data analysis was performed using descriptive and various multivariate approaches. (3) Results: A total of 11.5% of all patients described intensive uncertainty in their clinical decisions that was significantly correlated with anxiety, depression, loneliness and stress. Younger and female patients and those of higher educational status and treatment stage had the highest values for these stressors (p < 0.001). Only 15.3% of the patients (14.9% oncology, 16.2% psychiatry; p = 0.021) considered the additional risk of COVID-19 infections as very important for their disease-related decisions. Regression analysis identified determinants for patients at risk of a decisional dilemma, including information availability, educational level, age group and requirement of treatment decision making. (4) Conclusions: In patients, the COVID-19 pandemic induced specific decisional uncertainty and distress accompanied by intensified stress and psychological disturbances. Determinants of specific vulnerability were related to female sex, younger age, education level, disease stages and perception of pandemic-related treatment modifications, whereas availability of sufficient pandemic-related information prevented these problems. The most important decisional criteria for patients under these conditions were expected side effects/complications and treatment responses.

N-Acetylcysteine provides limited efficacy as treatment option for skin picking in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed genes in chromosome region 15q11-13. In addition to typical characteristics such as hyperphagia, PWS is evidenced by a certain behavioral phenotype. Common indicators are repetitive behaviors, temper tantrums, and self-injurious behaviors such as skin- and/or rectal picking. N-Acetylcysteine (NAC) was previously described as a promising therapeutic option for skin picking in PWS. In this case series, we retrospectively investigated the effect of pharmacotherapy with NAC in 14 individuals with PWS suffering from skin- and/or rectal picking. Treatment success was determined using the Clinical Global Impression-Improvement scale (CGI-I). The Clinical Global Impression-Efficacy index (CGI-EI) was used to put treatment success and side effects into perspective. Six of fourteen patients, all of which were female, showed improvement in symptoms (dosage 1800-2400 mg/day), whereas six patients did not show any change during treatment. Moreover, two male patients treated for solitary rectal picking showed new onset of skin picking. Across all cases, a CGI-I of 3 (corresponding to minimal improvement) was seen after 3 months of treatment, with a CGI-EI of 1.6 (corresponding to moderate efficacy). NAC remains a reasonable therapeutic option in certain cases of skin picking in PWS but provides only limited efficacy compared to previous studies on the topic. There was a higher rate of adverse drug reactions than previously reported. The results particularly suggest caution in future treatment in individuals with solitary rectal picking and reduced efficacy when coadministered with neuroleptics.

TNF-α Increase in a Cohort of Depressive Patients.

Background: The model of neuroinflammation has been proposed as a possible explanation of depression. Investigations of serum levels of tumor necrosis factor-α (TNF-α) in depressed patients have previously shown contradictory results of increased and decreased levels of TNF-α during the treatment of depression. Methods: We compared the serum levels of TNF-α in two cohorts of patients suffering from depression (ICD-10 criteria): one cohort from a psychotherapeutic unit (n = 18), where patients were treated with Cognitive Behavioral Analysis System of Psychotherapy (CBASP), and the other cohort from a psychiatric day care unit (n = 16). Both cohorts were investigated at the beginning and at the end of treatment. The intensity of depression was measured by means of the Beck Depression Inventory, 2nd edition (BDI-II) at both time points. Results: We observed a statistically significant increase of TNF-α in the psychotherapeutic unit at time point 2 compared to time point 1 (T = -14.71, p < 0.001), but not in the psychiatric day care unit. In both cohorts, BDI-II scores at time point 2 were significantly decreased compared to time point 1 (psychiatric day care unit: T = 3.32, p = 0.005; psychotherapeutic unit: T = 6.22, p < 0.001). There was a significant correlation in the psychotherapeutic unit at time point 2 (r = -0.682, p = 0.02). Conclusion: As TNF-α was increased at time point 2 in the psychotherapeutic unit but not in patients of the psychiatric day care unit, we propose the different durations of pretreatments in both cohorts and the associated processes of neuroinflammation as a possible explanation for our results. The lack of information about the time course of TNF-α in depression could in general explain the huge variety of TNF-α levels in different cohorts of depressed patients reported in the literature.

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs-Influence of Smoking Behavior and Inflammation on Pharmacokinetics.

Both inflammation and smoking can influence a drug's pharmacokinetic properties, i.e., its liberation, absorption, distribution, metabolism, and elimination. Depending on, e.g., pharmacogenetics, these changes may alter treatment response or cause serious adverse drug reactions and are thus of clinical relevance. Antipsychotic drugs, used in the treatment of psychosis and schizophrenia, should be closely monitored due to multiple factors (e.g., the narrow therapeutic window of certain psychotropic drugs, the chronicity of most mental illnesses, and the common occurrence of polypharmacotherapy in psychiatry). Therapeutic drug monitoring (TDM) aids with drug titration by enabling the quantification of patients' drug levels. Recommendations on the use of TDM during treatment with psychotropic drugs are presented in the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology; however, data on antipsychotic drug levels during inflammation or after changes in smoking behavior-both clinically relevant in psychiatry-that can aid clinical decision making are sparse. The following narrative review provides an overview of relevant literature regarding TDM in psychiatry, particularly in the context of second- and third-generation antipsychotic drugs, inflammation, and smoking behavior. It aims to spread awareness regarding TDM (most pronouncedly of clozapine and olanzapine) as a tool to optimize drug safety and provide patient-tailored treatment.

Promoter Methylation of LEP and LEPR before and after Bariatric Surgery: A Cross-Sectional Study.

INTRODUCTION: DNA methylation constitutes one important epigenetic mechanism that regulates gene expression in human cells. With regard to obesity, bariatric surgery-induced weight loss has been associated with promoter methylation changes in several genes. Hyperleptinemia is a characteristic feature of obesity. The underlying regulating mechanisms have not yet been completely elucidated. METHODS: We investigated the methylation of the promoters of the leptin gene (LEP) and the leptin receptor gene (LEPR) as well as leptin expression in pre- and postbariatric surgery patients using a comparative cross-sectional design. RESULTS: Our results revealed significantly higher LEP promoter methylation patterns in prebariatric surgery patients compared to postoperatively. DNA methylation of the LEPR promoter was significantly higher in the postoperative group. Moreover, we found significantly higher leptin serum levels in patients before the bariatric surgery than afterwards. DISCUSSION: These findings strengthen the suggestion that there is an association between LEP expression and LEP methylation in obesity. We suggest that the epigenetic profile of LEP might be influenced by leptin serum levels in the form of a regulating feedback mechanism.

Effect of SSRI exposure on the proliferation rate and glucose uptake in breast and ovary cancer cell lines.

Breast cancer is the most prevalent malignancy amongst women worldwide while ovarian cancer represents the leading cause of death among gynecological malignancies. Women suffering from these cancers displayed heightened rates of major depressive disorder, and antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) is frequently recommended. Recently, narrative reviews and meta-analyses showed increased recurrence risks and mortality rates in SSRI-treated women with breast and ovarian cancer. We therefore examined whether three commonly prescribed SSRIs, fluoxetine, sertraline and citalopram, affect proliferation or glucose uptake of human breast and ovarian cancer cell lines characterized by different malignancies and metastatic potential. SSRI treatment or serotonin stimulation with therapeutically relevant concentrations over various time periods revealed no consistent dose- or time-dependent effect on proliferation rates. A marginal, but significant increase in glucose uptake was observed in SK-OV-3 ovarian cancer cells upon fluoxetine or sertraline, but not citalopram treatment. In three breast cancer cell lines and in two additional ovarian cancer cell lines no significant effect of SSRIs on glucose uptake was observed. Our data suggest that the observed increase in recurrence- and mortality rates in SSRI-treated cancer patients is unlikely to be linked to antidepressant therapies.

Trauma Severity in Early Childhood Correlates with Stress and Satiety Hormone Levels in a Pilot Cohort Receiving Diamorphine Maintenance Treatment.

AIMS: Childhood trauma is of importance for the manifestation of substance-related disorders and maintenance of hypothalamic-pituitary-adrenal (HPA)-axis disorders. Since stress plays a crucial role in opioid compliance and craving, we investigated the immediate effects of diacetylmorphine application on the HPA axis. In particular, adrenocorticotropic hormone (ACTH) and cortisol secretion, as well as satiety regulating proopiomelanocortin peptides α-melanocyte-stimulating hormone (MSH) and ß-endorphin (END) in a cohort of opioid-dependent patients in diamorphine maintenance treatment concerning the clinical severity of their childhood trauma. METHODS: We compared the serum levels of ACTH, cortisol, MSH, and END in 15 opioid-dependent patients. All participants received treatment with diamorphine and were observed at 5 timepoints before and after injection. We split the cohort into 2 subgroups concerning childhood trauma measured by the Childhood Trauma Questionnaire. RESULTS: Splitting in 2 subgroups for mild (5) and severe trauma (10), we found that while both groups show a significant reduction of ACTH and cortisol levels over time, slopes display different progressions over time for cortisol (F[1.6] = 9.38, p = 0.02), while remaining identical for ACTH (F[1.6] = 1.69, p = 0.24). Also, levels of both MSH and END were significantly lower in severely traumatized patients. CONCLUSIONS: For the first time, we present a detailed representation of stress- and addiction-related proteins for the first 5 h after diamorphine application, demonstrating the interrelationship between stress hormones and childhood trauma as well as its potential effects on the progression of addictions such as opioid dependence.

Neuroleptic malignant syndrome: evaluation of drug safety data from the AMSP program during 1993-2015.

Neuroleptic malignant syndrome (NMS) is a rare, but severe adverse drug reaction of drugs with anti-dopaminergic properties. The main symptoms are fever and rigor. In addition, other symptoms such as creatine kinase elevation, alteration of consciousness and various neurological symptoms may occur. A total of 52 NMS cases have been documented in the drug safety program 'Arzneimittelsicherheit in der Psychiatrie' from 1993 to 2015. We calculated incidences and analyzed imputed substances and additional risk factors to study the impact of changing therapy regimes. The overall incidence was 0.16‰. High-potency first-generation antipsychotics (FGAs) had the highest incidences, e.g. flupentixol with 0.61‰. Second-generation antipsychotics (SGAs) had lower incidences. Low-potency FGAs had very low incidences, comparable to SGAs, but in contrast to SGAs, had not been imputed alone in any case of NMS. Preexisting organic pathologies of the central nervous system, lithium treatment, infection/exsiccosis and the withdrawal of medication with anticholinergic properties or alcohol were found to be additional risk factors. With the increasing use of SGAs, one should always be aware of the risk of NMS. Better suited diagnostic criteria for 'atypical NMS' would lead to a better understanding and, therefore, to improved treatment possibilities.