Policy and practice review: a first guideline on the use of pharmacogenetics in clinical psychiatric practice

Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.Public Health and primary carePrevention, Population and Disease management (PrePoD

Effects of propranolol on fear of dental extraction: Study protocol for a randomized controlled trial

Background: Undergoing an extraction has been shown to pose a significantly increased risk for the development of chronic apprehension for dental surgical procedures, disproportionate forms of dental anxiety (that is, dental phobia), and symptoms of post-traumatic stress. Evidence suggests that intrusive emotional memories of these events both induce and maintain these forms of anxiety. Addressing these problems effectively requires an intervention that durably reduces both the intrusiveness of key fear-related memories and state anxiety during surgery. Moreover, evidence suggests that propranolol is capable of inhibiting "memory reconsolidation" (that is, it blocks the process of storing a recently retrieved fear memory). Hence, the purpose of this trial is to determine the anxiolytic and fear memory reconsolidation inhibiting effects of the ß-adrenoreceptor antagonist propranolol on patients with high levels of fear in anticipation of a dental extraction. Methods/Design: This trial is designed as a multicenter, randomized, placebo-controlled, two-group, parallel, double-blind trial of 34 participants. Consecutive patients who have been referred by their dentist to the departments of oral and maxillofacial surgery of a University hospital or a secondary referral hospital in the Netherlands for at least two tooth and/or molar removals and with self-reported high to extreme fear in anticipation of a dental extraction will be recruited. The intervention is the administration of two 40 mg propranolol capsules 1 hour prior to a dental extraction, followed by one 40 mg capsule directly postoperatively. Placebo capsules will be used as a comparator. The primary outcome will be dental trait anxiety score reduction from baseline to 4-weeks follow-up. The secondary outcomes will be self-reported anxiety during surgery, physiological parameters (heart rate and blood pressure) during recall of the crucial fear-related memory, self-reported vividness, and emotional charge of the crucial fear-related memory. Discussion: This randomized trial is the first to test the efficacy of 120 mg of perioperative propranolol versus placebo in reducing short-term ("state") anxiety during dental extraction, fear memory reconsolidation, and lasting dental ("trait") anxiety in a clinical population. If the results show a reduction in anxiety, this would offer support for routinely prescribing propranolol in patients who are fearful of undergoing dental extractions. Trial registration: ClinicalTrials.gov identifier: NCT02268357 , registered on 7 October 2014. The Netherlands National Trial Register identifier: NTR5364 , registered on 16 August 2015

Perioperative Propranolol Against Dental Anxiety: A Randomized Controlled Trial

Background: Promising results from a trauma reactivation study on post-traumatic stress disorder suggest that propranolol is capable of attenuating symptoms of traumatically induced mental disorders by blocking memory reconsolidation. Methods: A randomized, parallel, placebo-controlled, quadruple-blind trial was designed to determine the effectiveness of perioperative propranolol during exposure to dental extractions in reducing dental anxiety in patients with dental anxiety or dental phobia. Between November 2014 and December 2018, 52 patients with high levels of fear in anticipation of dental extractions who were referred to a department of oral and maxillofacial surgery for at least two tooth and/or molar removals with 1 month in between were included. On the first visit participants received either 120 mg of perioperative oral propranolol (n = 19) or placebo (n = 17), and a core fear memory was reactivated 1 h preoperatively. The primary outcome was change in severity of dental anxiety from baseline to 1-month follow-up, as indexed by the short version of the dental anxiety inventory (S-DAI). Secondary outcome measures were change in intra-operative state anxiety and specific phobia diagnoses. Results: Linear mixed model (LMM) yielded no statistically significant difference in change of dental trait anxiety from baseline to 1-month follow-up between propranolol and placebo groups (Cohen's d = 0.23). S-DAI scores decreased in both study arms from baseline to follow-up (propranolol arm: from 32.1 [SD = 7.3] to 29.1 [SD = 8.8]; placebo arm: from 31.6 [SD = 7.5] to 27.1 [SD = 6.5]). Also, administering propranolol was not associated with a significant difference in change of intra-operative state anxiety or phobia diagnoses between groups over time. Conclusions: The results do not concur with earlier findings regarding post-traumatic stress disorder, and suggest that individuals with traumatically induced fears or phobias do not benefit from the application of perioperative propranolol

Timing of syncope in ictal asystole as a guide when considering pacemaker implantation

Introduction In patients with ictal asystole (IA) both cardioinhibition and vasodepression may contribute to syncopal loss of consciousness. We investigated the temporal relationship between onset of asystole and development of syncope in IA, to estimate the frequency with which pacemaker therapy, by preventing severe bradycardia, may diminish syncope risk. Methods In this retrospective cohort study, we searched video-EEG databases for individuals with focal seizures and IA (asystole >= 3 s preceded by heart rate deceleration) and assessed the durations of asystole and syncope and their temporal relationship. Syncope was evaluated using both video observations (loss of muscle tone) and EEG (generalized slowing/flattening). We assumed that asystole starting 3 s. Thus, in only two instances was vasodepression rather than cardioinhibition the dominant presumptive syncope triggering mechanism. Conclusions In IA, cardioinhibition played an important role in most seizure-induced syncopal events, thereby favoring the potential utility of pacemaker implantation in patients with difficult to suppress IA.Paroxysmal Cerebral Disorder

The extreme European summer 2012

The European summer of 2012 was marked by strongly contrasting rainfall anomalies, which led to flooding in northern Europe and droughts and wildfires in southern Europe. This season was not an isolated event, rather the latest in a string of summers characterized by a southward shifted Atlantic storm track as described by the negative phase of the SNAO. The degree of decadal variability in these features suggests a role for forcing from outside the dynamical atmosphere, and preliminary numerical experiments suggest that the global SST and low Arctic sea ice extent anomalies are likely to have played a role and that warm North Atlantic SSTs were a particular contributing factor. The direct effects of changes in radiative forcing from greenhouse gas and aerosol forcing are not included in these experiments, but both anthropogenic forcing and natural variability may have influenced the SST and sea ice changes

Explaining Extreme Events of 2012 from a Climate Perspective

Attribution of extreme events is a challenging science and one that is currently undergoing considerable evolution. In this paper are 19 analyses by 18 different research groups, often using quite different methodologies, of 12 extreme events that occurred in 2012. In addition to investigating the causes of these extreme events, the multiple analyses of four of the events, the high temperatures in the United States, the record low levels of Arctic sea ice, and the heavy rain in northern Europe and eastern Australia, provide an opportunity to compare and contrast the strengths and weaknesses of the various methodologies. The differences also provide insights into the structural uncertainty of event attribution, that is, the uncertainty that arises directly from the differences in analysis methodology. In these cases, there was considerable agreement between the different assessments of the same event. However, different events had very different causes. Approximately half the analyses found some evidence that anthropogenically caused climate change was a contributing factor to the extreme event examined, though the effects of natural fluctuations of weather and climate on the evolution of many of the extreme events played key roles as well.Peer Reviewe

Update on potential medical treatments for encapsulating peritoneal sclerosis; human and experimental data

Encapsulating peritoneal sclerosis (EPS) is an infrequent but serious complication of peritoneal dialysis (PD). The pathogenesis is unknown but speculation is ongoing. The current management of EPS focuses on prevention and treatment of the inflammatory and fibrotic changes at the level of the peritoneal membrane with immunosuppressive and antifibrotic agents, respectively. This article reviews the currently available human and animal data on potential agents to prevent and/or treat EPS. We propose a strategy for early diagnose EPS in an attempt to avoid the development of the full-blown and potentially life-threatening clinical syndrome of EPS. Future research should focus on studying potential prophylactic and therapeutic agents in humans in large, multicenter, randomized trials but also on early detection of EPS in the inflammatory phase by means of biomarkers and the establishment of a composite EPS score

Long-term safety of gamma knife radiosurgery (SRS) for acromegaly

Purpose Acromegaly has high morbidity and mortality when growth hormone secretion remains uncontrolled. Stereotactic radiosurgery (SRS) may be used when pituitary surgery is not suitable or unsuccessful, but there are few very long-term safety data available, especially for significant adverse events such as stroke. Methods 118 patients with acromegaly were treated with SRS between 1985 and 2015, at the National Centre for Stereotactic Radiosurgery, Sheffield, UK. Data were gathered from case notes, hospital databases, and patient questionnaires. Stroke incidence in comparison to the normal population was quantified using the standardised incidence ratio (SIR), and visual complications assessed. Results 88% (104/118) had complete morbidity follow up data for analysis. The mean follow-up was 134 months, and median SRS dose was 30 Gy. 81% of tumours had cavernous sinus invasion. There was no excess stroke rate relative to that seen in two age- and sex-matched large population studies (SIR = 1.36, 95% CI 0.27–3.96; SIR = 0.52, 95% CI 0.06–1.89). In 68/104 patients who had MRI-guided SRS with no further radiation treatment (SRS or fractionated radiotherapy) there was no loss of visual acuity and 3% developed ophthalmoplegia. There was a positive correlation between > 1 radiation treatment and both ophthalmoplegia and worsening visual acuity. Conclusion Stroke rate is not increased by SRS for acromegaly. Accurate MRI-based treatment planning and single SRS treatment allow the lowest complication rates. More than one radiation treatment (SRS or fractionated radiotherapy) was associated with increased visual complications