Impulsivity and compulsivity in anorexia nervosa: cognitive systems underlying variation in appetite restraint from an RDoC perspective

Contemporary nomenclature for anorexia nervosa (AN) describes the eating disorder as transdiagnostic, with overlapping facets of impulsivity and compulsivity contributing to variations in binge-purge, restrictive eating and maladaptive cognitions. It is important to understand how these facets interact, given that those diagnosed with AN often fluctuate and relapse - as opposed to maintaining a stable diagnosis - between Diagnostic and Statistical Manual version 5 (DSM-5) categories, over the life course. The National Institute of Health’s Research Domain Criteria (NIH RDoC) subscribes to the transdiagnostic view of mental disorders and provides progressive guidelines for neuroscience research. As such, using the RDoC guidelines may help to pinpoint how impulsivity and compulsivity contribute to the cognitive mechanisms underlying variations in appetite restraint in eating disorders and common psychiatric comorbidities such as anxiety and obsessive-compulsive disorder. Exploring impulsivity and compulsivity in AN from the perspective of the RDoC Cognitive Systems domain is aided by measures of genetic, molecular, cellular, neural, physiological, behavioural and cognitive task paradigms. Thus, from the standpoint of the RDoC measures, this chapter will describe some of the ways in which impulsivity and compulsivity contribute to the cognitive systems associated with appetite restraint in AN, with the aim of further clarifying a model of appetite restraint to improve treatment interventions

Migraine and gastrointestinal disorders in middle and old age: A UK Biobank study

Introduction: Migraine is a prevalent condition causing a substantial level of disability worldwide. Despite this, the pathophysiological mechanisms are not fully understood. Migraine often co-occurs with gastrointestinal disorders, but the direction of a potential causal link is unclear. The aim of this project was to investigate the associations between migraine and several gastrointestinal disorders in the same cohort in order to determine the relative strengths of these associations. Methods: This cross-sectional study examined whether migraine is associated with irritable bowel syndrome (IBS), peptic ulcers, Helicobacter pylori (HP) infections, celiac disease, Crohn's disease and ulcerative colitis. Baseline data covering 489,753 UK Biobank participants (migraine group: n = 14,180) were analyzed using Pearson's chi-square tests and adjusted binary logistic regression models. Results: Migraine was significantly associated with IBS (odds ratio [OR] 2.24, 95% confidence interval [CI] 2.08–2.40, p <.001) and peptic ulcers (OR 1.55, 95% CI 1.35–1.77, p <.001). Migraine was not associated with HP infection (OR 1.34, 95% CI 1.04–1.73, p =.024), celiac disease (OR 1.29, 95% CI 1.04–1.60, p =.023), Crohn's disease (OR 1.08, 95% CI 0.80–1.45, p =.617) or ulcerative colitis (OR 1.00, 95% CI 0.79–1.27, p =.979) after adjusting for multiple testing. Conclusions: Migraine was associated with IBS and peptic ulcers in this large population-based cohort. The associations with HP infection, celiac disease, Crohn's disease, and ulcerative colitis did not reach significance, suggesting a weaker link between migraine and autoimmune gastrointestinal conditions or HP infection

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants

The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p =.02) and ln CES-D score (p =.001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p =.02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p =.03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs

High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis

Background: Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression. Methods: A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October 30 th, 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random-effects empirical Bayes model. Results: Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of -8.94 points (CI [-10.04,-7.84], p < 0.01) in the BDI scale, of -5.90 points (CI [-9.92,-1.88], p < 0.01) in the BDI-II scale and of -6.19 points (CI [-9.52,-2.86], p < 0.01) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of -4.10 (CI [-7.31,-0.89], p = 0.01) points in the HIT6 scale, -32.05 (CI [-55.96,-8.14], p = 0.01) in the MIDAS scale, -1.7 (CI [-3.27,-0.13], p = 0.03) points in the VAS scale and of -6.27 (CI [-8.48,-4.07], p < 0.01) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores. Conclusion: Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features

CCAP regulates feeding behavior via the NPF pathway in Drosophila adults

The intake of macronutrients is crucial for the fitness of any animal and is mainly regulated by peripheral signals to the brain. How the brain receives and translates these peripheral signals or how these interactions lead to changes in feeding behavior is not well-understood. We discovered that 2 crustacean cardioactive peptide (CCAP)-expressing neurons in Drosophila adults regulate feeding behavior and metabolism. Notably, loss of CCAP, or knocking down the CCAP receptor (CCAP-R) in 2 dorsal median neurons, inhibits the release of neuropeptide F (NPF), which regulates feeding behavior. Furthermore, under starvation conditions, flies normally have an increased sensitivity to sugar; however, loss of CCAP, or CCAP-R in 2 dorsal median NPF neurons, inhibited sugar sensitivity in satiated and starved flies. Separate from its regulation of NPF signaling, the CCAP peptide also regulates triglyceride levels. Additionally, genetic and optogenetic studies demonstrate that CCAP signaling is necessary and sufficient to stimulate a reflexive feeding behavior, the proboscis extension reflex (PER), elicited when external food cues are interpreted as palatable. Dopaminergic signaling was also sufficient to induce a PER. On the other hand, although necessary, NPF neurons were not able to induce a PER. These data illustrate that the CCAP peptide is a central regulator of feeding behavior and metabolism in adult flies, and that NPF neurons have an important regulatory role within this system

The Solute Carrier Families Have a Remarkably Long Evolutionary History with the Majority of the Human Families Present before Divergence of Bilaterian Species

The Solute Carriers (SLCs) are membrane proteins that regulate transport of many types of substances over the cell membrane. The SLCs are found in at least 46 gene families in the human genome. Here, we performed the first evolutionary analysis of the entire SLC family based on whole genome sequences. We systematically mined and analyzed the genomes of 17 species to identify SLC genes. In all, we identified 4,813 SLC sequences in these genomes, and we delineated the evolutionary history of each of the subgroups. Moreover, we also identified ten new human sequences not previously classified as SLCs, which most likely belong to the SLC family. We found that 43 of the 46 SLC families found in Homo sapiens were also found in Caenorhabditis elegans, whereas 42 of them were also found in insects. Mammals have a higher number of SLC genes in most families, perhaps reflecting important roles for these in central nervous system functions. This study provides a systematic analysis of the evolutionary history of the SLC families in Eukaryotes showing that the SLC superfamily is ancient with multiple branches that were present before early divergence of Bilateria. The results provide foundation for overall classification of SLC genes and are valuable for annotation and prediction of substrates for the many SLCs that have not been tested in experimental transport assays

Loss of Regulator of G Protein Signaling 5 Exacerbates Obesity, Hepatic Steatosis, Inflammation and Insulin Resistance

BACKGROUND: The effect of regulator of G protein signaling 5 (RGS5) on cardiac hypertrophy, atherosclerosis and angiogenesis has been well demonstrated, but the role in the development of obesity and insulin resistance remains completely unknown. We determined the effect of RGS5 deficiency on obesity, hepatic steatosis, inflammation and insulin resistance in mice fed either a normal-chow diet (NC) or a high-fat diet (HF). METHODOLOGY/PRINCIPAL FINDINGS: Male, 8-week-old RGS5 knockout (KO) and littermate control mice were fed an NC or an HF for 24 weeks and were phenotyped accordingly. RGS5 KO mice exhibited increased obesity, fat mass and ectopic lipid deposition in the liver compared with littermate control mice, regardless of diet. When fed an HF, RGS5 KO mice had a markedly exacerbated metabolic dysfunction and inflammatory state in the blood serum. Meanwhile, macrophage recruitment and inflammation were increased and these increases were associated with the significant activation of JNK, IκBα and NF-κBp65 in the adipose tissue, liver and skeletal muscle of RGS5 KO mice fed an HF relative to control mice. These exacerbated metabolic dysfunction and inflammation are accompanied with decreased systemic insulin sensitivity in the adipose tissue, liver and skeletal muscle of RGS5 KO mice, reflected by weakened Akt/GSK3β phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that loss of RGS5 exacerbates HF-induced obesity, hepatic steatosis, inflammation and insulin resistance

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview.

The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate