Impact of Substance Use Disorder Pharmacotherapy on Executive Function: A Narrative Review

Substance use disorders are chronic, relapsing, and harmful conditions characterized by executive dysfunction. While there are currently no approved pharmacotherapy options for stimulant and cannabis use disorders, there are several evidence-based options available to help reduce symptoms during detoxification and aid long-term cessation for those with tobacco, alcohol and opioid use disorders. While these medication options have shown clinical efficacy, less is known regarding their potential to enhance executive function. This narrative review aims to provide a brief overview of research that has investigated whether commonly used pharmacotherapies for these substance use disorders (nicotine, bupropion, varenicline, disulfiram, acamprosate, nalmefene, naltrexone, methadone, buprenorphine, and lofexidine) effect three core executive function components (working memory, inhibitory control and cognitive flexibility). While pharmacotherapy-induced enhancement of executive function may improve cessation outcomes in dependent populations, there are limited and inconsistent findings regarding the effects of these medications on executive function. We discuss possible reasons for the mixed findings and suggest some future avenues of work that may enhance the understanding of addiction pharmacotherapy and cognitive training interventions and lead to improved patient outcomes

Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System

Due to size and accessibility, most information about the habenula is derived from rodent studies. To better understand the molecular signature of the habenula we characterized the genes that have high expression in the habenula. We compared anatomical expression profiles of three normal adult human brains and four fetal brains. We used gene set enrichment analyses to determine if genes annotated to specific molecular functions, cellular components, and biological processes are enriched in the habenula. We also tested gene sets related to depression and addiction to determine if they uniquely involve the habenula. As expected, we observed high habenular expression of GPR151, nicotinic cholinergic receptors, and cilia-associated genes (medial division). Genes identified in genetic studies of smoking and associated with nicotine response were enriched in the habenula. Genes associated with major depressive disorder did not have enriched expression in the habenula but genes negatively correlated with hedonic well-being were, providing a link to anhedonia. We observed enrichment of genes associated with diseases that are comorbid with addictions (hematopoiesis, thrombosis, liver cirrhosis, pneumonia, and pulmonary fibrosis) and depression (rheumatoid arthritis, multiple sclerosis, and kidney disease). These inflammatory diseases mark a neuroimmune signature that is supported by genes associated with mast cells, acute inflammatory response, and leukocyte migration. We also found enrichment of cytochrome p450 genes suggesting the habenula is uniquely sensitive to endogenous and xenobiotic compounds. Our results suggest the habenula receives negative reward signals from immune and drug processing molecules. This is consistent with the habenular role in the “anti-reward” system and suggests it may be a key bridge between autoimmune disorders, drug use, and psychiatric diseases

Survivable MPLS Over Optical Transport Networks: Cost and Resource Usage Analysis

In this paper we study different options for the survivability implementation in MPLS over Optical Transport Networks (OTN) in terms of network resource usage and configuration cost. We investigate two approaches to the survivability deployment: single layer and multilayer survivability and present various methods for spare capacity allocation (SCA) to reroute disrupted traffic. The comparative analysis shows the influence of the offered traffic granularity and the physical network structure on the survivability cost: for high bandwidth LSPs, close to the optical channel capacity, the multilayer survivability outperforms the single layer one, whereas for low bandwidth LSPs the single layer survivability is more cost-efficient. On the other hand, sparse networks of low connectivity parameter use more wavelengths for optical path routing and increase the configuration cost, as compared with dense networks. We demonstrate that by mapping efficiently the spare capacity of the MPLS layer onto the resources of the optical layer one can achieve up to 22% savings in the total configuration cost and up to 37% in the optical layer cost. Further savings (up to 9 %) in the wavelength use can be obtained with the integrated approach to network configuration over the sequential one, however, at the increase in the optimization problem complexity. These results are based on a cost model with different cost variations, and were obtained for networks targeted to a nationwide coverage

Optimized Design of Survivable MPLS over Optical Transport Networks. Optical Switching and Networking

In this paper we study different options for the survivability implementation in MPLS over Optical Transport Networks in terms of network resource usage and configuration cost. We investigate two approaches to the survivability deployment: single layer and multilayer survivability and present various methods for spare capacity allocation (SCA) to reroute disrupted traffic. The comparative analysis shows the influence of the traffic granularity on the survivability cost: for high bandwidth LSPs, close to the optical channel capacity, the multilayer survivability outperforms the single layer one, whereas for low bandwidth LSPs the single layer survivability is more cost-efficient. For the multilayer survivability we demonstrate that by mapping efficiently the spare capacity of the MPLS layer onto the resources of the optical layer one can achieve up to 22% savings in the total configuration cost and up to 37% in the optical layer cost. Further savings (up to 9 %) in the wavelength use can be obtained with the integrated approach to network configuration over the sequential one, however, at the increase in the optimization problem complexity. These results are based on a cost model with actual technology pricing and were obtained for networks targeted to a nationwide coverage

Retail Price and Point of Sale Display of Tobacco in the UK: A Descriptive Study of Small Retailers

Background: Since the implementation of the 2002 Tobacco Advertising and Promotion Act, point-of-sale (PoS) tobacco displays are one of few remaining means of communication between the tobacco industry and customers in the UK. This study aimed to explore the characteristics of tobacco displays in a UK city, and particularly to assess the tobacco prices and promotional offers, types and pack sizes on display. Methods: Digital pictures of PoS displays were taken in 117 small retail shops in Nottingham in mid 2010. Data were analysed using Windows Photo Gallery software and SPSS version 16. Results: Just over half (52%) of cigarette packs on display were packs of 20, and 43 % packs of 10. Cigarette prices differed substantially between brands, ranging from £4.19 to £6.85 for 20-packs, and from £2.12 to £3.59 for 10-packs. Forty four percent of cigarette packs and 40 % of RYO (Roll-Your-Own) tobacco pouches, almost exclusively lower priced brands, were displayed with a pricemark, implying a promotional price offer. Eighty percent of 20-pack cigarette brand or brand variants on sale were priced below the EU-defined Most Popular Price Category (MPPC) for the UK in 2010; 45 % were priced below the Weighted Average Price (WAP), which replaced the MPPC in 2011. Conclusion: PoS displays communicate value by displaying a high proportion of lower cost brands, and smaller and hence lower-cost packs, and by displaying price discounts on packs. The MPPC substantially overestimated the prices at whic

The Effectiveness of Alcohol Screening and Brief Intervention in Emergency Departments: A Multicentre Pragmatic Cluster Randomized Controlled Trial

BACKGROUND: Alcohol misuse is common in people attending emergency departments (EDs) and there is some evidence of efficacy of alcohol screening and brief interventions (SBI). This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in England: the SIPS ED trial. METHODS AND FINDINGS: Pragmatic multicentre cluster randomized controlled trial of SBI for hazardous and harmful drinkers presenting to ED. Nine EDs were randomized to three conditions: a patient information leaflet (PIL), 5 minutes of brief advice (BA), and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling (BLC). The primary outcome measure was the Alcohol Use Disorders Identification Test (AUDIT) status at 6 months. Of 5899 patients aged 18 or more presenting to EDs, 3737 (63·3%) were eligible to participate and 1497 (40·1%) screened positive for hazardous or harmful drinking, of whom 1204 (80·4%) gave consent to participate in the trial. Follow up rates were 72% (n?=?863) at six, and 67% (n?=?810) at 12 months. There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis. At month 6, compared to the PIL group, the odds ratio of being AUDIT negative for brief advice was 1·103 (95% CI 0·328 to 3·715). The odds ratio comparing BLC to PIL was 1·247 (95% CI 0·315 to 4·939). A per protocol analysis confirmed these findings. CONCLUSIONS: SBI is difficult to implement in typical EDs. The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information, which is likely to be easier and less expensive to implement than more complex interventions

Characterization of the Psychological, Physiological and EEG Profile of Acute Betel Quid Intoxication in Naïve Subjects

Betel quid use and abuse is wide spread in Asia but the physiological basis of intoxication and addiction are unknown. In subjects naïve to the habit of betel quid intoxication, the psychological and physiological profile of intoxication has never been reported. We compared the effect of chewing gum or chewing betel quid, and subsequent betel quid intoxication, on psychological assessment, prospective time interval estimation, numerical and character digit span, computerized 2 choice tests and mental tasks such as reading and mathematics with concurrent monitoring of ECG, EEG and face temperature in healthy, non-sleep deprived, male subjects naïve to the habit of chewing betel quid. Betel quid intoxication, dose dependently induced tachycardia (max 30 bpm) and elevated face temperature (0.7°C) (P<0.001) above the effects observed in response to chewing gum (max 12 bpm and 0.3°C) in 12 subjects. Gross behavioral indices of working memory such as numerical or character digit span in 8 subjects, or simple visual-motor performance such as reaction speed or accuracy in a two choice scenario in 8 subjects were not affected by betel quid intoxication. Betel quid intoxication strongly influenced the psychological aspects of perception such as slowing of the prospective perception of passage of a 1 minute time interval in 8 subjects (P<0.05) and perceived increased arousal (P<0.01) and perceived decreased ability to think (P<0.05) in 31 subjects. The EEG spectral profile recorded from mental states associated with open and closed eyes, and mental tasks such as reading and eyes closed mental arithmetic were significantly modified (P<0.05) relative to chewing gum by betel quid intoxication in 10 subjects. The prevalence of betel quid consumption across a range of social and work settings warrants greater investigation of this widespread but largely under researched drug

Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial

BACKGROUND: The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA. METHODS AND FINDINGS: We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference = 5.0%, 95% CI -0.9,10.8, p = 0.098). Motivation to make another quit attempt among those (n = 331) not abstinent at six months was not significantly different between groups (p = 0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference = 5.8%, 95% CI 1.0,10.7, p = 0.018). CONCLUSIONS: Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN14352545.</p

Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders

Suicide is a serious public health concern, and it is partly genetic. The brain-derived neurotrophic factor (BDNF) gene has been a strong candidate in genetic studies of suicide (Zai et al, 2012; Dwivedi et al, 2010) and BDNF regulates the expression of the dopamine D3 receptor