Inequity in clinical research access for service users presenting comorbidity within alcohol treatment settings: findings from a focused ethnographic study.

BACKGROUND: While healthcare policy has fostered implementation strategies to improve inclusion and access of under-served groups to clinical care, systemic and structural elements still disproportionately prevent service users from accessing research opportunities embedded within clinical settings. This contributes to the widening of health inequalities, as the absence of representativeness prevents the applicability and effectiveness of evidence-based interventions in under-served clinical populations. The present study aims to identify the individual (micro), organisational (meso) and structural (macro) barriers to clinical research access in patients with comorbid alcohol use disorder and alcohol-related liver disease. METHODS: A focused ethnography approach was employed to explore the challenges experienced by patients in the access to and implementation of research processes within clinical settings. Data were collected through an iterative-inductive approach, using field notes and patient interview transcripts. The framework method was utilised for data analysis, and themes were identified at the micro, meso and macro levels. RESULTS: At the micro-level, alcohol-related barriers included encephalopathy and acute withdrawal symptoms. Alcohol-unrelated barriers also shaped the engagement of service users in research. At the meso-level, staff and resource pressures, as well as familiarity with clinical and research facilities were noted as influencing intervention delivery and study retention. At the wider, macro-level, circumstances including the 'cost of living crisis' and national industrial action within healthcare settings had an impact on research processes. The findings emphasise a 'domino effect' across all levels, demonstrating an interplay between individual, organisational and structural elements influencing access to clinical research. CONCLUSIONS: A combination of individual, organisational and structural barriers, exacerbated by the COVID-19 pandemic, and the socioeconomic landscape in which the study was conducted further contributed to the unequal access of under-served groups to clinical research participation. For patients with comorbid alcohol use disorder and alcohol-related liver disease, limited access to research further contributes towards a gap in effective evidence-based treatment, exacerbating health inequalities in this clinical population.

A multi-school study in England, to assess problematic smartphone usage and anxiety and depression.

AIM: To assess the association between problematic smartphone usage and anxiety and depression in adolescents. METHODS: A cross-sectional study in five schools in the UK were included. The primary outcome was moderate anxiety (GAD-7 ≥10) symptoms and secondary outcomes were moderate depression symptoms (PHQ-9 ≥10) and insomnia. Problematic smartphone usage was assessed using screentime and the Smartphone Addiction Scale. A multi-level logistic regression was fitted and adjusted Odds Ratio (aOR) with 95% confidence intervals (95% CI) reported. A mediation analysis was conducted. RESULTS: Of the five included schools, 657 adolescents aged 16-18 years were enrolled. The median age was 17.5 years (17-18 [IQR]) and 508 (77.3%) were female. Of these 188 (28.6%) exhibited moderate anxiety and 226 (34.4%) moderate depression symptoms. Almost two thirds (421, 64.1%) have tried to cut down their smartphone use and 81 (12.5%) wanted help to reduce use. Problematic smartphone use was associated with increased anxiety (aOR = 2.03, 95% CI 1.28-3.23); depression (aOR = 2.96, 95% CI 1.80-4.86); and insomnia (aOR = 1.64, 95% CI 1.08-2.50). Screentime was not associated with anxiety (ß = 0.99, 95% CI 0.91-1.08); or depression (ß = 0.98, 95% CI 0.89-1.07). Problematic smartphone use had a significant direct, indirect and total effect on both anxiety and depression. CONCLUSION: Problematic smartphone usage was associated with anxiety and depression, independent of screentime. Interventions are needed to reduce problematic use.

Substance use in psychiatric crisis: relationship to violence.

BACKGROUND: Substance use and psychiatric illness, particularly psychotic disorders, contribute to violence in emergency healthcare settings. However, there is limited research regarding the relationship between specific substances, psychotic symptoms and violent behaviour in such settings. We investigated the interaction between recent cannabinoid and stimulant use, and acute psychotic symptoms, in relation to violent behaviour in a British emergency healthcare setting. METHODS: We used electronic medical records from detentions of 1089 individuals under Section 136 of the UK Mental Health Act (1983 amended 2007), an emergency police power used to detain people for 24-36 h for psychiatric assessment. The relationship between recent cannabinoids and/or stimulant use, psychotic symptoms, and violent behaviour, was estimated using logistic regression. FINDINGS: There was evidence of recent alcohol or drug use in 64.5% of detentions. Violent incidents occurred in 12.6% of detentions. Psychotic symptoms increased the odds of violence by 4.0 [95% confidence intervals (CI) 2.2-7.4; p < 0.0001]. Cannabinoid use combined with psychotic symptoms increased the odds of violence further [odds ratios (OR) 7.1, 95% CI 3.7-13.6; p < 0.0001]. Recent use of cannabinoids with stimulants but without psychotic symptoms was also associated with increased odds of violence (OR 3.3, 95% CI 1.4-7.9; p < 0.0001). INTERPRETATION: In the emergency setting, patients who have recently used cannabinoids and exhibit psychotic symptoms are at higher risk of violent behaviour. Those who have used both stimulants and cannabinoids without psychotic symptoms may also be at increased risk. De-escalation protocols in emergency healthcare settings should account explicitly for substance use.

Fatalities associated with gabapentinoids in England (2004-2020).

The gabapentinoids were reclassified as Schedule II medications and Class C drugs in the UK in 2019 due to their potential misuse. In this study we examined deaths following gabapentinoid use in England reported to the National Programme on Substance Abuse Deaths. A total of 3051 deaths were reported (gabapentin: 913 cases; pregabalin: 2322 cases [both detected in 184 cases]). Prescribed and illicitly obtained gabapentinoids accounted for similar proportions of deaths (gabapentin illicit 38.0%, prescribed 37.1%; pregabalin illicit 41.0%, prescribed 34.6%). Opioids were co-detected in most cases (92.0%), and co-prescribed in a quarter (25.3%). Postmortem blood gabapentinoid concentrations were commonly (sub)therapeutic (65.0% of gabapentin cases; 50.8% of pregabalin cases). In only two cases was gabapentinoid toxicity alone attributed in causing death. Gabapentinoids alone rarely cause death. Clinically relevant doses can, however, prove fatal, possibly by reducing tolerance to opioids. Doctors and patients should be aware of this interaction. Gabapentinoid-opioid co-prescribing needs urgent revision.

Correction to: Prevalence of problematic smartphone usage and associated mental health outcomes amongst children and young people: a systematic review, meta-analysis and GRADE of the evidence.

After publication of our article [1] we were notified that one of the author names was misspelled.

Prevalence of problematic smartphone usage and associated mental health outcomes amongst children and young people: a systematic review, meta-analysis and GRADE of the evidence.

BACKGROUND: Over the past decade, smartphone use has become widespread amongst today's children and young people (CYP) which parallels increases in poor mental health in this group. Simultaneously, media concern abounds about the existence of 'smartphone addiction' or problematic smartphone use. There has been much recent research concerning the prevalence of problematic smartphone use is in children and young people who use smartphones, and how this syndrome relates to mental health outcomes, but this has not been synthesized and critically evaluated. AIMS: To conduct a systematic review and meta-analysis to examine the prevalence of PSU and quantify the association with mental health harms. METHODS: A search strategy using Medical Subject Headings was developed and adapted for eight databases between January 1, 1st 2011 to October 15th 2017. No language restriction was applied. Of 924 studies identified, 41 were included in this review, three of which were cohort studies and 38 were cross sectional studies. The mental health outcomes were self-reported: depression; anxiety; stress; poor sleep quality; and decreased educational attainment, which were synthesized according to an a priori protocol. RESULTS: The studies included 41,871 CYP, and 55% were female. The median prevalence of PSU amongst CYP was 23.3% (14.0-31.2%). PSU was associated with an increased odds of depression (OR = 3.17;95%CI 2.30-4.37;I2 = 78%); increased anxiety (OR = 3.05 95%CI 2.64-3.53;I2 = 0%); higher perceived stress (OR = 1.86;95%CI 1.24-2.77;I2 = 65%); and poorer sleep quality (OR = 2.60; 95%CI; 1.39-4.85, I2 = 78%). CONCLUSIONS: PSU was reported in approximately one in every four CYP and accompanied by an increased odds of poorer mental health. PSU is an evolving public health concern that requires greater study to determine the boundary between helpful and harmful technology use. Policy guidance is needed to outline harm reduction strategies.

Bipolar disorder and addictions: the elephant in the room.

Addictions are highly prevalent in bipolar disorder and greatly affect clinical outcomes. In this editorial, we review the evidence that addictions are a key challenge in bipolar disorder, examine putative neurobiological mechanisms, and reflect on the limited clinical trial evidence base with suggestions for treatment strategies and further developments.

Alcohol and Alzheimer's Disease-Does Alcohol Dependence Contribute to Beta-Amyloid Deposition, Neuroinflammation and Neurodegeneration in Alzheimer's Disease?

AIMS: To investigate the underlying neurobiology between alcohol use, misuse and dependence and cognitive impairment, particularly Alzheimer's disease (AD). METHODS: Review of the literature using searches of Medline, Pubmed, EMBASE, PsycInfo, and meeting abstracts and presentations. RESULTS: The role of alcohol as a risk factor and contributor for cognitive decline associated with AD has received little attention. This is despite the high prevalence of alcohol use, the potential reversibility of a degree of cognitive impairment and the global burden of AD. Until now the focus has largely been on the toxic effects of alcohol, neuronal loss and the role of thiamine. CONCLUSION: We propose alcohol adds to the cognitive burden seen in dementia through additional mechanisms to neurodegenerative processes or may contribute at various mechanistic points in the genesis and sustenance of AD pathology via neuroinflammation. We describe the common underlying neurobiology in alcohol and AD, and examine ways alcohol likely contributes to neuroinflammation directly via stimulation of Toll-like receptors and indirectly from small bowel changes, hepatic changes, withdrawal and traumatic brain injury to the pathogenesis of AD. SHORT SUMMARY: Alcohol use, misuse and dependence cause cognitive impairment. We propose alcohol adds to the cognitive burden seen in dementia through additional mechanisms to neurodegenerative processes or may contribute at various mechanistic points in the genesis and sustenance of AD pathology via neuroinflammation.

Using [(11)C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism.

The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [(11)C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [(11)C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [(11)C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [(11)C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n=12) underwent an [(11)C]Ro15 4513 PET scan and compared with matched healthy controls (n=13). We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [(11)C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [(11)C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [(11)C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.

Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [(11)C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [(11)C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system.

Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine.

Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission.

The clinical pharmacology of acamprosate.

Acamprosate is one of the few medications licensed for prevention of relapse in alcohol dependence, and over time it has proved to be significantly, if moderately, effective, safe and tolerable. Its use is now being extended into other addictions and neurodevelopmental disorders. The mechanism of action of acamprosate has been less clear, but in the decade or more that has elapsed since its licensing, a body of translational evidence has accumulated, in which preclinical findings are replicated in clinical populations. Acamprosate modulates N-methyl-d-aspartic acid receptor transmission and may have indirect effects on γ-aminobutyric acid type A receptor transmission. It is known to decrease brain glutamate and increase ß-endorphins in rodents and man. Acamprosate diminishes reinstatement in ethanolized rodents and promotes abstinence in humans. Although acamprosate has been called an anticraving drug, its subjective effects are subtle and relate to diminished arousal, anxiety and insomnia, which parallel preclinical findings of decreased withdrawal symptoms in animals treated with acamprosate. Further understanding of the pharmacology of acamprosate will allow appropriate targeting of therapy in individuals with alcohol dependence and extension of its use to other addictions.

'There's more to life than staring at a small screen': a mixed methods cohort study of problematic smartphone use and the relationship to anxiety, depression and sleep in students aged 13-16 years old in the UK.

BACKGROUND: Depression and anxiety are common in adolescents and have increased over the last decade. During that period, smartphone usage has become ubiquitous. OBJECTIVES: The study aim was to assess the association between problematic smartphone usage (PSU) and anxiety. METHODS: Using a prospective mixed methods cohort study design, students aged 13-16 year old from two schools were enrolled regarding their smartphone use, mood and sleep via a semistructured questionnaire at baseline and week 4. The primary outcome was symptoms of anxiety (Generalised Anxiety Disorder Questionnaire, GAD-7) and exposure was PSU (Smartphone Addiction Scale Short Version). A linear regression was fitted to assess the change in anxiety. Thematic analysis of free-text responses was conducted. FINDINGS: The sample included 69 participants that were enrolled and followed up between 28 March and 3 June 2022. Of those with PSU, 44.4% exhibited symptoms of moderate to severe anxiety compared with 26.4% of those without PSU. There was a linear association between change in symptoms of anxiety and PSU ß=0.18 (95% CI 0.04 to 0.32, p=0.013). Several themes were found: both positive and negative effects of smartphones on relationships; negative effects on school performance and productivity; mixed effects on mood; a desire to reduce the amount of time spent on smartphones. CONCLUSIONS: Increased anxiety, depression and inability to sleep were seen in participants as their PSU score increased over time. Participants reported both positive and negative effects of smartphones and almost all used strategies to reduce use. CLINICAL IMPLICATIONS: Interventions need to be developed and evaluated for those seeking support.

Developing a coordinated response to chemsex across health, justice and social care settings: expert consensus statement.

SUMMARY: Chemsex occurs primarily among gay, bisexual and other men who have sex with men (GBMSM), and there is evidence of a subgroup of users who carry out chemsex-related criminal offences and experience harm. Challenges with chemsex can present to various settings; there are concerns that harm is increasing, including at interfaces between health, social care and criminal justice systems. The UK response to date has lacked a coordinated approach. An expert reference group was convened to share chemsex knowledge, articulate priorities for research and pathway development, and foster collaborative working between agencies. It made three key recommendations: develop and increase training and awareness across all services; implement a coordinated research programme with the development of a common data-set and assessment tool to fully characterise population-level needs; develop a professional network to share information, provide professional support and act as a knowledge hub. There was support for a unified multi-agency strategy incorporating the priorities identified as overarching principles.

History of cigarette smoking is associated with higher limbic GABAA receptor availability.

Cigarette smoking presents a significant worldwide healthcare challenge. Preclinical, genetic association and clinical trials studies provide considerable evidence for the involvement of the human γ-aminobutyric acid (GABA) system in the neurobiology of nicotine addiction. However there are few human GABA neurochemical imaging studies of nicotine addiction. We investigated limbic GABA(A) receptor availability in volunteers with a history of cigarette smoking using [(11)C]Ro15 4513 positron emission tomography (PET). Eight [(11)C]Ro15 4513 PET scans from volunteers with a history of cigarette smoking were compared to twelve scans from volunteers who were non-smokers. Total, α1 and α5 GABA(A) receptor subtype [(11)C]Ro15 4513 V(T) values were quantified using spectral analysis of limbic regions implicated in nicotine addiction. Spectral analysis allows quantification of the overall [(11)C]Ro15 4513 spectral frequency as well as α1 and α5 GABA(A) receptor subtype specific spectral frequency components. Volunteers with a history of cigarette smoking showed significantly higher total [(11)C]Ro15 4513 V(T) values in the presubgenual cingulate and parahippocampal gyrus, and at a trend level in the insula, nucleus accumbens and subgenual cingulate. In six abstinent previous smokers ('ex-smokers'), total [(11)C]Ro15 4513 binding was significantly higher in all limbic regions studied, with higher α5 availability in the amygdala, anterior cingulate, nucleus accumbens and presubgenual cingulate. These results suggest that limbic GABA(A) receptor availability is higher in volunteers with a history of cigarette smoking which may reflect either higher expression of GABA(A) receptors or lower endogenous GABA levels. The findings in ex-smokers suggest that higher GABA(A) receptor availability continues with abstinence indicating that this may be a trait marker for nicotine addiction or that alterations in GABA function associated with cigarette smoking persist.

Resting state synchrony in anxiety-related circuits of abstinent alcohol-dependent patients.

BACKGROUND: Anxiety has been linked to initiation, maintenance and relapse of alcohol dependence. Neurobiological models of anxiety have proposed important roles for amygdala-insula and amygdala-medial prefrontal cortex interactions in the generation and regulation of anxiety states, respectively. OBJECTIVES: This study tested the hypotheses that abstinent alcohol-dependent patients would show a disruption of synchrony in these circuits as measured by resting state functional MRI. METHODS: The study examined recently abstinent (n = 13), longer-term abstinent (n = 16) alcohol-dependent patients and healthy controls (n = 22). Resting-state synchrony (RSS) was examined in specific circuits, where degree of synchrony has been found to correlate with state anxiety levels in previous studies. RESULTS: Alcohol-dependent patients showed significantly elevated scores on anxiety and depression inventories compared with controls. No significant group differences in synchrony were observed between right amygdala and right ventromedial prefrontal cortex (vmPFC), between left amygdala and left vmPFC, or, after correction for multiple comparisons, right amygdala and dorsomedial prefrontal cortex (dmPFC). However, significantly decreased positive synchrony was found between left basolateral amygdala and left anterior insula, in patients relative to controls. CONCLUSION: Both early and longer-term abstinent alcohol-dependent patients showed increased anxiety levels relative to controls and altered resting state synchrony in circuits previously linked to state anxiety. Notably, the significant group differences in synchrony were in the opposite direction to our predictions based on the literature. These results may point to a lack of generalizability of models derived from young healthy homogeneous samples.

Outcomes following suicidal crisis among hazardous and harmful alcohol users in the Crisis Resolution Team.

Despite associations between alcohol use and suicidal acts, little research measures prognoses of alcohol-using patients treated by Crisis Resolution Teams (CRTs), an intensive community-based intervention. We estimated the association of alcohol use amongst patients accepted following suicidal acts or ideation in four London-based Crisis Resolution Teams, with death-by-any-cause or recontact with crisis care. We analysed the electronic health records of 1615 CRT patients accepted following suicidal acts or ideation over 38 months, following STROBE guidelines. Using logistic regression we estimated the association of alcohol use (indicated by risk-assessment, AUDIT, or ICD-10 diagnosis) with death-or-recontact at (i) 30-days and (ii) 1-year after treatment start, adjusted for age, sex, ethnicity, psychiatric diagnosis, and severity of need. Hazardous, harmful, or dependent drinking was identified in 270 cases at baseline (16.7%); 73 (4.5%) were alcohol dependent. By 1-year, 622 patients (38.5%) had recontacted crisis care or died. After adjustment, alcohol use at a hazardous, harmful, or dependent level was not associated with increased odds of death-or-recontact at 30-days (AOR 1.17, 95%CI 0.73, 1.88) or 1-year (AOR 1.17, 95%CI 0.85, 1.60). Patients with hazardous, harmful, and dependent alcohol use are a small proportion of CRT patients, despite being more commonly encountered in emergency settings from which patients may be referred to CRTs, indicating a potential gap in provision. Those who are included in CRTs are not at increased risk of death-or-recontact within 1 year of treatment, suggesting that their inclusion can work, at least in a sample with predominantly hazardous or harmful alcohol use.

Trends in deaths following drug use in England before, during, and after the COVID-19 lockdowns.

Aim: This research aimed to describe how the characteristics of deaths following drug use changed during the COVID-19 pandemic in England, and how this can inform future strategy to support the health and social care of people who use drugs in future emergency scenarios. Method: All deaths reported to the National Programme on Substance Abuse Deaths which occurred between January 2018 and December 2021 inclusive were extracted for analysis. Exponential smoothing models were constructed to determine any differences between forecasted vs. actual trends. Key results: Following the first lockdown period in England there were significant increases in the proportion of people who died at home beyond the 95% confidence bounds of the exponential smoothing model and concurrent decreases in the proportion of people who died in hospital. Whilst the overall proportion of deaths attributable to opioids did not significantly deviate from the forecasted trend, there were significant increases in methadone-related deaths and decreases in heroin/morphine-related death beyond the 95% confidence bounds. The proportion of deaths concluded as suicide increased, as did those implicating antidepressant use. There were no changes in the proportion of deaths following use of other drug classes, alcohol use in combination with psychoactive drugs, or on decedent demographics (gender, age, and drug user status). A small number of deaths due to drug use had COVID-19 infection itself listed as a cause of death (n = 23). Conclusion: For people who use drugs, the impact of the restrictions due to the COVID-19 pandemic was greater than that of infection from the virus itself. The health and social care strategy for these people needs to be pre-emptively adapted to mitigate against the specific risk factors for fatal drug overdose associated with future emergency scenarios.