Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Validity of root cause analysis in investigating adverse events in psychiatry.

Root cause analysis (RCA), imported from high-reliability industries into health two decades ago, is the mandated methodology to investigate adverse events in most health systems. In this analysis, we argue that the validity of RCA in health and in psychiatry must be established, given the impact of these investigations on mental health policy and practice.

Identifying the most important research, policy and practice questions for substance use, problematic alcohol use and behavioural addictions in autism (SABA-A): A priority setting partnership.

BACKGROUND: Autistic people are more likely to report problematic alcohol and other substance use when compared to the general population. Evidence suggests that up to one in three autistic adults may have an alcohol or other substance use disorder (AUD/SUD), although the evidence base for behavioural addictions is less clear. Autistic people may use substances or engage in potentially addictive behaviours as a means of coping with social anxiety, challenging life problems, or camouflaging in social contexts. Despite the prevalence and detrimental effects of AUD, SUD and behavioural addictions in community samples, literature focusing on the intersection between autism and these conditions is scarce, hindering health policy, research, and clinical practice. METHODS: We aimed to identify the top 10 priorities to build the evidence for research, policy, and clinical practice at this intersection. A priority-setting partnership was used to address this aim, comprising an international steering committee and stakeholders from various backgrounds, including people with declared lived experience of autism and/or addiction. First, an online survey was used to identify what people considered key questions about Substance use, alcohol use, or behavioural addictions in autistic people (SABA-A). These initial questions were reviewed and amended by stakeholders, and then classified and refined to form the final list of top priorities via an online consensus process. OUTCOMES: The top ten priorities were identified: three research, three policy, and four practice questions. Future research suggestions are discussed.

Alcohol Consumption Is a Modifiable Risk Factor for Breast Cancer: Are Women Aware of This Relationship?

AIMS: Despite alcohol consumption being a dose-dependent risk factor for breast cancer, a recent study conducted in the UK found <20% of women attending breast screening programmes were aware of this relationship and proposed proper information campaigns need to be conducted. We aimed to investigate the awareness of this relationship among a related sample of Italian women to evaluate whether similar information campaigns should also be conducted in Italy. METHODS: The questionnaire used by the UK study was translated into Italian, slightly modified for the Italian context, validated and submitted to a sample of Italian women. RESULTS: Overall 507 women were interviewed. Among them, 160 were classified as breast cancer screening attenders (SG), 44 as symptomatic breast clinic attenders (CAG) and 303 as non-screening group (NSG). Alcohol was correctly identified as a risk factor for breast cancer by 16.9, 11.4 and 14.9% of participants of SG, CAG and NSG, respectively without differences between the three groups. Despite the methodological differences, the rates of participants who correctly identified alcohol as a risk factor among women attending breast screening programmes were surprisingly similar between the study conducted in UK (15.7%) and the present study (16.9%). CONCLUSION: The results of the present study confirm the limited awareness of the relationship between alcohol consumption and risk of developing breast cancer among women and suggest the urgent need to conduct proper awareness-raising campaigns to counter this in the Italian female population.

Alcohol use and breast cancer risk: A qualitative study of women's perspectives to inform the development of a preventative intervention in breast clinics.

OBJECTIVE: This study aimed to explore women's views about breast cancer risk and alcohol use, to inform the design of a prototype for an intervention in breast clinics about alcohol as a modifiable risk factor for breast cancer. METHODS: Women recruited in NHS breast screening and symptomatic clinics in Southampton, UK, were invited to take part in semi-structured telephone interviews or a focus group to discuss their perspectives of breast cancer risk, alcohol consumption and their information needs about these topics. Data were analysed thematically. Twenty-eight women took part in telephone interviews, and 16 attended one of three focus groups. RESULTS: While most women reported a personal responsibility for their health and were interested in advice about modifiable risk factors, few without (or prior to) experience of breast symptoms independently sought information. Many considered alcohol advice irrelevant as the association with breast cancer was largely unknown, and participants did not consider their drinking to be problematic. Women reported trusting information from health organisations like the NHS, but advice needs to be sensitive and non-blaming. CONCLUSION: NHS breast screening and symptomatic clinics offer a "teachable moment" to engage women with context-specific advice about alcohol and cancer risk that, if targeted correctly, may assist them in making informed lifestyle choices.

Attentional biases in patients with alcohol dependence: influence of coexisting psychopathology.

OBJECTIVE: The effects of coexisting psychopathology on disorder-specific attentional biases in patients with alcohol dependence are uncertain. We undertook a cross-sectional study assessing attentional biases to alcohol-, depression-, and anxiety- related stimuli using the visual probe task in patients with alcohol dependence, attending a community alcohol service. METHODS: Using the visual probe task, we presented disorder-specific words (relating to alcohol, anxiety, and depression) for 500 ms and measured reaction times. RESULTS: Participants demonstrated a significant attentional bias towards alcohol-related cues (mean 8.5, p = 0.03) but significant avoidance of depression-related cues (mean -8.4, p = 0.01). The subgroup of participants who were recently abstinent (n = 70) showed greatest avoidance of depression-related cues (t(69) = 2.68, p < 0.01) but no significant vigilance towards alcohol or anxiety cues, whereas those still drinking (n = 43) showed attentional biases towards alcohol-related (t(42) = 2.70, p = 0.01) and social anxiety-related cues (t(42) = 2.84, p < 0.01). In the whole sample, the magnitude of attentional bias to alcohol was not correlated with length of drinking history, number of comorbid conditions, or severity of anxiety/depression. CONCLUSIONS: In a clinical sample of alcohol-dependent patients, further investigation is required to explore whether these attentional biases reflect current drinking status or factors indicating prognosis.

Alcohol-medication interactions: A systematic review and meta-analysis of placebo-controlled trials.

Alcohol and other xenobiotics may limit the therapeutic effects of medications. We aimed at investigating alcohol-medication interactions (AMI) after the exclusion of confounding effects related to other xenobiotics. We performed a systematic review and meta-analysis of controlled studies comparing the effects induced by alcohol versus placebo on pharmacodynamic and/or pharmacokinetic parameters of approved medications. Certainty in the evidence of AMI was assessed when at least 3 independent studies and at least 200 participants were available. We included 107 articles (3097 participants): for diazepam, cannabis, opioids, and methylphenidate, we found significant AMI and enough data to assign the certainty of evidence. Alcohol consumption significantly increases the peak plasma concentration of diazepam (low certainty; almost 290 participants), cannabis (high certainty; almost 650 participants), opioids (low certainty; 560 participants), and methylphenidate (moderate certainty; 290 participants). For most medications, we found some AMI but not enough data to assign them the certainty grades; for some medications, we found no differences between alcohol and placebo in any outcomes evaluated. Our results add further evidence for interactions between alcohol and certain medications after the exclusion of confounding effects related to other xenobiotics. Physicians should advise patients who use these specific medications to avoid alcohol consumption. Further studies with appropriate control groups, enough female participants to investigate sex differences, and elderly population are needed to expand our knowledge in this field. Short phrases suitable for indexing terms.

Healthcare and social services resource use and costs of self-harm patients.

BACKGROUND: Patients who have self-harmed have increased morbidity across a wide range of health outcomes, but there is no evidence on their pattern of health and social service use, and its relationship with repetition of self-harm. Previous studies have shown that resource use and costs in the short-term hospital management of self-harm is associated with certain patient and service characteristics but their impact in the longer term has not been demonstrated. The aim of this study is to test the association between changing levels of costs of health and social care with further episodes of self-harm and to identify the clinical and social factors associated with this. METHOD: This was a cost-analysis incidence study of a sample of patients from a cohort of self-harm patients who remained within one region over the course of their follow-up. Resource use was retrospectively observed from their first episode of self-harm (dating back on some occasions to the 1970's), and costs applied. Panel data analyses were used to identify factors associated with observed costs over time. RESULTS: Patients with five or more episodes of self-harm had the highest levels of resource costs. Health and social care costs reduced with time from last episode of self-harm. In the year following the first episode of self-harm, psychiatric care accounted for 69% and psychotropic drug prescriptions 1% of the mean resource costs. CONCLUSIONS: The management of self-harm occurs within a complex system of health and social care. Major self-harm repeaters place the greatest cost burden on the system. Better understanding of the impact of risk assessment models and consequent service provision on clinical outcome may help in the design of effective services for this patient group.

Slow associative learning in alcohol dependence and the alcohol cue exposure treatment paradox.

AIMS: To examine two explanations for the observation that cue-exposure treatment has not been clearly effective in the treatment of alcohol dependence: do alcohol-dependent individuals have either (1) slower extinction and/or (2) greater contextual specificity of extinction than non-dependent individuals? DESIGN: In two exploratory laboratory experiments we used mixed factorial designs with two-group between-subjects factors and within-subjects factors corresponding to performance in different parts of a computer-based learning task. SETTING: University of Southampton psychology research laboratories and two addiction treatment services in the city of Southampton, UK. PARTICIPANTS: Experiment 1: 74 (54 female) undergraduates from the University of Southampton (age mean = 20.4 years). Experiment 2: 102 (40 female) participants from the University of Southampton, the local community, and from two Southampton alcohol treatment services (age mean = 41.3 years). MEASUREMENTS: The Alcohol Use Disorders Identification Test, a 1-week time-line follow-back alcohol consumption questionnaire, the Barratt Impulsiveness Scale (11th edn), and a computerized learning task. Experiment 2 additionally used the 44-item Big Five Inventory, a drug use history checklist, and the Hospital Anxiety and Depression Scale. FINDINGS: Experiment 1: light and heavy drinkers did not differ significantly in extinction [extinction block × drinking status interaction, P = 0.761, ηp2=0.005 , 95% confidence interval (CI) = (0,0.028)] or on contextual control of extinction [recovery block × drinking status interaction, P = 0.514, ηp2=0.009 , 95% CI =(0, 0.084)]. Experiment 2: slower extinction in abstinent alcohol-dependent participants compared with light drinkers [extinction block × drinking status interaction, P = 0.023, ηp2=0.031 , 95% CI = 0, 0.069)] but no significant difference on contextual control of extinction [recovery block × drinking status interaction, P = 0.069, ηp2=0.033 , 95% CI = (0, 0.125)]. CONCLUSION: Abstinent alcohol-dependent people may have slower extinction learning for alcohol-related cues than non-dependent light drinkers.

Alcohol use disorder and the liver.

Alcohol use disorders (AUD) cause a range of physical harms, but the major cause of alcohol-related mortality is alcohol-related liver disease (ALD), in some countries accounting for almost 90% of alcohol-related deaths. The risk of ALD has an exponential relationship with increasing alcohol consumption, but is also associated with genetic factors, other life-style factors and social deprivation. ALD includes a spectrum of progressive pathology, from liver steatosis to fibrosis and liver cirrhosis. There are no specific treatments for liver cirrhosis, but abstinence from alcohol is key to limit progression of the disease. Over time, cirrhosis can progress (often silently) to decompensated cirrhosis and hepatocellular carcinoma (HCC). Liver transplantation may be suitable for patients with decompensated liver cirrhosis and may also be used as a curative intervention for HCC, but only for a few selected patients, and complete abstinence is a prerequisite. Patients with AUD are also at risk of developing alcoholic hepatitis, which has a high mortality and limited evidence for effective therapies. There is a strong evidence base for the effectiveness of psychosocial and pharmacological interventions for AUD, but very few of these have been trialled in patients with comorbid ALD. Integrated specialist alcohol and hepatology collaborations are required to develop interventions and pathways for patients with ALD and ongoing AUD.

The influence of anxiety symptoms on clinical outcomes during baclofen treatment of alcohol use disorder: A systematic review and meta-analysis.

Given the high coexistence of anxiety symptoms in people with alcohol use disorder (AUD), we aimed to determine the influence of anxiety symptoms on outcomes in patients with AUD treated with the GABAB receptor agonist baclofen. A meta-analysis of 13 comparisons (published 2010-2020) including baseline and outcome data on alcohol consumption and anxiety after 12 weeks was undertaken. There were significantly higher rates of abstinent days in patients treated with baclofen compared to placebo (p = 0.004; high certainty evidence); specifically in those with higher baseline anxiety levels (p < 0.00001; high certainty evidence) compared to those with lower baseline anxiety levels (p = 0.20; moderate certainty evidence). The change in anxiety ratings over 12 weeks did not differ between those treated with baclofen or placebo (p = 0.84; moderate certainty evidence). This may be due to different anxiety constructs being measured by scales not validated in this patient group, or that anxiety is not a biobehavioral mechanism by which baclofen may reduce alcohol drinking. Given the prevalence of anxiety symptoms in AUD all these factors warrant further research.

Attentional biases in clinical populations with alcohol use disorders: is co-morbidity ignored?

OBJECTIVE: To identify how psychiatric co-morbidity was identified and assessed, in studies of attentional bias in clinical samples of patients with alcohol use disorders (AUDs). DESIGN: Systematic review methodology was used to identify studies and abstract data on alcohol-related attentional biases and measurement of psychiatric co-morbidity. RESULTS: Seventeen papers were identified that met the criteria for inclusion. All but one study were in patients meeting criteria for alcohol dependence. In 10 of the 17 studies, either no mention or minimal statements were made pertaining to possible co-morbid conditions (including other substance use): five excluded patients with psychiatric diagnoses, (variously defined), and two excluded patients on 'psychotropic medication'. Slow response latencies to all word types were found in studies where co-morbid conditions were not considered. CONCLUSIONS: Despite the high prevalence of psychiatric pathology in patients with AUDs (particularly depression), and the acknowledged impact that this has on aetiology, presentation and outcome, psychiatric co-morbidity has not been consistently measured or described in experimental studies on alcohol-related attentional biases in clinical samples. In order to have an accurate appreciation of the role of attentional biases in patients with AUDs, there needs to be a consistent approach to measuring the co-occurrence of other psychopathology. Further research is needed to assess the impact of co-morbidities on attentional biases in AUDs, to enable the development of more targeted psychological and pharmacological treatments.

Course and outcome of patients with alcohol use disorders following an alcohol intervention during hospital attendance: mixed method study.

BACKGROUND: Alcohol-related presentations to acute hospitals in the UK are increasing, but little is known of the clinical characteristics or natural history of this patient group. AIMS: To describe the clinical characteristics, drinking profile and trajectory of a cohort of patients with alcohol use disorder (AUD) attending hospital, and explore participant perspectives of the impact of hospital attendance on their relationship with alcohol. METHOD: We conducted a mixed method, prospective, observational cohort study of patients with AUD seen in an acute hospital. Participants were interviewed with a range of questionnaires at baseline and followed up on at 6 months. A subsample also completed in-depth qualitative interviews. RESULTS: We recruited 141 patients; 132 (93.6%) were followed up at 6 months and 26 completed qualitative interviews. Of the 141 patients, 60 (42.6%) stated the index hospital episode included the first discussion of their alcohol use in a secondary care setting. Most rated discussion of their alcohol use in hospital as 'very positive' or 'positive' (102/141, 72.3%), but lack of coordinated care with community services undermined efforts to sustain change. At 6 months, 11 (7.8%) patients had died, but in those who survived and completed assessment (n = 121), significant and clinically meaningful improvements were seen across a range of outcomes, with 55 patients (45.5%) showing a favourable drinking outcome at 6 months. CONCLUSIONS: Patients with AUD have high levels of morbidity and mortality, yet many made substantial changes following intervention in hospital for their alcohol use. Prospective trials need to identify the effect of alcohol care teams in optimising this 'teachable moment' for patients.

A Context-Specific Digital Alcohol Brief Intervention in Symptomatic Breast Clinics (Abreast of Health): Development and Usability Study.

BACKGROUND: Potentially modifiable risk factors account for approximately 23% of breast cancer cases. In the United Kingdom, alcohol consumption alone is held responsible for 8% to 10% of cases diagnosed every year. Symptomatic breast clinics focus on early detection and treatment, but they also offer scope for delivery of low-cost lifestyle interventions to encourage a cancer prevention culture within the cancer care system. Careful development work is required to effectively translate such interventions to novel settings. OBJECTIVE: The aim of this study was to develop a theory of change and delivery mechanism for a context-specific alcohol and lifestyle brief intervention aimed at women attending screening and symptomatic breast clinics. METHODS: A formative study combined evidence reviews, analysis of mixed method data, and user experience research to develop an intervention model, following the 6 Steps in Quality Intervention Development (6SQuID) framework. RESULTS: A Web app focused on improving awareness, encouraging self-monitoring, and reframing alcohol reduction as a positive choice to improve health was found to be acceptable to women. Accessing this in the clinic waiting area on a tablet computer was shown to be feasible. An important facilitator for change may be the heightened readiness to learn associated with a salient health visit (a teachable moment). Women may have increased motivation to change if they can develop a belief in their capability to monitor and, if necessary, reduce their alcohol consumption. CONCLUSIONS: Using the 6SQuID framework supported the prototyping and maximized acceptability and feasibility of an alcohol brief intervention for women attending symptomatic breast clinics, regardless of their level of alcohol consumption.

Alcohol consumption among veterinary surgeons in the UK.

BACKGROUND: Alcohol consumption can have both medical and occupational implications and may affect fitness to practise among veterinary surgeons (vets). AIMS: To investigate alcohol consumption and the prevalence and associations of 'at-risk' drinking among vets in the UK. METHODS: Alcohol consumption was measured using the Alcohol Use Disorders Identification Test alcohol consumption questions (AUDIT-C) embedded in a questionnaire which included measures of mental health and psychosocial working conditions, administered to a representative sample of 1796 vets. Scores of >or=4 for women and >or=5 for men were used as an indicator of 'at-risk' drinking. RESULTS: The response rate was 56%. Five per cent of respondents were non-drinkers, 32% low-risk drinkers and 63% at-risk drinkers. The estimated odds of at-risk drinking was not significantly different for men and women. A 1-year increase in age was associated with a 2% reduction in the odds of at-risk drinking (OR 0.98, 95% CI: 0.97-0.99, P < 0.01). There was no significant difference across hours worked or on call in a typical week. Lower psychological demands at work were associated with reduced odds of at-risk drinking (OR 0.75, 95% CI: 0.63-0.90, P < 0.01). CONCLUSIONS: It is estimated that vets drink more frequently than the general population, but consume less on a typical drinking day and have a prevalence of daily and weekly binge drinking that is similar to the general population. The level of alcohol consumption does not appear to be a negative influence on mental health within the profession as a whole.

Co-morbid substance misuse in psychiatric patients: prevalence and association with length of inpatient stay.

Improved management of mental illness with co-morbid substance misuse is an important clinical objective. This study aimed to assess the prevalence of substance misuse in psychiatric inpatients, and to examine the relationship between alcohol misuse and length of hospital admission. A prevalence study conducted over four months, examined rates of co-morbid substance misuse in patients admitted for psychiatric inpatient care. Demographic details and length of hospital stay were collected for all patients and those who gave informed consent were screened for levels of alcohol and substance misuse. Two hundred and thirty-eight patients were admitted during the study period in which 178 (74.8%) consented to take part in the study. A group of 44 (50.6%) men and 26 (29.2%) women were screened positive for alcohol misuse (chi(2) = 8.7, P = 0.003). Cannabis use was acknowledged by 31 (35.2%) men and 10 (11.2%) women (chi(2) = 13.5, P < 0.0001). Presence of co-morbid alcohol misuse was associated with a significantly shorter hospital admission (z = 3.34, P = 0.0008). Co-morbid substance misuse (including alcohol) was reported significantly more frequently by men than women. Overall, patients with co-morbid alcohol misuse had shorter hospital admissions, suggesting different patterns of presentation and progress in hospital. Hospital admission presents an opportunity to identify substance misuse and evaluate treatments for co-morbid conditions within a safe environment.

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30-80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an "off-label" prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

The role of autobiographical memory specificity in deliberate self-harm: correlates and consequences.

BACKGROUND: Several studies have identified reduced specificity of autobiographical memory in deliberate self-harm (DSH) patients. However it is not clear which clinical variables are associated with low memory specificity in this group, or whether low specificity is particularly associated with recent DSH. METHOD: 68 individuals followed up seven years after an index episode of DSH were re-interviewed and data collected on current psychiatric disorder, repetition of DSH in the intervening period and autobiographical memory specificity. Data on history of sexual and physical abuse during childhood were available from the index assessment. RESULTS: A hierarchical regression analysis identified older age, current affective disorder and level of familial sexual abuse during childhood as independent predictors of reduced memory specificity. Sixteen participants who had a further episode of DSH in the year prior to the current assessment were classified as having 'recent' DSH. Results of logistic regression suggest that low memory specificity mediates the association between childhood sexual abuse and recent DSH and partially mediates the association between current affective disorder and recent DSH. LIMITATIONS: The results are based on a relatively small sample of patients from a mixed clinical group, limiting the statistical power of the analysis. CONCLUSIONS: The findings confirm the association between low memory specificity and DSH. They are consistent with a multi-factorial model of impaired specificity and suggest that low specificity may be one of the mechanisms through which abuse history and affective disorder increase an individual's vulnerability to deliberate self-harm.