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.

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.

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.

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-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.

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.

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.

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 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.

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.

Identity in recovery from problematic alcohol use: A qualitative study of online mutual aid.

AIM: To explore how engagement with online mutual aid facilitates recovery from problematic alcohol use, focusing on identity construction processes. DESIGN: Qualitative in-depth interview study of a maximum variation sample. SETTING: Telephone interviews with UK-based users of Soberistas, an online mutual aid group for people who are trying to resolve their problematic alcohol use. PARTICIPANTS: Thirty-one members, ex-members and browsers of Soberistas (25 women, 6 men): seven currently drinking, the remainder with varying lengths of sobriety (two weeks to five years). FINDINGS: Three key stages of engagement were identified: 1) 'Lurking' tended to occur early in participants' recovery journeys, where they were keen to maintain a degree of secrecy about their problematic alcohol use, but desired support from likeminded people. 2) Actively 'participating' on the site and creating accountability with other members often reflected an offline commitment to make changes in drinking behaviour. 3) 'Leading' was typically reserved for those securely alcohol-free and demonstrated a long-standing commitment to Soberistas; leaders described a sense of duty to give back to newer members in early recovery and many reported an authentic identity, defined by honesty, both on- and off-line. CONCLUSIONS: Engagement with online mutual aid might support recovery by affording users the opportunity to construct and adjust their identities in relation to their problematic alcohol use; individuals can use the parameters of being online to protect their identity, but also as a mechanism to change and consolidate their offline alcohol-related identity.

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.

Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence.

Alcohol use disorders (AUD) cause significant morbidity and mortality worldwide, but pharmacological treatments for them are underused, despite evidence of efficacy. Acamprosate, naltrexone, nalmefene and disulfiram are all approved in one or more region for the treatment of AUD. Baclofen currently has a temporary indication in France. Safety considerations for using psychopharmacological treatments in this patient group include the impact of concurrent alcohol consumption at high levels; multiple physical comorbidities that may interfere with pharmacological effects, distribution and metabolism; and concomitant medication for the treatment of comorbid physical and psychiatric conditions. The five drugs, including an extended-release injectable suspension of naltrexone, have different safety profiles that need to be balanced with the treatment objective (initiation or continuation of abstinence, or reduction of drinking), individual patient preferences and comorbid conditions. Appropriate treatment will be based on the unique risk-benefit profile in each case.

The use of leverage in community mental health: ethical guidance for practitioners.

BACKGROUND: Leverage is a particular type of treatment pressure that is used within community mental health services to increase patients' adherence to treatment. Because leverage involves practitioners making proposals that attempt to influence patients' behaviours and choices, the use of leverage raises ethical issues. AIM: To provide guidance that can assist practitioners in making judgements about whether it is ethically acceptable to use leverage in a particular clinical context. METHOD: Methods of ethical analysis. RESULTS: Four ethical duties relevant to making such judgements are outlined. These four duties are (1) benefitting the individual patient, (2) benefitting other individuals, (3) treating patients fairly and (4) respecting patients' autonomy. The practical requirements that follow from each of these duties are considered in detail. It is argued that practitioners should determine whether the use of leverage will mean that care is provided in ways that are consistent with the requirements of these four duties, regardless of whether the patient accepts or rejects the terms of the proposal made. CONCLUSION: Particular attention must be paid to determine how the requirements of the four duties should be applied in each specific treatment scenario, and in making careful judgements when these duties pull in opposing directions.

"Craving": exploring the components of the Desires for Alcohol Questionnaire (DAQ) and the relation to the severity of alcohol problems.

OBJECTIVE: The aims of this study were (a) to explore the components of craving, as measured by the Desires for Alcohol Questionnaire (DAQ), and (b) to examine how craving may relate to the severity of alcohol problems. METHOD: A total of 106 patients seeking treatment for an alcohol use disorder (AUD) completed the DAQ and Alcohol Use Disorders Identification Test (AUDIT). The overall sample was predominantly male (63%) with a mean age of 44 years. Sixty-one percent of the participants were abstinent from alcohol at the time of the study. Principal components analysis was conducted on the DAQ for the overall, abstinent, and currently drinking samples. Correlations were computed between the DAQ and AUDIT scores, and differences in craving between the abstinent and currently drinking samples were investigated. RESULTS: Components of craving, as measured by the DAQ, included the desire to drink, the ability to control drinking, positive reinforcement and negative reinforcement. Drinkers displayed stronger cravings (Mdn = 47.00, interquartile range [IQR] = 32.0-65.0) than those currently abstinent (Mdn = 33.00, IQR = 26.0-43.0; U = 850.0; z = 3.127, p < .01; r = .30). The intensity of craving increased with the severity of the AUD in current drinkers (r = .739, p < .001). CONCLUSIONS: Because of the small sample size, the results of the study should be regarded as preliminary. The components of craving, as measured by the DAQ, support those previously identified in the literature. The study supports the notion that craving is positively associated with the severity of an AUD.