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In a test of theoretical predictions made by MacRae and Falahee (1995), trained assessors evaluated water samples which sometimes contained 10-5 mg/l of trichloroanisole, using three different procedures. Compared with the blue-book method of single-sample assessment, providing a reference sample identified to the assessor as beingodour-free increased the proportion of responses reporting an odour.This decreased the number of odorous samples missed. Although this outcome may be valuable in itself, discrimination between odorous and odour-free samples was not really enhanced since `false alarms' increased correspondingly. Incorporating additional, different odours intothe sequence of samples and giving knowledge of results when these were judged, dramatically improved performance - the rates both of missing trichloroanisole and of mistakenly attributing odour to odour-free samples were halved. [ABSTRACT FROM AUTHOR]

Ecological Momentary Assessment using smartphone technology (smart EMA) has grown substantially over the last decade. However, little is known about the factors associated with completion rates in populations who have a higher likelihood of cognitive impairment. A systematic review of Smart EMA studies in populations who have a higher likelihood of cognitive impairment was carried out (PROSPERO; ref no CRD42022375829). Smartphone EMA studies in neurological, neurodevelopmental and neurogenetic conditions were included. Six databases were searched, and bias was assessed using Egger's test. Completion rates and moderators were analyzed using meta-regression. Fifty-five cohorts were included with 18 cohorts reporting confirmed cognitive impairment. In the overall cohort, the completion rate was 74.4% and EMA protocol characteristics moderated completion rates. Participants with cognitive impairment had significantly lower completion rates compared with those without ( p  = .021). There were no significant moderators in the cognitive impairment group. Limitations included significant methodological issues in reporting of completion rates, sample characteristics, and associations with completion and dropout rates. These findings conclude that smart EMA is feasible for people with cognitive impairment. Future research should focus on the efficacy of using smart EMA within populations with cognitive impairment to develop an appropriate methodological evidence base., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: England's primary care service for psychological therapy (Improving Access to Psychological Therapies [IAPT]) treats anxiety and depression, with a target recovery rate of 50%. Identifying the characteristics of patients who achieve recovery may assist in optimizing future treatment. This naturalistic cohort study investigated pre-therapy characteristics as predictors of recovery and improvement after IAPT therapy., Methods: In a cohort of patients attending an IAPT service in South London, we recruited 263 participants and conducted a baseline interview to gather extensive pre-therapy characteristics. Bayesian prediction models and variable selection were used to identify baseline variables prognostic of good clinical outcomes. Recovery (primary outcome) was defined using (IAPT) service-defined score thresholds for both depression (Patient Health Questionnaire [PHQ-9]) and anxiety (Generalized Anxiety Disorder [GAD-7]). Depression and anxiety outcomes were also evaluated as standalone (PHQ-9/GAD-7) scores after therapy. Prediction model performance metrics were estimated using cross-validation., Results: Predictor variables explained 26% (recovery), 37% (depression), and 31% (anxiety) of the variance in outcomes, respectively. Variables prognostic of recovery were lower pre-treatment depression severity and not meeting criteria for obsessive compulsive disorder. Post-therapy depression and anxiety severity scores were predicted by lower symptom severity and higher ratings of health-related quality of life (EuroQol questionnaire [EQ5D]) at baseline., Conclusion: Almost a third of the variance in clinical outcomes was explained by pre-treatment symptom severity scores. These constructs benefit from being rapidly accessible in healthcare services. If replicated in external samples, the early identification of patients who are less likely to recover may facilitate earlier triage to alternative interventions.

Functional neurological symptom disorder (FNSD) is a neuropsychiatric diagnosis referring to symptoms resembling those of neurological disorders, occurring without causal neuropathology. FNSD has a complex biopsychosocial aetiology but its mechanisms are poorly understood. Remote monitoring technologies (RMT) could provide critical insights into functional neurological symptoms (FNS) in real-world contexts. We examined the feasibility and acceptability of a novel RMT protocol, to identify psychobiological correlates and antecedents of FNS in everyday life. Seventeen individuals with FNS (seizures/motor) and 17 healthy controls (HC) completed ecological momentary assessments (EMA) eight times daily for 1-week, reporting FNS severity, associated physical and psychological symptoms, and subjectively significant events. Sleep quality was reported daily. Physiological variables were measured using wearable Fitbit 5 devices. Multilevel modelling examined variables associated with FNS variability. Average EMA completion rates were good in both groups (≥80%). At week-level, the FNS group reported significantly greater subjective arousal, pain, fatigue, dissociation, negative affect, daily events, stressful events, and sleep duration, compared to HC. Objective sleep disturbance and duration, and resting heartrate, were also significantly greater in the FNS sample. FNS severity correlated significantly with daily events, affect, subjective arousal, pain, fatigue and sleep disturbance, at day- or within-day levels. Daily events and negative affect were the most prominent time-lagged predictors of within-day moment-to-moment FNS severity. RMTs are feasible and acceptable tools for investigation of FNS in real-world settings, revealing daily events and negative affect as possible triggers of FNS. Interventions targeting affective reactivity and regulation might be beneficial in this group. Larger-scale, longer-term RMT studies are needed in this population., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Data on associations between inflammation and depressive symptoms largely originate from high income population settings, despite the greatest disease burden in major depressive disorder being attributed to populations in lower-middle income countries (LMICs)., Aims: We assessed the prevalence of low-grade inflammation in adults with treatment-resistant depression (TRD) in Pakistan, an LMIC, and investigated associations between peripheral C-reactive protein (CRP) levels and depressive symptoms., Method: This is a secondary analysis of two randomised controlled trials investigating adjunctive immunomodulatory agents (minocycline and simvastatin) for Pakistani adults with TRD ( n = 191). Logistic regression models were built to assess the relationship between pre-treatment CRP (≥ or <3 mg/L) and individual depressive symptoms measured using the Hamilton Depression Rating Scale. Descriptive statistics and regression were used to assess treatment response for inflammation-associated symptoms., Results: High plasma CRP (≥3 mg/L) was detected in 87% ( n = 146) of participants. Early night insomnia (odds ratio 2.33, 95% CI 1.16-5.25), early morning waking (odds ratio 2.65, 95% CI 1.29-6.38) and psychic anxiety (odds ratio 3.79, 95% CI 1.39-21.7) were positively associated, while gastrointestinal (odds ratio 0.38, 95% CI 0.14-0.86) and general somatic symptoms (odds ratio 0.34, 95% CI 0.14-0.74) were negatively associated with inflammation. Minocycline, but not simvastatin, improved symptoms positively associated with inflammation., Conclusions: The prevalence of inflammation in this LMIC sample with TRD was higher than that reported in high income countries. Insomnia and anxiety symptoms may represent possible targets for personalised treatment with immunomodulatory agents in people with elevated CRP. These findings require replication in independent clinical samples.

Introduction: Advances have been made in understanding the aetiology of functional neurological disorder (FND); however, its pathophysiological mechanisms have not been definitively demonstrated. Evidence suggests interacting roles for altered emotional processing and interoception, elevated autonomic arousal, and dissociation, but there is limited evidence demonstrating their causal influence on specific FND symptoms. Our superordinate aim is to elucidate potentially shared and distinct aetiological factors and mechanisms in two common FND subtypes, functional seizures (FS) and functional motor symptoms (FMS)., Methods: This study has a multimodal, mixed between- and within-groups design. The target sample is 50 individuals with FS, 50 with FMS, 50 clinical controls (anxiety/depression), and 50 healthy controls. Potential aetiological factors (e.g., adverse life events, physical/mental health symptoms, dissociative tendencies, interoceptive insight/sensibility) will be assessed with a detailed medical history interview and self-report questionnaires. A laboratory session will include a neurocognitive battery, psychophysiological testing, cardiac interoception and time estimation tasks and an isometric handgrip task. A subsample will undergo magnetic resonance imaging, including structural, resting-state and task-based scans combined with psychophysiological recording. Remote monitoring with ecological momentary assessment and wearables will measure variability in FND symptoms and their potential predictors/correlates for ≥2 weeks in patients' daily lives. Longitudinal follow-ups at 3, 6, and 12-months will monitor longer-term outcomes in the clinical groups., Discussion: This study employs multimodal research methods to rigorously examine several putative mechanisms in FND, at subjective/experiential, behavioural, and physiological levels. The study will test causal hypotheses about the role of altered emotional processing, autonomic arousal, dissociation and interoception in the initiation or exacerbation of FND symptoms, directly comparing these processes in FS and FMS to healthy and clinical controls. This is the first study of its kind, with potential to reveal important targets for prevention and treatment of FND in future., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pick et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: People with functional/dissociative seizures (FDS) are at elevated suicidality risk., Objective: To identify risk factors for suicidality in FDS or epilepsy., Methods: Retrospective cohort study from the UK's largest tertiary mental healthcare provider, with linked national admission data from the Hospital Episode Statistics. Participants were 2383 people with a primary or secondary diagnosis of FDS or epilepsy attending between 01 January 2007 and 18 June 2021. Outcomes were a first report of suicidal ideation and a first hospital admission for suicide attempt (International Classification of Diseases, version 10: X60-X84). Demographic and clinical risk factors were assessed using multivariable bias-reduced binomial-response generalised linear models., Findings: In both groups, ethnic minorities had significantly reduced odds of hospitalisation following suicide attempt (OR: 0.45-0.49). Disorder-specific risk factors were gender, age and comorbidity profile. In FDS, both genders had similar suicidality risk; younger age was a risk factor for both outcomes (OR: 0.16-1.91). A diagnosis of depression or personality disorders was associated with higher odds of suicidal ideation (OR: 1.91-3.01). In epilepsy, females had higher odds of suicide attempt-related hospitalisation (OR: 1.64). Age had a quadratic association with both outcomes (OR: 0.88-1.06). A substance abuse disorder was associated with higher suicidal ideation (OR: 2.67). Developmental disorders lowered the risk (OR: 0.16-0.24)., Conclusions: This is the first study systematically reporting risk factors for suicidality in people with FDS. Results for the large epilepsy cohort complement previous studies and will be useful in future meta-analyses., Clinical Implications: Risk factors identified will help identify higher-risk groups in clinical settings., Competing Interests: Competing interests: IF, JH, IJ and PS—none to declare. AY—employed by King’s College London; honorary consultant of SLaM (NHS UK); deputy editor of BJPsych Open; paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, LivaNova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage and Novartis; consultant to Johnson & Johnson and LivaNova; received honoraria for attending advisory boards and presenting talks at meetings organised by LivaNova; principal investigator in the Restore-Life VNS registry study funded by LivaNova; principal investigator on ESKETINTRD3004: ‘An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression’; principal investigator on ‘The Effects of Psilocybin on Cognitive Function in Healthy Participants’; principal investigator on ‘The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)’; UK chief investigator for Novartis MDD Study MIJ821A12201; grant funding (past and present): NIMH (USA), CIHR (Canada), NARSAD (USA), Stanley Medical Research Institute (USA), MRC (UK), Wellcome Trust (UK), Royal College of Physicians (Edin), BMA (UK), UBC-VGH Foundation (Canada), WEDC (Canada), CCS Depression Research Fund (Canada), MSFHR (Canada), NIHR (UK) and Janssen (UK); no shareholdings in pharmaceutical companies., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers. Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers ( n =46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry. Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) ( p <0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] ( p <0.05), respectively. Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).

Aims: To test how attentional bias and explicit liking are influenced by delta-9-tetrahydrocannabinol (THC) and whether these effects are moderated by cannabidiol (CBD)., Design: Double-blind, randomised, within-subjects cross-over study., Setting: NIHR Wellcome Trust Clinical Research Facility at King's College Hospital, London, United Kingdom., Participants/cases: Forty-six infrequent cannabis users (cannabis use <1 per week)., Intervention(s): Across four sessions, participants inhaled vaporised cannabis containing 10 mg of THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1) or 30 mg (3:1) of CBD, administered in a randomised order and counter-balanced across participants (a total of 24 order groups)., Measurements: Participants completed two tasks: (1) Attentional Bias (AB), comparing reaction times toward visual probes presented behind 28 target stimuli (cannabis/food) compared with probes behind corresponding non-target (neutral) stimuli. Participants responding more quickly to probes behind target than non-target stimuli would indicate greater attentional bias to cannabis/food; (2) Picture Rating (PR), where all AB stimuli were rated on a 7-point pleasantness scale, measuring explicit liking., Findings: During the AB task, participants were more biased toward cannabis stimuli in the 0:1 condition compared with baseline (mean difference = 12.2, 95% confidence intervals [CIs] = 1.20-23.3, d = 0.41, P = 0.03). No other significant AB or PR differences were found between cannabis and food stimuli between baseline and 0:1 condition (P > 0.05). No significant CBD effect was found on AB or PR task performance at any dose (P > 0.05). There was additionally no cumulative effect of THC exposure on AB or PR outcomes (P > 0.05)., Conclusions: A double-blind, randomised, cross-over study among infrequent cannabis users found that inhaled delta-9-tetrahydrocannabinol increased attentional bias toward cannabis in the absence of explicit liking, a marker of liability toward cannabis use disorder. At the concentrations normally found in legal and illegal cannabis, cannabidiol had no influence on this effect., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background and Hypothesis: Use of clozapine in treatment-resistant schizophrenia is often limited due to risk of adverse effects. Cross-sectional associations between clozapine treatment and low immunoglobulin levels have been reported, however prospective studies are required to establish temporal relationships. We tested the hypothesis that reductions in immunoglobulin levels would occur over the first 6 months following initiation of clozapine treatment. Relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment were also explored., Design: This prospective observational study measured immunoglobulin (Ig) levels (A, M and G) in 56 patients with treatment-resistant schizophrenia at 6-, 12- and 24-weeks following initiation with clozapine. Clinical symptoms were also measured at 12 weeks using the positive and negative syndrome scale (PANSS)., Results: IgA, IgG and IgM all decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: β = -32.66, 95% CI = -62.38, -2.93, p = 0.03; IgG: β = -63.96, 95% CI = -118.00, -9.31, p = 0.02). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: β = -23.48, 95% CI = -39.56, -7.42, p = 0.004; 24 weeks: β = -33.12, 95 %CI = -50.30, -15.94, p = <0.001). Reductions in IgA and IgG during clozapine treatment were correlated with reductions in PANSS-total over 12 weeks (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.48, p = 0.03)., Conclusions: The observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. Associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Objective: There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan., Methods: The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or < 3 mg/L and log10CRP) and clinical and demographic features of interest and symptoms of depression. Baseline clinical trial data was used to extract clinical and demographic features and symptoms of depression were assessed using the 24-item Hamilton Depression Rating Scale., Results: The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation., Conclusions: Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.

Introduction: Multi-family therapy for anorexia nervosa (MFT-AN) is a novel, group-based intervention that intensifies single-family therapy for anorexia nervosa (FT-AN), with the aim of improving outcomes. The current study explored treatment moderators in a randomised controlled trial (N = 167) of FT-AN and MFT-AN for young people (adolescents/emerging adults aged 13-20 years) with anorexia nervosa., Methods: Data were analysed using multiple linear regression. Six hypothesised baseline participant and parent factors were tested as possible moderators of treatment effect on end-of-treatment and follow-up percentage of median Body Mass Index (%mBMI); age, eating disorder symptom severity, perceived family conflict (young person and parent ratings) and parent-rated experiences of caregiving (positive and negative)., Results: Greater parent-rated positive caregiving experiences moderated treatment outcomes at follow-up (β = -0.47, 95%CI: -0.91, -0.03, p = 0.04), but not end-of-treatment. Participants who had fewer parent-rated positive caregiving experiences at baseline had higher weight at follow-up if they had MFT-AN compared to FT-AN. No other hypothesised baseline factors moderated treatment outcome (p's > 0.05)., Discussion: The current study suggests MFT-AN may be indicated for families who present with fewer positive caregiving experiences to treatment. The MFT-AN group context may help to promote mentalisation and hope for these families, which may be harder to achieve in single-family treatment. Future research is needed to empirically evaluate how and why MFT-AN supports this group more., Trial Registration: ISRCTN registry: ISRCTN11275465, registered 29 January 2007., (© 2023 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.)

Background: Mental wellbeing encompasses life satisfaction, social connectedness, agency and resilience. In adolescence, mental wellbeing reduces sexual health risk behaviours, substance use and violence; improves educational outcomes; and protects mental health in adulthood. Mental health promotion seeks to improve mental wellbeing and can include activities to engage participants in sport. However, few high-quality trials of mental health promotion interventions have been conducted with adolescents, especially in low- and middle-income countries. We sought to address this gap by testing SMART (Sports-based Mental heAlth pRomotion for adolescenTs) in a pilot cluster-randomised controlled trial (cRCT) in Bardiya, Nepal., Methods: The objectives of the trial are to assess the acceptability and feasibility of SMART, test trial procedures, explore outcome distributions in intervention and control clusters and calculate the total annual cost of the intervention and unit cost per adolescent. The trial design is a parallel-group, two-arm superiority pilot cRCT with a 1:1 allocation ratio and two cross-sectional census surveys with adolescents aged 12-19, one pre-intervention (baseline) and one post-intervention (endline). The study area is four communities of approximately 1000 population (166 adolescents per community). Each community represents one cluster. SMART comprises twice weekly football, martial arts and dance coaching, open to all adolescents in the community, led by local sports coaches who have received psychosocial training. Sports melas (festivals) and theatre performances will raise community awareness about SMART, mental health and the benefits of sport. Adolescents in control clusters will participate in sport as usual. In baseline and endline surveys, we will measure mental wellbeing, self-esteem, self-efficacy, emotion regulation, social support, depression, anxiety and functional impairment. Using observation checklists, unstructured observation and attendance registers from coaching sessions, and minutes of meetings between coaches and supervisors, we will assess intervention fidelity, exposure and reach. In focus group discussions and interviews with coaches, teachers, caregivers and adolescents, we will explore intervention acceptability and mechanisms of change. Intervention costs will be captured from monthly project accounts, timesheets and discussions with staff members., Discussion: Findings will identify elements of the intervention and trial procedures requiring revision prior to a full cRCT to evaluate the effectiveness of SMART., Trial Registration: ISRCTN, ISRCTN15973986 , registered on 6 September 2022; ClinicalTrials.gov, NCT05394311 , registered 27 May 2022., (© 2023. BioMed Central Ltd., part of Springer Nature.)

As countries adopt more permissive cannabis policies, it is increasingly important to identify strategies that can reduce the harmful effects of cannabis use. This study aimed to determine if increasing the CBD content of cannabis can reduce its harmful effects. Forty-six healthy, infrequent cannabis users participated in a double-blind, within-subject, randomised trial of cannabis preparations varying in CBD content. There was an initial baseline visit followed by four drug administration visits, in which participants inhaled vaporised cannabis containing 10 mg THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg (3:1) CBD, in a randomised, counter-balanced order. The primary outcome was change in delayed verbal recall on the Hopkins Verbal Learning Task. Secondary outcomes included change in severity of psychotic symptoms (e.g., Positive and Negative Syndrome Scale [PANSS] positive subscale), plus further cognitive, subjective, pleasurable, pharmacological and physiological effects. Serial plasma concentrations of THC and CBD were measured. THC (0:1) was associated with impaired delayed verbal recall (t(45) = 3.399, d = 0.50, p = 0.001) and induced positive psychotic symptoms on the PANSS (t(45) = -4.709, d = 0.69, p = 2.41 × 10 -5 ). These effects were not significantly modulated by any dose of CBD. Furthermore, there was no evidence of CBD modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, and physiological measures. There was a dose-response relationship between CBD dose and plasma CBD concentration, with no effect on plasma THC concentrations. At CBD:THC ratios most common in medicinal and recreational cannabis products, we found no evidence that CBD protects against the acute adverse effects of cannabis. This should be considered in health policy and safety decisions about medicinal and recreational cannabis., (© 2022. The Author(s).)

Autism spectrum disorder (ASD) often co-occurs with attention-deficit/hyperactivity disorder (ADHD) and people with these conditions have frontostriatal functional atypicality during motor inhibition. We compared the neural and neurocognitive correlates of motor inhibition and performance monitoring in young adult males with "pure" and combined presentations with age-and sex-matched typically developing controls, to explore shared or disorder-specific atypicality. Males aged 20-27 years with typical development (TD; n = 22), ASD (n = 21), combined diagnoses ASD + ADHD (n = 23), and ADHD (n = 25) were compared using a modified tracking fMRI stop-signal task that measures motor inhibition and performance monitoring while controlling for selective attention. In addition, they performed a behavioural go/no-go task outside the scanner. While groups did not differ behaviourally during successful stop trials, the ASD + ADHD group relative to other groups had underactivation in typical performance monitoring regions of bilateral anterior insula/inferior frontal gyrus, right posterior thalamus, and right middle temporal gyrus/hippocampus during failed inhibition, which was associated with increased stop-signal reaction time. In the behavioural go/no-go task, both ADHD groups, with and without ASD, had significantly lower motor inhibition performance compared to TD controls. In conclusion, only young adult males with ASD + ADHD had neurofunctional atypicality in brain regions associated with performance monitoring, while inhibition difficulties on go/no-go task performance was shared with ADHD. The suggests that young people with ASD + ADHD are most severely impaired during motor inhibition tasks compared to ASD and ADHD but do not reflect a combination of the difficulties associated with the pure disorders., (© 2023. The Author(s).)

Importance: Immune-metabolic disturbances have been implicated in the pathophysiology of major depressive disorder and may be more prominent in individuals with treatment-resistant depression (TRD). Preliminary trials suggest that lipid-lowering agents, including statins, may be useful adjunctive treatments for major depressive disorder. However, no adequately powered clinical trials have assessed the antidepressant efficacy of these agents in TRD., Objective: To assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD., Design, Setting, and Participants: This 12-week, double-blind, placebo-controlled randomized clinical trial was conducted in 5 centers in Pakistan. The study involved adults (aged 18-75 years) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) major depressive episode that had failed to respond to at least 2 adequate trials of antidepressants. Participants were enrolled between March 1, 2019, and February 28, 2021; statistical analysis was performed from February 1 to June 15, 2022, using mixed models., Intervention: Participants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo., Main Outcomes and Measures: The primary outcome was the difference between the 2 groups in change in Montgomery-Åsberg Depression Rating Scale total scores at week 12. Secondary outcomes included changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, and the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. C-reactive protein and plasma lipids were measured at baseline and week 12., Results: A total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n = 73; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-Åsberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, -0.61; 95% CI, -3.69 to 2.46; P = .70). Similarly, there were no significant group differences in any of the secondary outcomes or evidence for differences in adverse effects between groups. A planned secondary analysis indicated that changes in plasma C-reactive protein and lipids from baseline to end point did not mediate response to simvastatin., Conclusions and Relevance: In this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care., Trial Registration: ClinicalTrials.gov Identifier: NCT03435744.

Background and Objectives: We know little about how symptoms of obsessive-compulsive disorder and depression interact during psychological therapy. Although some previous research suggests that reductions in the severity of depression are driven by reductions in OCD, support for this conclusion is limited due to the exclusion of individuals with severe depression and limitations of the statistical approaches used., Methods: This study re-examined the interaction between symptoms of OCD and depression during therapy in a sample of 137 adults with a primary diagnosis of OCD and a full range of depression severity. All participants received a 12 to 16-week specialist residential treatment. Participants completed the Florida Obsessive Compulsive Inventory and Patient Health Questionnaire for depression weekly. The relationship between severity of OCD and depression was examined using a random intercept cross-lagged panel model., Results: Both cross-lagged paths were significant, with prior levels of OCD influencing subsequent levels of depression, and prior levels of depression influencing subsequent levels of OCD., Limitations: The present study was conducted in a residential setting, meaning the findings may not generalise to outpatient settings characterised by less severe OCD and depression., Conclusions: Contrary to previous findings, which suggest that the influence of OCD on depression is far greater than the reverse, our findings suggest that OCD and depression influence each other equally. As improvements in mood can help to improve symptoms of OCD, it appears important to target depression concurrently during treatment for OCD. This would be a new treatment target for improvement outcomes in OCD., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To test the hypothesis that people with concurrent diagnosis of epilepsy and psychogenic nonepileptic seizures (PNES) are at increased risk of attempting suicide as compared to people with epilepsy or PNES alone. To report on suicide rates., Methods: Retrospective cohort study from the UK largest tertiary mental health care provider, with linked nationwide admission and mortality data from the Hospital Episode Statistics and Office for National Statistics. Participants were 2460 people with a primary or secondary diagnosis of epilepsy, PNES or concurrent epilepsy and PNES attending between 1 January 2007 and 18 June 2021. The primary outcome was a first hospital admission for suicide attempt (International Classification of Diseases, version 10 X60-X84)., Results: 9% of participants had at least one suicide attempt-related hospital admission. For people with concurrent diagnosis of epilepsy and PNES, the odds for suicide attempt-related admissions were 2.52 times the odds of people with epilepsy alone (OR 0.40; 95% CI 0.21 to 0.79; p=0.01). Odds were comparable between people with concurrent diagnosis and people with PNES alone (OR 0.75; 95% CI 0.41 to 1.48; p=0.40). Post hoc analyses revealed that the odds of people with PNES alone were 1.93 times the odds of people with epilepsy alone (OR 0.52; 95% CI 0.38 to 0.70; p<0.001)., Conclusions: People with concurrent diagnosis of epilepsy and PNES or PNES alone have significantly increased odds of hospitalisation due to suicide attempt as compared to people with epilepsy alone (152% and 93% increase, respectively). These findings have direct implications for the clinical management of suicide risk in people with epilepsy., Competing Interests: Competing interests: IF, JH and PS: none to declare. Allan H. Young: Employed by King’s College London; Honorary Consultant SLaM (NHS UK). Deputy Editor, BJPsych Open. Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis. Consultant to Johnson & Johnson. Consultant to Livanova. Received honoraria for attending advisory boards and presenting talks at meetings organised by LivaNova. Principal Investigator in the Restore-Life VNS registry study funded by LivaNova. Principal investigator on ESKETINTRD3004: ‘An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.’ Principal Investigator on ‘The Effects of Psilocybin on Cognitive Function in Healthy Participants’. Principal investigator on ‘The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)’. UK Chief Investigator for Novartis MDD study MIJ821A12201. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK). No shareholdings in pharmaceutical companies., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: This trial examined the feasibility, acceptability, and effect sizes of clinical outcomes of an intervention that combines inhibitory control training (ICT) and implementation intentions (if-then planning) to target binge eating and eating disorder psychopathology., Methods: Seventy-eight adult participants with bulimia nervosa or binge eating disorder were randomly allocated to receive food-specific, or general, ICT and if-then planning for 4 weeks., Results: Recruitment and retention rates at 4 weeks (97.5% and 79.5%, respectively) met the pre-set cut-offs. The pre-set adherence to the intervention was met for the ICT sessions (84.6%), but not for if-then planning (53.4%). Binge eating frequency and eating disorder psychopathology decreased in both intervention groups at post-intervention (4 weeks) and follow-up (8 weeks), with moderate to large effect sizes. There was a tendency for greater reductions in binge eating frequency and eating disorders psychopathology (i.e. larger effect sizes) in the food-specific intervention group. Across both groups, ICT and if-then planning were associated with small-to-moderate reductions in high energy-dense food valuation (post-intervention), food approach (post-intervention and follow-up), anxiety (follow-up), and depression (follow-up). Participants indicated that both interventions were acceptable., Conclusions: The study findings reveal that combined ICT and if-then planning is associated with reductions in binge eating frequency and eating disorder psychopathology and that the feasibility of ICT is promising, while improvements to if-then planning condition may be needed.

Differences in infant caregiving behavior between cultures have long been noted, although the quantified comparison of touch-based caregiving using uniform standardized methodology has been much more limited. The Parent-Infant Caregiving Touch scale (PICTS) was developed for this purpose and programming effects of early parental tactile stimulation (stroking) on infant hypothalamic-pituitary adrenal (HPA)-axis functioning (stress-response system), cardiovascular regulation and behavioral outcomes, similar to that reported in animals, have now been demonstrated. In order to inform future studies examining such programming effects in India, we first aimed to describe and examine, using parametric and non-parametric item-response methods, the item-response frequencies and characteristics of responses on the PICTS, and evidence for cross-cultural differential item functioning (DIF) in the United Kingdom (UK) and India. Second, in the context of a cultural favoring of male children in India, we also aimed to test the association between the sex of the infant and infant "stroking" in both cultural settings. The PICTS was administered at 8-12 weeks postpartum to mothers in two-cohort studies: The Wirral Child Health and Development Study, United Kingdom ( n  = 874) and the Bangalore Child Health and Development Study, India ( n  = 395). Mokken scale analysis, parametric item-response analysis, and structural equation modeling for categorical items were used. Items for two dimensions, one for stroking behavior and one for holding behavior, could be identified as meeting many of the criteria required for Mokken scales in the United Kingdom, only the stroking scale met these criteria in the sample from India. Thus, while a comparison between the two cultures was possible for the stroking construct, comparisons for the other non-verbal parenting constructs within PICTS were not. Analyses revealed higher rates of early stroking being reported for the United Kingdom than India, but no sex differences in rates in either country and no differential sex difference by culture. We conclude that PICTS items can be used reliably in both countries to conduct further research on the role of early tactile stimulation in shaping important child development outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hodsoll, Pickles, Bozicevic, Supraja, Hill, Chandra and Sharp.)

Background: Findings from randomised control trials inform the development of evidence-based eating disorder (ED) practice guidelines internationally. Only recently are data beginning to emerge regarding how these treatments perform outside of research settings. This study aimed to evaluate treatment pathways and outcomes for a specialist child and adolescent ED service across a five-year period., Methods: All consecutive referrals between August 2009 and January 2014 seen at the Maudsley Centre for Child and Adolescent Eating Disorders in London were included. Data are reported on for all young people who were offered treatment (N = 357)., Results: Most young people referred to the service were diagnosed with anorexia nervosa (AN)/Atypical AN (81%). Treatment for AN/Atypical AN (median 11 months) was predominantly ED focused family therapy (99%). Treatment for bulimia nervosa (BN)/Atypical BN (median seven months) was most commonly a combination of cognitive behavioural therapy and ED focused family therapy (87%). At discharge, 77% of the AN/Atypical AN group had a good or intermediate outcome and 59% of the BN/Atypical BN group reported no or fewer than weekly bulimic episodes. 27% of the AN/Atypical AN group had enhanced treatment with either day- and/or inpatient admissions (AIM group). The %mBMI at 3 months of treatment was strongest predictor of the need for treatment enhancement and more modestly EDE-Q and age at assessment. The AIM group at assessment had significantly lower weight, and higher ED and comorbid symptomatology and went on to have significantly longer treatment (16 vs. 10 months). At discharge, this group had significantly fewer good and more poor outcomes on the Morgan Russell criteria, but similar outcomes regarding ED and comorbid symptoms and quality of life. When analysis was adjusted for %mBMI at assessment, 1 and 3 months of treatment, differences in Morgan Russell outcomes and %mBMI were small and compatible with no difference in outcome by treatment group., Conclusions: This study shows that outcomes in routine clinical practice in a specialist community-based service compare well to those reported in research trials. The finding from research trials that early weight gain is associated with improved outcomes was also replicated in this study. Enhancing outpatient treatment with day treatment and/or inpatient care is associated with favourable outcome for most of the young people, although a longer duration of treatment is required., (© 2022. The Author(s).)

Background: Metabolic dysfunction is prevalent in bipolar disorder (BD) and associated with illness severity and treatment outcomes. There is little research exploring this relationship in low and middle-income countries (LMICs) and little is known about the moderating effect of metabolic health on treatment response to anti-inflammatory drugs in BD., Methods: MINDCARE, a randomized-controlled-trial conducted in Pakistan, investigated the efficacy of minocycline and celecoxib in 266 adults with bipolar depression. This secondary analysis evaluated the association between depression severity at baseline and treatment outcome with metabolic parameters including body mass index (BMI), waist circumference (WC), heart rate (HR), systolic blood pressure (s-BP), and diastolic blood pressure (d-BP). Depression severity was measured using the Hamilton Depression Rating Scale-17. The exploratory aim was to assess whether treatment impacted change in metabolic variables. Associations were evaluated using linear regression., Results: Higher BMI (B=-0.38, 95%CI: -0.55 to -0.21) and WC (B=-0.68, 95%CI: -0.97 to -0.39) were associated with lower baseline depression severity in both the unadjusted and the adjusted models. Baseline metabolic parameters were not associated with treatment response to minocycline or celecoxib nor did treatment significantly impact metabolic variables., Limitations: Our sample represents patients in an RCT and may not be fully representative of the overall BD population in Pakistan., Conclusions: Our findings indicate a potential association of poor metabolic health and lower severity of bipolar depression but not treatment outcomes. Future work should evaluate potential relationships of metabolic parameters and BD in diverse populations to increase the transferability of this line of work., (Copyright © 2021. Published by Elsevier B.V.)

Current treatments for binge eating disorder (BED) and bulimia nervosa (BN) only show moderate efficacy, warranting the need for novel interventions. Impairments in food-related inhibitory control contribute to BED/BN and could be targeted by food-specific inhibitory control training (ICT). The aim of this study was to establish the feasibility and acceptability of augmenting treatment for individuals with BN/BED with an ICT app (FoodT), which targets motor inhibition to food stimuli using a go/no-go paradigm. Eighty patients with BED/BN receiving psychological and/or pharmacological treatment were randomly allocated to a treatment-as-usual group (TAU; n = 40) or TAU augmented with the 5-min FoodT app daily (n = 40) for 4 weeks. This mixed-methods study assessed feasibility outcomes, effect sizes of clinical change, and acceptability using self-report measures. Pre-registered cut-offs for recruitment, retention, and adherence were met, with 100% of the targeted sample size (n = 80) recruited within 12 months, 85% of participants retained at 4 weeks, and 80% of the FoodT + TAU group completing ≤8 sessions. The reduction in binge eating did not differ between groups. However, moderate reductions in secondary outcomes (eating disorder psychopathology: SES = -0.57, 95% CI [-1.12, -0.03]; valuation of high energy-dense foods: SES = -0.61, 95% CI [-0.87, -0.05]) were found in the FoodT group compared to TAU. Furthermore, small greater reductions in food addiction (SES = -0.46, 95% CI [-1.14, 0.22]) and lack of premeditation (SES = -0.42, 95% CI [-0.77, -0.07]) were found in the FoodT group when compared to TAU. The focus groups revealed acceptability of FoodT. Participants discussed personal barriers (e.g. distractions) and suggested changes to the app (e.g. adding a meditation exercise). Augmenting treatment for BED/BN with a food-specific ICT app is feasible, acceptable, and may reduce clinical symptomatology with high reach and wide dissemination., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Infection after stroke is associated with unfavorable outcome. Randomized controlled studies did not show benefit of preventive antibiotics in stroke but lacked power for subgroup analyses. Aim of this study is to assess whether preventive antibiotic therapy after stroke improves functional outcome for specific patient groups in an individual patient data meta-analysis., Patients and Methods: We searched MEDLINE (1946-7 May 2021), Embase (1947-7 May 2021), CENTRAL (17th September 2021), trial registries, cross-checked references and contacted researchers for randomized controlled trials of preventive antibiotic therapy versus placebo or standard care in ischemic or hemorrhagic stroke patients. Meta-analysis was performed by a one-step and two-step approach. Primary outcome was functional outcome adjusted for age and stroke severity. Secondary outcomes were infections and mortality., Results: 4197 patients from nine trials were included. Preventive antibiotic therapy was not associated with a shift in functional outcome (mRS) at 3 months (OR1.13, 95%CI 0.98-1.31) or unfavorable functional outcome (mRS 3-6) (OR0.85, 95%CI 0.60-1.19). Preventive antibiotics did not improve functional outcome in pre-defined subgroups (age, stroke severity, timing and type of antibiotic therapy, pneumonia prediction scores, dysphagia, type of stroke, and type of trial). Preventive antibiotics reduced infections (276/2066 (13.4%) in the preventive antibiotic group vs. 417/2059 (20.3%) in the control group, OR 0.60, 95% CI 0.51-0.71, p < 0.001), but not pneumonia (191/2066 (9.2%) in the preventive antibiotic group vs. 205/2061 (9.9%) in the control group (OR 0.92 (0.75-1.14), p = 0.450)., Discussion and Conclusion: Preventive antibiotic therapy did not benefit any subgroup of patients with acute stroke and currently cannot be recommended., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: WFW, JDV, CJS, AK, JH, LK, AM, AC, JJC, YR, MRAN, FAF, JAS, MGWD, PJN, DvdB declare no competing interests. DB is clinical advisor and stockholder in Argenica Therapeutics, a biotech company developing a neuroprotective drug., (© European Stroke Organisation 2021.)

Social interactions are partly driven by our ability to empathize-the capacity to share and understand others' inner states. While a growing body of evidence suggests a link between past experiences and empathy, to what degree empathy is dependent on our own previous experiences (autobiographical memories, AMs) is still unclear. Whereas neuroimaging studies have shown wide overlapping brain networks underpinning AM and empathic processes, studies on clinical populations with memory loss have not always shown empathy is impaired. The current transcranial magnetic stimulation (TMS) and electroencephalography study will seek to shed light on this neuropsychological puzzle by testing whether self-perceived empathy is causally linked to AM retrieval. Cortical activity, together with self-rating of empathy, will be recorded for scenarios that echo personal experiences while a brain region critical for AM retrieval will be transiently inhibited using TMS before task performance., (© 2021 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Objectives: To investigate a novel methodology and explore whether artificially reducing the depth of penetration during intercourse matters to women., Study Design and Methods: A study with a single-case experimental design ('n of 1'), in which a heterosexual couple act as their own control and the study is then replicated in subsequent couples, was conducted. Thirty-five couples were assessed for eligibility to participate. Twenty-nine couples without any sexual problems were randomized and 12 submitted sufficient data to analyse. As a proxy for reducing penis length, we artificially reduced the depth of penetration by using different sizes of silicone rings around the base of the man's erect penis. The main outcome measures were provided by the female partner on a scale of 0-100 and comprised: degree of (i) overall sexual pleasure; (ii) sexual pleasure from intercourse alone; and (iii) emotional connection to the male partner. The female partner was also asked before the experiment began to rate the degree of positive or negative change that would be personally meaningful for her., Results: On average, reducing the depth of penetration led to a statistically significant 18% reduction of overall sexual pleasure with an average 15% reduction in length of the penis. The longer the erect penis, the less likely the rings were to have an impact on sexual pleasure. There was a range of individual responses, however, with a minority of women reporting that reducing the depth of penetration was more pleasurable on some occasions., Conclusions: Size may matter in women in a healthy stable relationship when there is penile shortening. Because of the small number of couples and the inclusion of men with an apparently long penis, our results are preliminary, and we welcome replication in a larger sample with a more diverse range of penile lengths. Our results should not be misinterpreted as meaning that increasing penile length will increase sexual pleasure in women., (© 2021 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Quantitative markers extracted from resting-state electroencephalogram (EEG) reveal subtle neurophysiological dynamics which may provide useful information to support the diagnosis of seizure disorders. We performed a systematic review to summarize evidence on markers extracted from interictal, visually normal resting-state EEG in adults with idiopathic epilepsy or psychogenic nonepileptic seizures (PNES). Studies were selected from 5 databases and evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. 26 studies were identified, 19 focusing on people with epilepsy, 6 on people with PNES, and one comparing epilepsy and PNES directly. Results suggest that oscillations along the theta frequency (4-8 Hz) may have a relevant role in idiopathic epilepsy, whereas in PNES there was no evident trend. However, studies were subject to a number of methodological limitations potentially introducing bias. There was often a lack of appropriate reporting and high heterogeneity. Results were not appropriate for quantitative synthesis. We identify and discuss the challenges that must be addressed for valid resting-state EEG markers of epilepsy and PNES to be developed., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The prevalence and risk factors of suicidal ideation in bipolar depression in low- and middle-income countries (LMICs) are poorly understood. This study is a secondary, cross-sectional analysis of a randomized controlled trial from Pakistan, a lower middle-income country. Participants included psychiatric outpatients aged 18 to 65 with a known diagnosis of bipolar disorder and currently in a depressive episode. Suicidality was assessed using the suicide item of the 17-item Hamilton Depression Rating Scale (HAM-D) and levels of severity were categorized as absent, mild/moderate, or severe. Biometric data and biomarkers were obtained. Descriptive statistics were used to describe prevalence and logistic regression applied to establish correlates to suicidal ideation. Among the 266 participants, 67% indicated suicidality of any level and 16% endorsed severe suicidality. Lower body mass index (BMI) (OR = 0.93, 95% CI = 0.88-0.98), higher HAM-D score (OR = 1.29, 95% CI = 1.16-1.43), lower C-reactive protein (CRP) level (OR = 0.53, 95% CI = 0.40-0.70), and increased number of inpatient hospitalizations (OR = 1.16, 95% CI = 1.03-1.31) were identified as significant predictors of suicidality in the fully adjusted regression model. Our findings add to the limited literature on suicidality in bipolar disorder in the LMIC context and suggest roles of biological variables such as BMI and CRP level in predicting suicidal ideation and potentially suicidal behaviours in bipolar depression., (Copyright © 2021 Elsevier B.V. All rights reserved.)