Evocative gene-environment correlation between genetic risk for schizophrenia and bullying victimization

Bullying exposure concerns over 10% of adolescents in Europe. Moreover, bullying victimization is heritable and victims are liable to psychotic symptoms, partly because of shared heritability with psychosis. The genetic component of bullying victimization has been proposed to involve the social reactions elicited by victims – a mechanism called “evocative gene-environment correlation”. We hypothesized that genetic risk for schizophrenia, a heritable disease also associated with social stress during childhood and adolescence, is related with social experiences during adolescence and is involved in the risk of developing psychotic symptoms. We studied 908 individuals of the TRAILS sample and found that 13-14-year-old adolescents with greater genetic risk for schizophrenia are more exposed to bullying assessed via peer nomination scores than their peers with lower genetic risk. Importantly, bullying victimization mediated the path from genetic risk to the frequency of psychotic symptoms about three years later. These findings provide evidence of a previously unreported form of gene-environment interplay that may be a mechanism of risk for psychosis and schizophrenia. To the extent that genetic risk translation into clinical symptoms is mediated by environmental risk factors, this evidence supports mental health prevention aimed at antagonizing bullying victimization in vulnerable individuals

Reasons for initiating long-acting antipsychotics in psychiatric practice: findings from the STAR Network Depot Study

Background: Long Acting Injectable (LAI) antipsychotics have been claimed to ensure treatment adherence and possibly reduce the daily burden of oral formulations. So far, only surveys investigating the theoretical prescribing attitudes of clinicians have been employed. On this basis, we aimed to investigate reasons for prescribing LAIs in a real- world, unselected sample of patients. Methods: The STAR Network Depot Study is an observational, multicentre study consecutively enrolling adults initiating a LAI over a 12-months period. Clinical severity was assessed with the Brief Psychiatric Rating Scale, and patient\u2019s attitude toward medications with the Drug Attitude Inventory 10 items. Psychiatrists recorded reasons for LAI prescribing for each study participant. Responses were grouped into six non- mutually exclusive categories: aggressiveness, patient engagement, ease of drug taking, side-effects, stigma, adherence. Results: Of the 451 patients included, two-thirds suffered from chronic psychoses. Improving patient engagement with the outpatient psychiatric service was the most common reason for prescribing LAIs (almost 80% of participants), followed by increasing treatment adherence (57%), decreasing aggressiveness (54%), and improving ease of drug taking (52%). After adjusting for confounders, logistic regression analyses showed that reasons for LAI use were associated with LAI choice (e.g. first-generation LAIs for reducing aggressiveness). Conclusions: Despite the wide availability of novel LAI formulation and the emphasis on their wider use, our data suggest that the main reasons for LAI use have remained substantially unchanged over the years, focusing mostly on improving patient\u2019s engagement. Further, clinicians follow implicit prescribing patterns when choosing LAIs, and this may generate hypotheses for future experimental studies

Ground-breaking change to the mental health section of the WHO Model List of Essential Medicines: implications for low- and middle-income countries

[no abstract available

Mapping the evidence on pharmacological interventions for non-affective psychosis in humanitarian non-specialised settings: a UNHCR clinical guidance.

BACKGROUND: Populations exposed to humanitarian emergencies are particularly vulnerable to mental health problems, including new onset, relapse and deterioration of psychotic disorders. Inadequate care for this group may lead to human rights abuses and even premature death. The WHO Mental Health Gap Action Programme Intervention Guide (mhGAP-IG), and its adaptation for humanitarian settings (mhGAP-HIG), provides guidance for management of mental health conditions by non-specialised healthcare professionals. However, the pharmacological treatment of people with non-affective psychosis who do not improve with mhGAP first-line antipsychotic treatments is not addressed. In order to fill this gap, UNHCR has formulated specific guidance on the second-line pharmacological treatment of non-affective psychosis in humanitarian, non-specialised settings. METHODS: Following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, a group of international experts performed an extensive search and retrieval of evidence on the basis of four scoping questions. Available data were critically appraised and summarised. Clinical guidance was produced by integrating this evidence base with context-related feasibility issues, preferences, values and resource-use considerations. RESULTS: When first-line treatments recommended by mhGAP (namely haloperidol and chlorpromazine) are not effective, no other first-generation antipsychotics are likely to provide clinically meaningful improvements. Risperidone or olanzapine may represent beneficial second-line options. However, if these second-line medications do not produce clinically significant beneficial effects, there are two possibilities. First, to switch to the alternative (olanzapine to risperidone or vice versa) or, second, to consider clozapine, provided that specialist supervision and regular laboratory monitoring are available in the long term. If clinically relevant depressive, cognitive or negative symptoms occur, the use of a selective serotonin reuptake inhibitor may be considered in addition or as an alternative to standard psychological interventions. CONCLUSIONS: Adapting scientific evidence into practical guidance for non-specialised health workers in humanitarian settings was challenging due to the paucity of relevant evidence as well as the imprecision and inconsistency of results between studies. Pragmatic outcome evaluation studies from low-resource contexts are urgently needed. Nonetheless, the UNHCR clinical guidance is based on best available evidence and can help to address the compelling issue of undertreated, non-affective psychosis in humanitarian settings

Imputing the Number of Responders from the Mean and Standard Deviation of CGI-Improvement in Clinical Trials Investigating Medications for Autism Spectrum Disorder

Introduction: Response to treatment, according to Clinical Global Impression-Improvement (CGI-I) scale, is an easily interpretable outcome in clinical trials of autism spectrum disorder (ASD). Yet, the CGI-I rating is sometimes reported as a continuous outcome, and converting it to dichotomous would allow meta-analysis to incorporate more evidence. Methods: Clinical trials investigating medications for ASD and presenting both dichotomous and continuous CGI-I data were included. The number of patients with at least much improvement (CGI-I ≤ 2) were imputed from the CGI-I scale, assuming an underlying normal distribution of a latent continuous score using a primary threshold θ = 2.5 instead of θ = 2, which is the original cut-off in the CGI-I scale. The original and imputed values were used to calculate responder rates and odds ratios. The performance of the imputation method was investigated with a concordance correlation coefficient (CCC), linear regression, Bland–Altman plots, and subgroup differences of summary estimates obtained from random-effects meta-analysis. Results: Data from 27 studies, 58 arms, and 1428 participants were used. The imputation method using the primary threshold (θ = 2.5) had good performance for the responder rates (CCC = 0.93 95% confidence intervals [0.86, 0.96]; β of linear regression = 1.04 [0.95, 1.13]; bias and limits of agreements = 4.32% [−8.1%, 16.74%]; no subgroup differences χ(2) = 1.24, p-value = 0.266) and odds ratios (CCC = 0.91 [0.86, 0.96]; β = 0.96 [0.78, 1.14]; bias = 0.09 [−0.87, 1.04]; χ(2) = 0.02, p-value = 0.894). The imputation method had poorer performance when the secondary threshold (θ = 2) was used. Discussion: Assuming a normal distribution of the CGI-I scale, the number of responders could be imputed from the mean and standard deviation and used in meta-analysis. Due to the wide limits of agreement of the imputation method, sensitivity analysis excluding studies with imputed values should be performed

The role of attitudes toward medication and treatment adherence in the clinical response to LAIs: findings from the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network "Depot Study" was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS ≥ 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions-conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently-showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Psychological interventions for psychosis:Contemporary perspectives on the evidence base from novel approaches

Overview of research This thesis consists of five studies investigating the effects of psychological interventions for psychosis patients. Each study utilises a different methodology allowing a variety conclusions to be drawn. Chapter 1 provides a general introduction to the topic, including the background and history of psychological interventions for psychosis and their development in context to the dominant medical model, alongside an overview of the current evidence for psychological interventions. The critical questions that this thesis aims to address are also introduced. Four of the five studies included in this thesis use meta-analytical methods. Meta-analysis is a statistical procedure that allows the comparison of multiple existing published studies to provide an overall estimate. When conducted carefully, meta-analyses can provide more information than individual trials alone and forms the basis of most guidelines on healthcare interventions. Meta-analyses typically include randomised controlled trials (RCTs), which are scientific studies testing interventions against control conditions. These RCTs are conducted under strict conditions to improve the validity of results. The final study in this thesis uses RCT methodology to test a brief intervention. A general discussion is then provided which considers the implications of the findings alongside strengths, weaknesses and suggestions for future research. Summary of research Chapter 2 provides a comparative meta-analysis of psychological interventions, which includes any major form of psychological interventions for psychosis for which there was sufficient available research comparing them against other interventions to qualify. The meta-analysis therefore included randomised controlled trials on cognitive-behavioural therapy for psychosis (CBTp), social skills training, cognitive remediation, psycho-education, supportive therapy and befriending. A systematic search was conducted of four key databases resulting in the selection of 48 RCTs including 3,295 participants with psychosis. The data from all RCTs was analysed to pool the effect size from each study, which provided an aggregated statistic for each comparison. The quality of the RCTs was also assessed and the results of this assessment were used in further analyses to ensure the validity of results. Results showed that CBTp was more beneficial than other interventions for positive symptoms (which include key psychosis symptoms such as hallucinations and delusions) while social skills training was more beneficial for negative symptoms (which include apathy and lack of motivation). Cognitive remediation also showed a beneficial effect for overall symptoms, as did CBTp, although these findings did not survive the extra ‘sensitivity analyses’ we conducted based on methodological quality of the included RCTs. Based on these results, it was concluded that there are small but reliable differences between psychological interventions for psychosis. Chapter 3 provides a network meta-analysis focused on the impact of psychological interventions on psychotic symptoms. Network meta-analysis is an alternative methodology which allows researchers to draw statistical conclusions not only from direct comparisons between interventions but also indirect evidence using the network model. A systematic search was conducted resulting in the inclusion of 90 RCTs and 8,440 randomised participants with psychosis. Network meta-analysis was used to examine direct and indirect evidence for ‘total symptoms’ of psychosis, which is an overall measure including all relevant psychotic symptoms. Study quality was again assessed to help ensure validity of results. Results demonstrated that psychological interventions were of significant benefit compared to control groups. Mindfulness-based psycho-education was shown as the intervention most likely to reduce total symptoms. However, all included RCTs for this intervention were from China, meaning that future research investigating the efficacy of mindfulness-based psycho-education in a variety of cultural contexts may help determine whether these findings generalise to other international settings. While the previous chapters apply conventional meta-analytic techniques, chapter 4 provides a cumulative meta-analysis investigating the impact of individualised, case-formulation based CBTp on hallucinations and delusions, which are the key features of positive symptoms. Case formulation refers to an essential technique in CBT that helps to individualise a patient’s treatment and allows a close conceptual link between research and clinical practice. Cumulative meta-analysis is a novel technique that, alongside providing information on the effectiveness of a treatment, can also help us determine whether the evidence base for that treatment is sufficient and stable. A systematic search resulted in the inclusion of 35 RCTs and 2407 participants with psychosis. Meta-analyses were conducted and study quality was again assessed to help determine the validity of results. Results demonstrated that the evidence base for CBTp has been sufficient and stable since 2016 for hallucinations and 2015 for delusions. CBTp was demonstrated as beneficial for hallucinations compared to any control, treatment as usual and active controls. For delusions, CBTp was beneficial when compared to any control and treatment as usual, but did not demonstrate significant benefit against active controls although there were a limited number of RCTs included in this comparison, which may limit validity. The effects of CBTp were also shown as stronger when case-formulation was used and also when the primary focus of the study was the reduction of hallucinations or delusions instead of other outcomes. The fact that the evidence for CBTp has been shown as sufficient and stable means that there may be limited worth in continuing to spend vital resources on similar RCTs testing ‘generic’ CBTp and resources may better be directed into developing new or improved variants. Chapter 5 utilises another novel meta-analytic technique allowing the application of individual-participant data (IPD). In this approach, the original databases from published RCTs are requested from authors meaning that the individual data for each participant can be used in analyses rather than relying on the summary effect size data available in published manuscripts. The IPD approach allows a more precise estimation of effects and allows the investigation of ‘moderator’ variables, which refer to demographic or clinical variables at the individual level that may impact who benefits most from treatment. This study was initially developed as follow-on from chapter 1 and attempted to source databases all the included CBTp RCTs alongside conducting a new systematic search to determine whether any new RCTs were eligible. After contacting relevant authors, databases for 14 of 23 eligible RCTs were included resulting in the data for 898 participants with psychosis being included. CBTp was demonstrated as beneficial for total psychotic symptoms and general symptoms, although not for positive symptoms. This finding contrasts results from the previous chapters, although may be explained by the exclusion of a proportion of eligible RCTs due to failure to obtain these databases from original authors. The moderator analysis did not show any demographic or clinical variables as influencing treatment outcome although the number of therapy sessions a patient received had impact on outcome. The results of this IPD meta-analysis suggest that patient characteristics, including severity of psychotic symptoms, do not significantly influence treatment outcome while sufficient ‘dosage’ of CBTp is important. Finally, chapter 6 reports on a secondary analysis of an RCT conducted in a clinical setting in the UK National Health Service (NHS). This study examined the effects of a brief psychological intervention aiming to address overconfidence in perceptual decision-making among patients diagnosed with psychosis. 31 patients aged 16-65 were randomly assigned to one of two groups; 1) a brief intervention based on ‘metacognitive training’ which aimed to address a common thinking bias called the “jumping-to-conclusions” bias, or 2) an attention-control condition designed to account for therapist time and attention. Participants completed outcome measures assessing overconfidence and the “jumping-to-conclusions” bias. Results demonstrated that those receiving meta-cognitive training experienced a significant reduction in overconfident reasoning when compared to those receiving the control condition. This RCT provides preliminary evidence that meta-cognitive training is a worthwhile method by which to address overconfident reasoning in psychosis. There were however methodological limitations of this RCT due to limited resources. A larger RCT with stronger methodology is therefore warranted. Conclusions When considered collectively, the findings from the body of research included in this thesis provide strong evidence for the validity of psychological interventions for psychosis. The evidence base for CBTp was demonstrated as sufficient and stable, while social skills training was demonstrated as an effective intervention for negative symptoms. The results for CBTp are important in the on-going debate about effectiveness and whether or not it has been “oversold.” In light of the accumulated evidence, future research on psychological interventions for psychosis may best focus on the development of new or improved approaches and move on from the debate on whether psychological intervention “works” or not

Factors associated with first- versus second generation long-acting antipsychotics prescribed un-der ordinary clinical practice in Italy.

Background For many years, long-acting intramuscular (LAI) antipsychotics have been prescribed predominantly to chronic and severe patients, as a last resort when other treatments failed. Recently, a broader and earlier use of LAIs, particularly second-generation LAIs, has been emphasized. To date, few studies attempted to frame how this change in prescribing took place in real-world practice. Therefore, this study aimed to describe the clinical features of patients prescribed with LAIs, and to explore possible prescribing differences between first- and second-generations LAIs under ordinary clinical practice in Italy. Methods The STAR Network \u201cDepot\u201d Study is an observational, longitudinal, multicenter study involving 35 centers in Italy. In the cross-sectional phase, patients prescribed with LAIs were consecutively recruited and assessed over a period of 12 months. Descriptive statistics and multivariable logistic regression analyses were employed. Results Of the 451 recruited patients, 61% were males. The level of social and working functioning was heterogeneous, as was the severity of disease. Seventy-two per cent of the patients had a diagnosis of the schizophrenia spectrum. Seventy per cent were prescribed with second-generation antipsychotic (SGA) LAIs (mostly paliperidone, aripiprazole and risperidone). Compared to first-generation antipsychotic (FGA) LAIs, patients prescribed with SGA LAIs were more often younger; employed; with a diagnosis of the schizophrenia spectrum or bipolar disorder; with higher levels of affective symptoms; with fewer LAI prescriptions in the past. Discussion LAIs' prescribing practices appear to be more flexible as compared to the past, although this change is mostly restricted to SGA LAI