Background Transcranial direct current stimulation (tDCS) could be a side-effect-free alternative to psychostimulants in attention-deficit/hyperactivity disorder (ADHD). Although there is limited evidence for clinical and cognitive effects, most studies were small, single-session and stimulated left dorsolateral prefrontal cortex (dlPFC). No sham-controlled study has stimulated the right inferior frontal cortex (rIFC), which is the most consistently under-functioning region in ADHD, with multiple anodal-tDCS sessions combined with cognitive training (CT) to enhance effects. Thus, we investigated the clinical and cognitive effects of multi-session anodal-tDCS over rIFC combined with CT in double-blind, randomised, sham-controlled trial (RCT, ISRCTN48265228). Methods Fifty boys with ADHD (10–18 years) received 15 weekday sessions of anodal- or sham-tDCS over rIFC combined with CT (20 min, 1 mA). ANCOVA, adjusting for baseline measures, age and medication status, tested group differences in clinical and ADHD-relevant executive functions at posttreatment and after 6 months. Results ADHD-Rating Scale, Conners ADHD Index and adverse effects were significantly lower at post-treatment after sham relative to anodal tDCS. No other effects were significant. Conclusions This rigorous and largest RCT of tDCS in adolescent boys with ADHD found no evidence of improved ADHD symptoms or cognitive performance following multi-session anodal tDCS over rIFC combined with CT. These findings extend limited meta-analytic evidence of cognitive and clinical effects in ADHD after 1–5 tDCS sessions over mainly left dlPFC. Given that tDCS is commercially and clinically available, the findings are important as they suggest that rIFC stimulation may not be indicated as a neurotherapy for cognitive or clinical remediation for ADHD.

and the Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) IMPORTANCE About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts.OBJECTIVE To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples.DESIGN, SETTING, AND PARTICIPANTS Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]).MAIN OUTCOMES AND MEASURES GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. RESULTSThe study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r 2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r 2 = 1.09%; P = .04). CONCLUSIONS AND RELEVANCEIn this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patie...

Randomised controlled trials (RCTs) have shown the efficacy of CBTp, however, few studies have considered its long-term effectiveness in routine services. This study reports the outcomes of clients seen in a psychological therapies clinic, set up following positive results obtained from an RCT (Peters et al., 2010). The aims were to evaluate the effectiveness of CBTp, using data from the service’s routine assessments for consecutive referrals over a 12 years period, and assess whether gains were maintained at a 6+ months’ follow-up. Of the 476 consenting referrals, all clients (N = 358) who received ≥5 therapy sessions were offered an assessment at four time points (baseline, pre-, mid-, and end of therapy) on measures assessing current psychosis symptoms, emotional problems, general well-being and life satisfaction. A sub-set (N = 113) was assessed at a median of 12 months after finishing therapy. Following the waiting list (median of 3 months) clients received individualized, formulation-based CBTp for a median number of 19 sessions from 121 therapists with a range of experience receiving regular supervision. Clients showed no meaningful change on any measure while on the waiting list (Cohen’s d <= 0.23). In contrast, highly significant improvements following therapy, all of which were significantly greater than changes during the waiting list, were found on all domains assessed (Cohen’s d: 0.44–0.75). All gains were maintained at follow-up (Cohen’s d: 0.29–0.82), with little change between end of therapy and follow-up (Cohen’s d <= 0.18). Drop-out rate from therapy was low (13%). These results demonstrate the positive and potentially enduring impact of psychological therapy on a range of meaningful outcomes for clients with psychosis. The follow-up assessments were conducted on only a sub-set, which may not generalize to the full sample. Nevertheless this study is the largest of its kind in psychosis, and has important implications for the practice of CBTp in clinical services.

BackgroundUp to 35% of first-episode schizophrenia patients are estimated to meet criteria for treatment resistant schizophrenia (TRS) over the five years after illness onset (Lally et al., 2016).Emerging evidence demonstrates that around 70% of TRS patients did not respond to antipsychotic medications from the start of first treatment (i.e., early treatment resistant (E-TR) schizophrenia); whereas, the remaining 30% of TRS patients, broadly defined as latetreatment resistant (L-TR) schizophrenia, gradually transition to treatment resistance during the 5-year period, having initially responded to antipsychotic medications (Lally et al., 2016).Given TRS is a major cause of disability and is associated with high social and economic costs (Kennedy et al., 2014), having reliable prediction models for estimating an individual risk for E-TR and L-TR would advance our understanding of patients' risk of developing treatment resistance, especially after a period of favourable response to the ongoing treatment with antipsychotic medications. Development of accurate prediction models for estimating individual, rather than average, risk for a disorder outcome during the illness (Steyerberg et al., 2010), based on available patient characteristics and clinical findings, is generally thought to require large datasets (Califf et al., 1997), mainly when the outcome of interest is a rare event. As they are often unavailable in schizophrenia research, stepwise selection techniques, particularly with the traditional p-value of 0.05, are frequently employed, which tend to provide readily interpretable models (Steyerberg et al., 2000). However, these stepwise selection techniques increase the risk of biased regression coefficients and overfitting (Derksen and Keselman, 1992) potentially leading to development of a prediction model with inaccurate predictions in new cases (Osborne et al., 2012;Steyerberg et al., 1999).Computer intensive statistical learning methods, particularly regularised regression methods (RRMs), have been suggested as optimal methods for clinical and personalised risk prediction (Steyerberg, 2019), especially for small datasets (Steyerberg et al., 2000). Through an

BackgroundA recent randomised controlled trial (RCT) of acupuncture as a treatment for irritable bowel syndrome (IBS) demonstrated sustained benefits over a period of 12 months post-randomisation.AimTo extend the trial follow-up to evaluate the effects of acupuncture at 24 months post-randomisation.MethodsPatients in primary care with ongoing IBS were recruited to a two-arm pragmatic RCT of acupuncture for IBS. Participants were randomised to the offer of up to 10 weekly sessions of acupuncture plus usual care (n=116 patients) or to continue with usual care alone (n=117). The primary outcome was the self-reported IBS symptom severity score (IBS SSS) measured at 24 months post-randomisation. Analysis was by intention-to-treat using an unstructured multivariate linear model incorporating all repeated measures.ResultsThe overall response rate was 61%. The adjusted difference in mean IBS SSS at 24 months was −18.28 (95% CI −40.95 to 4.40) in favour of the acupuncture arm. Differences at earlier time points estimated from the multivariate model were: −27.27 (−47.69 to −6.86) at 3 months; −23.69 (−45.17 to −2.21) at 6 months; −24.09 (−45.59 to −2.59) at 9 months; and −23.06 (−44.52 to −1.59) at 12 months.ConclusionsThere were no statistically significant differences between the acupuncture and usual care groups in IBS SSS at 24 months post-randomisation, and the point estimate for the mean difference was approximately 80% of the size of the statistically significant results seen at 6, 9 and 12 months.Trial registration numberISRCTN08827905.

No abstract

BackgroundTranscranial direct current stimulation (tDCS) could be a side-effect free alternative to psychostimulants in Attention-Deficit/Hyperactivity Disorder (ADHD). Although there is limited evidence for clinical and cognitive effects, most studies were small, single-session, and stimulated left dorsolateral prefrontal cortex (dlPFC). No sham-controlled study has stimulated right inferior frontal cortex (rIFC), which is the most consistently under-functioning region in ADHD, with multiple sessions of anodal tDCS combined with cognitive training (CT) to enhance effects.Objective/HypothesisTo investigate clinical and cognitive effects of multi-session anodal tDCS over rIFC combined with CT in a double-blind, randomised, sham-controlled trial (RCT).Methods50 boys with ADHD (10-18 years) received 15 weekday sessions of anodal or sham tDCS over rIFC combined with CT (20mins, 1mA). ANCOVA, adjusting for baseline measures, age, and medication status, tested group differences in clinical and ADHD-relevant executive functions at posttreatment and after 6-months.ResultsADHD-Rating Scale, Conners ADHD Index, and adverse effects were significantly lower at post-treatment after sham relative to real tDCS. No other effects were significant.ConclusionsThis rigorous multi-session RCT of tDCS over the rIFC in ADHD combined with CT, showed no evidence of improvement of ADHD symptoms or cognitive performance. Findings extend limited meta-analytic evidence of cognitive and clinical effects in ADHD after 1-5 tDCS sessions over mainly left dlPFC. Given that tDCS is commercially and clinically available, the findings are important as they suggest that rIFC stimulation may not be indicated as a neurotherapy for cognitive or clinical remediation for ADHDHighlightstDCS has been suggested as an alternative treatment for ADHDWe combined 15-session anodal tDCS over the rIFC with cognitive training in ADHD childrenReal versus sham tDCS showed no cognitive or symptom improvementsConversely, real tDCS showed lower ADHD symptoms and higher adverse effectsMulti-session tDCS of rIFC shows no clinical or cognitive benefits in ADHD

Background: A proportion of people with treatment-resistant schizophrenia fail to show improvement on clozapine treatment. Knowledge of the sociodemographic and clinical factors predicting clozapine response may be useful in developing personalised approaches to treatment. Methods: This retrospective cohort study used data from the electronic health records of the South London and Maudsley (SLaM) hospital between 2007 and 2011. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression statistical learning approach, we examined 35 sociodemographic and clinical factors’ predictive ability of response to clozapine at 3 months of treatment. Response was assessed by the level of change in the severity of the symptoms using the Clinical Global Impression (CGI) scale. Results: We identified 242 service-users with a treatment-resistant psychotic disorder who had their first trial of clozapine and continued the treatment for at least 3 months. The LASSO regression identified three predictors of response to clozapine: higher severity of illness at baseline, female gender and having a comorbid mood disorder. These factors are estimated to explain 18% of the variance in clozapine response. The model’s optimism-corrected calibration slope was 1.37, suggesting that the model will underfit when applied to new data. Conclusions: These findings suggest that women, people with a comorbid mood disorder and those who are most ill at baseline respond better to clozapine. However, the accuracy of the internally validated and recalibrated model was low. Therefore, future research should indicate whether a prediction model developed by including routinely collected data, in combination with biological information, presents adequate predictive ability to be applied in clinical settings.