The possible role of glutamate in the pathophysiology and treatment of depression is of intense current interest. Proton magnetic resonance spectroscopy (MRS) enables the detection of glutamate in the living human brain and meta-analyses of previous MRS studies in depressed patients have suggested that glutamate levels are decreased in anterior brain regions. Nevertheless, at conventional magnetic field strengths [1.5–3 Tesla (T)], it is difficult to separate glutamate from its metabolite and precursor, glutamine, with the two often being measured together as Glx. In contrast, MRS at 7 T allows clear spectral resolution of glutamate and glutamine.

We studied 55 un-medicated depressed patients and 50 healthy controls who underwent MRS scanning at 7 T with voxels placed in anterior cingulate cortex, occipital cortex and putamen (PUT). Neurometabolites were calculated using the unsuppressed water signal as a reference.

Compared with controls, depressed patients showed no significant difference in glutamate in any of the three voxels studied; however, glutamine concentrations in the patients were elevated by about 12% in the PUT (p < 0.001).

The increase in glutamine in PUT is of interest in view of the postulated role of the basal ganglia in the neuropsychology of depression and is consistent with elevated activity in the descending cortical glutamatergic innervation to the PUT. The basal ganglia have rarely been the subject of MRS investigations in depressed patients and further MRS studies of these structures in depression are warranted.

Acting on harmful command hallucinations is a major clinical concern. Our COMMAND CBT trial approximately halved the rate of harmful compliance (OR = 0.45, 95% CI 0.23–0.88, p = 0.021). The focus of the therapy was a single mechanism, the power dimension of voice appraisal, was also significantly reduced. We hypothesised that voice power differential (between voice and voice hearer) was the mediator of the treatment effect.

The trial sample (n = 197) was used. A logistic regression model predicting 18-month compliance was used to identify predictors, and an exploratory principal component analysis (PCA) of baseline variables used as potential predictors (confounders) in their own right. Stata's paramed command used to obtain estimates of the direct, indirect and total effects of treatment.

Voice omnipotence was the best predictor although the PCA identified a highly predictive cognitive-affective dimension comprising: voices’ power, childhood trauma, depression and self-harm. In the mediation analysis, the indirect effect of treatment was fully explained by its effect on the hypothesised mediator: voice power differential.

Voice power and treatment allocation were the best predictors of harmful compliance up to 18 months; post-treatment, voice power differential measured at nine months was the mediator of the effect of treatment on compliance at 18 months.

Psychotic episodes during exposure to very high or extreme altitude have been frequently reported in mountain literature, but not systematically analysed and acknowledged as a distinct clinical entity.

Episodes reported above 3500 m altitude with possible psychosis were collected from the lay literature and provide the basis for this observational study. Dimensional criteria of the Diagnostic and Statistical Manual of Mental Disorders were used for psychosis, and the Lake Louise Scoring criteria for acute mountain sickness and high-altitude cerebral oedema (HACE). Eighty-three of the episodes collected underwent a cluster analysis to identify similar groups. Ratings were done by two independent, trained researchers (κ values 0.6–1).

Cluster 1 included 51% (42/83) episodes without psychosis; cluster 2 22% (18/83) cases with psychosis, plus symptoms of HACE or mental status change from other origins; and cluster 3 28% (23/83) episodes with isolated psychosis. Possible risk factors of psychosis and associated somatic symptoms were analysed between the three clusters and revealed differences regarding the factors ‘starvation’ (χ2 test, p = 0.002), ‘frostbite’ (p = 0.024) and ‘supplemental oxygen’ (p = 0.046). Episodes with psychosis were reversible but associated with near accidents and accidents (p = 0.007, odds ratio 4.44).

Episodes of psychosis during exposure to high altitude are frequently reported, but have not been specifically examined or assigned to medical diagnoses. In addition to the risk of suffering from somatic mountain illnesses, climbers and workers at high altitude should be aware of the potential occurrence of psychotic episodes, the associated risks and respective coping strategies.

Studying secular trends in the exposure to risk and protective factors of depression and whether these trends are associated with secular trends in the prevalence of depression is important to estimate future healthcare demands and to identify targets for prevention.

Three birth cohorts of 55–64-year olds from the population-based Longitudinal Aging Study Amsterdam were examined using identical methods in 1992 (n = 944), 2002 (n = 964) and 2012 (n = 957). A two-stage screening design was used to identify subthreshold depression (SUBD) and major depressive disorder (MDD). Multinomial logistic regression analyses were used to identify secular trends in depression prevalence and to identify factors from the biopsychosocial domains of functioning that were associated with these trends.

Compared with 1992, MDD became more prevalent in 2002 (OR 1.90, 95% CI 1.10–3.28, p = 0.022) and 2012 (OR 1.80, 95% CI 1.03–3.14, p = 0.039). This was largely attributable to an increase in the prevalence of chronic diseases and functional limitations. Socioeconomic and psychosocial improvements, including an increase in labor market participation, social support and mastery, hampered MDD rates to rise more and were also associated with a 32% decline of SUBD-rates in 2012 as compared with 2002 (OR 0.68, 95% CI 0.48–0.96, p = 0.03).

Among late middle-aged adults, there is a substantial net increase of MDD, which is associated with deteriorating physical health. If morbidity and disability continue to increase, a further expansion of MDD rates may be expected. Improving socioeconomic and psychosocial conditions may benefit public health, as these factors were protective against a higher prevalence of both MDD and SUBD.

The prevalence and severity of neurocognitive dysfunctioning of patients with somatic symptom and related disorders (SSRD) is unknown. Furthermore, the influence of comorbid depression and anxiety has not been evaluated. This study examines neurocognitive dysfunctioning of patients with SSRD and explores if comorbid depression and anxiety is associated with specific neurocognitive dysfunctioning.

Cross-sectional study with consecutive patients suffering from SSRD visiting an outpatient specialty mental health care Centre of Excellence for SSRD. Extensive neuropsychological assessment and assessment of depression and anxiety symptom levels using the Patient-Health-Questionnaire-9 and General Anxiety Disorder questionnaire-7 were performed at intake. Multivariate analysis was performed.

The study sample consisted of 201 SSRD patients, with a mean age of 43 years (Standard deviation = 13) years; 37.8% were male. Neurocognitive dysfunction in the domains information processing speed, sustained and divided attention, working memory, verbal and visual memory were reported, compared with normative data. Comorbid depression and anxiety occurred frequently within the sample (75.1% and 65.7%, respectively). Neurocognitive dysfunctioning was worse in patients suffering from comorbid depression [multivariate F (7,161) = 2.839, p = 0.008] but not in patients with comorbid anxiety.

Poor neurocognitive performance of patients with SSRD is common and worsens in case of comorbid depression. This may explain treatment dropout of patients with SSRD from neurocognitive behavioral therapy. Research on novel interventions is needed targeting neurocognitive functioning of patients with SSRD, particularly those with comorbid depression.

Polygenic risk scores (PRS) for depression correlate with depression status and chronicity, and provide causal anchors to identify depressive mechanisms. Neuroticism is phenotypically and genetically positively associated with depression, whereas psychological resilience demonstrates negative phenotypic associations. Whether increased neuroticism and reduced resilience are downstream mediators of genetic risk for depression, and whether they contribute independently to risk remains unknown.

Moderating and mediating relationships between depression PRS, neuroticism, resilience and both clinical and self-reported depression were examined in a large, population-based cohort, Generation Scotland: Scottish Family Health Study (N = 4166), using linear regression and structural equation modelling. Neuroticism and resilience were measured by the Eysenck Personality Scale Short Form Revised and the Brief Resilience Scale, respectively.

PRS for depression was associated with increased likelihood of self-reported and clinical depression. No interaction was found between PRS and neuroticism, or between PRS and resilience. Neuroticism was associated with increased likelihood of self-reported and clinical depression, whereas resilience was associated with reduced risk. Structural equation modelling suggested the association between PRS and self-reported and clinical depression was mediated by neuroticism (43–57%), while resilience mediated the association in the opposite direction (37–40%). For both self-reported and clinical diagnoses, the genetic risk for depression was independently mediated by neuroticism and resilience.

Findings suggest polygenic risk for depression increases vulnerability for self-reported and clinical depression through independent effects on increased neuroticism and reduced psychological resilience. In addition, two partially independent mechanisms – neuroticism and resilience – may form part of the pathway of vulnerability to depression.

To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms.

IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms.

Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose–response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68–0.95); that for IL-6 was 1.20 (95% CI, 1.03–1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship.

The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people.

When patients are admitted onto psychiatric wards, sleep problems are highly prevalent. We carried out the first trial testing a psychological sleep treatment at acute admission (Oxford Ward sLeep Solution, OWLS).

This assessor-blind parallel-group pilot trial randomised patients to receive sleep treatment at acute crisis [STAC, plus standard care (SC)], or SC alone (1 : 1). STAC included cognitive–behavioural therapy (CBT) for insomnia, sleep monitoring and light/dark exposure for circadian entrainment, delivered over 2 weeks. Assessments took place at 0, 2, 4 and 12 weeks. Feasibility outcomes assessed recruitment, retention of participants and uptake of the therapy. Primary efficacy outcomes were the Insomnia Severity Index and Warwick–Edinburgh Mental Wellbeing Scale at week 2. Analyses were intention-to-treat, estimating treatment effect with 95% confidence intervals.

Between October 2015 and July 2016, 40 participants were recruited (from 43 assessed eligible). All participants offered STAC completed treatment (mean sessions received = 8.6, s.d. = 1.5). All participants completed the primary end point. Compared with SC, STAC led to large effect size (ES) reductions in insomnia at week 2 (adjusted mean difference −4.6, 95% CI −7.7 to −1.4, ES −0.9), a small improvement in psychological wellbeing (adjusted mean difference 3.7, 95% CI −2.8 to 10.1, ES 0.3) and patients were discharged 8.5 days earlier. One patient in the STAC group had an adverse event, unrelated to participation.

In this challenging environment for research, the trial was feasible. Therapy uptake was high. STAC may be a highly effective treatment for sleep disturbance on wards with potential wider benefits on wellbeing and admission length.

Whilst preterm-born individuals have an increased risk of developing attention-deficit/hyperactivity disorder (ADHD), and are reported to have ADHD-like attention and arousal impairments, direct group comparisons are scarce.

We directly compared preterm-born adolescents (n = 186) to term-born adolescents with ADHD (n = 69), and term-born controls (n = 135), aged 11–23, on cognitive-performance, event-related potential and skin conductance level (SCL) measures associated with attention and arousal. The measures are from baseline and fast-incentive conditions of a four-choice reaction time task, previously shown to discriminate between the individuals with ADHD and controls. We aimed to establish whether preterm-born adolescents show: (a) identical cognitive-neurophysiological impairments to term-born adolescents with ADHD (b) possible additional impairments, and whether (c) the observed impairments correlate with ADHD symptom scores.

The preterm group, like the term-born ADHD group, showed increased mean reaction time (MRT) and reaction time variability (RTV) in the baseline condition, and attenuated contingent negative variation (CNV) amplitude (response preparation) in the fast-incentive condition. The preterm group, only, did not show significant within-group adjustments in P3 amplitude (attention allocation) and SCL (peripheral arousal). Dimensional analyses showed that ADHD symptoms scores correlated significantly with MRT, RTV and CNV amplitude only.

We find impairments in cognition and brain function in preterm-born adolescents that are linked to increased ADHD symptoms, as well as further impairments, in lack of malleability in neurophysiological processes. Our findings indicate that such impairments extend at least to adolescence. Future studies should extend these investigations into adulthood.

Anxiety and depression are both important correlates of cognitive function. However, longitudinal studies investigating how they covary with cognition within the same individual are scarce. We aimed to simultaneously estimate associations of between-person differences and within-person variability in anxiety and depression with cognitive performance in a sample of non-demented older people.

Participants in the Lothian Birth Cohort 1921 study, a population-based narrow-age sample (mean age at wave 1 = 79 years, n = 535), were examined on five occasions across 13 years. Anxiety and depression were measured with the Hospital Anxiety and Depression Scale (HADS) and cognitive performance was assessed with tests of reasoning, logical memory, and letter fluency. Data were analyzed using two-level linear mixed-effects models with within-person centering.

Divergent patterns were observed for anxiety and depression. For anxiety, between-person differences were more influential; people who scored higher on HADS anxiety relative to other same-aged individuals demonstrated poorer cognitive performance on average. For depression, on the other hand, time-varying within-person differences were more important; scoring higher than usual on HADS depression was associated with poorer cognitive performance relative to the average level for that participant. Adjusting for gender, childhood mental ability, emotional stability, and disease burden attenuated these associations.

The results from this study highlight the importance of addressing both between- and within-person effects of negative mood and suggest that anxiety and depression affect cognitive function in different ways. The current findings have implications for assessment and treatment of older age cognitive deficits.

Paranoia involves thoughts and beliefs about the harmful intent of others but the social consequences have been much less studied. We investigated whether paranoia predicts maladaptive social behaviour in terms of cooperative and punitive behaviour using experimental game theory paradigms, and examined whether reduced cooperation is best explained in terms of distrust as previous studies have claimed.

We recruited a large population sample (N = 2132) online. All participants completed the Green et al. Paranoid Thoughts Scale and (i) a Dictator Game and (ii) an Ultimatum Game, the former with an option for costly punishment. Following distrust-based accounts, we predicted highly paranoid people would make higher offers when the outcome depended on receiving a positive response from their partner (Ultimatum Game) but no difference when the partner's response was irrelevant (Dictator Game). We also predicted paranoia would increase punitive responses. Predictions were pre-registered in advance of data collection. Data and materials are open access.

Highly paranoid participants actually made lower offers than non-paranoid participants both in the Dictator Game and in the Ultimatum Game. Paranoia positively predicted punitive responses.

These findings suggest that distrust is not the best explanation for reduced cooperation in paranoia and alternative explanations, such as increased self-interest, may apply. However, the tendency to attribute harmful intent to partners was important in motivating punitive responses. These results highlight differing motivations underlying adverse social behaviour in paranoia and suggest that accounts based solely on the presenting features of paranoia may need to be rethought.

Paliperidone palmitate is one of the most widely prescribed long-acting injectable (LAI) antipsychotics in the UK. However, it is relatively expensive and there are few data comparing its effectiveness to that of other LAI antipsychotics. We sought to address this issue by analyzing a large anonymized electronic health record (EHR) dataset from patients treated with LAI antipsychotics.

EHR data were obtained from 1281 patients in the South London and Maudsley NHS Foundation Trust (SLaM) who started treatment with a LAI antipsychotic between 1 April 2011 and 31 January 2015. The number of days spent as a psychiatric inpatient and the number of admissions to a psychiatric hospital were analyzed in each of the 3 years before and after LAI prescription.

Patients treated with paliperidone palmitate (n = 430; 33.6%) had a greater number of inpatient days and a greater number of admissions in the year prior to treatment than those treated with other LAI antipsychotics. Nevertheless, in the 3 years after initiation there were no significant differences between paliperidone and the other LAI antipsychotics in the number of days as an inpatient (B coefficient 5.4 days, 95% confidence interval (CI) −57.3 to 68.2, p = 0.86) or number of hospital admissions (Incidence rate ratio 1.07, 95% CI 0.62 to 1.83, p = 0.82).

Paliperidone palmitate was more likely to be prescribed in patients with more frequent and lengthy hospital admissions prior to initiation. However, the absence of differences in outcomes after initiation indicates that paliperidone palmitate was not more effective than other cheaper LAI antipsychotics.

Systemic inflammation may play a role in the development of idiopathic fatigue, that is, fatigue not explained by infections or diagnosed chronic illness, but this relationship has never been investigated in community studies including the entire adult age span. We examine the association of the inflammatory marker C-reactive protein (CRP) and fatigue assessed annually in a 3-year outcome period for UK adults aged 16–98.

Multilevel models were used to track fatigue 7, 19, and 31 months after CRP measurement, in 10 606 UK individuals. Models accounted for baseline fatigue, demographics, health conditions diagnosed at baseline and during follow-up, adiposity, and psychological distress. Sensitivity analyses considered factors including smoking, sub-clinical disease (blood pressure, anaemia, glycated haemoglobin), medications, ethnicity, and alcohol consumption.

Fatigue and CRP increased with age, and women had higher values than men. CRP was associated with future self-reported fatigue, but only for the oldest participants. Thus, in those aged 61–98 years, high CRP (>3 mg/L) independently predicted greater fatigue 7, 19, and 31 months after CRP measurement [odds ratio for new-onset fatigue after 7 months: 1.88, 95% confidence interval (CI) 1.21–2.92; 19 months: 2.25, CI 1.46–3.49; 31 months: 1.65, CI 1.07–2.54]. No significant longitudinal associations were seen for younger participants.

Our findings support previously described CRP–fatigue associations in older individuals. However, there are clear age modifications in these associations, which may reflect a contribution of unmeasured sub-clinical disease of limited relevance to younger individuals. Further work is necessary to clarify intervening processes linking CRP and fatigue in older individuals.

Differences between verbal and non-verbal cognitive development from childhood to adulthood may differentiate between those with and without psychotic symptoms and affective symptoms in later life. However, there has been no study exploring this in a population-based cohort.

The sample was drawn from the MRC National Survey of Health and Development, and consisted of 2384 study members with self-reported psychotic experiences and affective symptoms at the age of 53 years, and with complete cognitive data at the ages of 8 and 15 years. The association between verbal and non-verbal cognition at age 8 years and relative developmental lag from age 8 to 15 years, and both adult outcomes were tested with the covariates adjusted, and mutually adjusted for verbal and non-verbal cognition.

Those with psychotic experiences [thought interference (n = 433), strange experience (n = 296), hallucination (n = 88)] had lower cognition at both the ages of 8 and 15 years in both verbal and non-verbal domains. After mutual adjustment, lower verbal cognition at age 8 years and greater verbal developmental lag were associated with higher likelihood of psychotic experiences within individuals, whereas there was no association between non-verbal cognition and any psychotic experience. In contrast, those with case-level affective symptoms (n = 453) had lower non-verbal cognition at age 15 years, and greater developmental lag in the non-verbal domain. After adjustment, lower non-verbal cognition at age 8 years and greater non-verbal developmental lag were associated with higher risk of case-level affective symptoms within individuals.

These results suggest that cognitive profiles in childhood and adolescence differentiate psychiatric disease spectra.

Accelerated cellular ageing, which can be examined by telomere length (TL), may be an overarching mechanism underlying the association between personality and adverse health outcomes. This 6-year longitudinal study examined the relation between personality and leukocyte telomere length (LTL) across time among adults with a wide age-range.

Data from the Netherlands Study of Depression and Anxiety were used and included patients with a depression and/or anxiety disorder and healthy controls. Overall, 2936 persons (18–65 years, 66% female) had data on LTL at baseline and 1883 persons had LTL at 6-year follow-up. The Big Five personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) and Type D personality were assessed.

Neuroticism was negatively (B = −2.11, p = 0.03) and agreeableness was positively (B = 3.84, p = 0.03) related to LTL measured across two time points, which became just non-significant after adjusting for somatic health, lifestyle factors, and recent life stress (B = −1.99, p = 0.06; and B = 3.01, p = 0.10). Type D personality was negatively (B = −50.16, p < 0.01) related to LTL across two time points, which still remained statistically significant after full adjustment (B = −47.37, p = 0.01). Associations did not differ by age, gender, and current psychiatric status.

The Big Five traits high neuroticism and low agreeableness, and Type D personality were associated with shorter LTL measured across a 6-year period. Associations with the Big Five traits became non-significant after controlling for somatic health, lifestyle factors, and recent life stress, yet similar trends were observed. Type D personality remained independently associated with shorter LTL after full adjustment.

An efficient indicated prevention of psychotic disorders requires valid risk criteria that work in both clinical and community samples. Yet, ultra-high risk and basic symptom criteria were recently recommended for use in clinical samples only. Their use in the community was discouraged for lack of knowledge about their prevalence, clinical relevance and risk factors in non-clinical, community settings when validly assessed with the same instruments used in the clinic.

Using semi-structured telephone interviews with established psychosis-risk instruments, we studied the prevalence of psychosis-risk symptoms and criteria, their clinical relevance (using presence of a non-psychotic mental disorder or of functional deficits as proxy measures) and their risk factors in a random, representative young adult community sample (N=2683; age 16–40 years; response rate: 63.4%).

The point-prevalence of psychosis-risk symptoms was 13.8%. As these mostly occurred too infrequent to meet frequency requirements of psychosis-risk criteria, only 2.4% of participants met psychosis-risk criteria. A stepwise relationship underlay the association of ultra-high risk and basic symptoms with proxy measures of clinical relevance, this being most significant when both occurred together. In line with models of their formation, basic symptoms were selectively associated with age, ultra-high risk symptoms with traumatic events and lifetime substance misuse.

Psychosis-risk criteria were uncommon, indicating little risk of falsely labelling individuals from the community at-risk for psychosis. Besides, both psychosis-risk symptoms and criteria seem to possess sufficient clinical relevance to warrant their broader attention in clinical practice, especially if ultra-high risk and basic symptoms occur together.

Treatment of medical patients with the inflammatory cytokine, interferon-α (IFN-α), is frequently associated with the development of clinical depressive symptomatology. Several important biological correlates of the effect of IFN-α on mood have been described, but the neuropsychological changes associated with IFN-α treatment are largely unexplored. The aim of the present preliminary study was to assess the effect of IFN-α on measures of emotional processing.

We measured changes in emotional processing over 6–8 weeks in 17 patients receiving IFN-α as part of their treatment for hepatitis C virus infection. Emotional processing tasks included those which have previously been shown to be sensitive to the effects of depression and antidepressant treatment, namely facial expression recognition, emotional categorisation and the dot probe attentional task.

Following IFN-α, patients were more accurate at detecting facial expressions of disgust; they also showed diminished attentional vigilance to happy faces. IFN-α produced the expected increases in scores on depression rating scales, but there was no correlation between these scores and the changes in emotional processing.

Our preliminary findings suggest that IFN-α treatment produces negative biases in emotional processing, and this effect is not simply a consequence of depression. It is possible that increased recognition of disgust may represent a neuropsychological marker of depressive disorders related to inflammation.

Cognitive remediation (CR) is a psychological therapy, which improves cognitive and social functioning in people with schizophrenia. It is now being implemented within routine clinical services and mechanisms of change are being explored. We designed a new generation computerised CR programme, CIRCuiTS (Computerised Interactive Remediation of Cognition – a Training for Schizophrenia), to enhance strategic and metacognitive processing, with an integrated focus on the transfer of cognitive skills to daily living. This large trial tested its feasibility to be delivered in therapist-led and independent sessions, and its efficacy for improved cognitive and social functioning.

A two arm single blind randomised superiority trial comparing CIRCuiTS plus treatment-as-usual (TAU) with TAU alone in 93 people with a diagnosis of schizophrenia. Cognitive, social functioning and symptom outcomes were assessed at pre- and post-therapy and 3 months later.

85% adhered to CIRCuiTS, completing a median of 28 sessions. There were significant improvements in visual memory at post-treatment (p = 0.009) and follow-up (p = 0.001), and a trend for improvements in executive function at post-treatment (p = 0.056) in favour of the CIRCuiTS group. Community function was also differentially and significantly improved in the CIRCuiTS group at post-treatment (p = 0.003) but not follow-up, and was specifically predicted by improved executive functions.

CIRCuiTS was beneficial for improving memory and social functioning. Improved executive functioning emerges as a consistent predictor of functional gains and should be considered an important CR target to achieve functional change. A larger-scale effectiveness trial of CIRCuiTS is now indicated.