Sleep disruption in adolescent inpatients: prevalence, associations with clinical outcomes, and clinician perspectives.

Sleep problems are common for adolescents with psychiatric disorders, and sleep treatment may aid mental health recovery. Inpatient admissions are likely a particularly challenging time for sleep. Despite this little is known about the nature of sleep problems, and how sleep treatments could be optimised for this setting. This mixed-methods study set out to better understand sleep disturbances in adolescent inpatients. Study 1 examined the prevalence of Sleep Condition Indicator-assessed insomnia at admission and associations with psychiatric symptoms and admission length in 100 inpatients (aged 11-17 years) on one unit in Oxford. Data were gathered from admission routine measures and medical records. Associations were analysed using linear regressions. Half of the inpatients (n = 50) screened positive for insomnia at admission. Moderate-large significant associations were observed between more severe insomnia and more severe depression (ß = -0.56), anxiety (ß = -0.51), self-harm (ß = -0.49), psychotic experiences (ß = -0.32), and conduct problems (ß = -0.30), but not admission length. Study 2 gained 12 clinicians' perspectives on sleep problems on the unit via a focus group and semi-structured interviews, analysed using thematic analysis. Ward staff observed insomnia and excessive daytime sleepiness in adolescent inpatients and a reciprocal relationship with mental health symptoms. Ward processes were barriers (e.g., night-time observations) and facilitators (e.g., regular routines) of sleep. Cognitive behavioural therapy for insomnia was not routinely offered but viewed as potentially helpful. Insomnia may be a common problem for adolescent inpatients, associated with greater psychopathology, but not admission length. The possible benefits of psychological sleep interventions for adolescents admitted to psychiatric units now require testing.

Low risk of some common cancers in women with anorexia nervosa: Evidence from a national record-linkage study.

BACKGROUND: Some studies report that women with anorexia nervosa (AN) have lower risk than others of breast cancer, but increased risk of cancers of other sites. No work has been done to quantify the risk in the English population. METHODS: Retrospective cohort study using a national linked dataset of Hospital Episode Statistics for 1999-2021. We selected individuals with a hospital admission for AN, and compared their relative risk (RR) of developing site-specific cancers, with that in a reference cohort. RESULTS: We identified 75 cancers in 15,029 women hospitalised with AN. There was a low RR of all cancers combined at 0.75 (95%CI 0.59-0.94), and, notably, low RR for breast cancer 0.43 (0.20-0.81), cancers of secondary and ill-defined sites 0.52 (0.26-0.93). The RR for parotid gland cancer was 4.4 (1.4-10.6) within a year of first recorded diagnosis of AN. In men, we found 12 cancers in 1413 individuals hospitalised with AN, but no increased risks beyond the first year of diagnosis of AN. CONCLUSIONS: This is the first report on the association between AN and cancers in the all-England population. The study showed low rates of breast cancer, and of all cancers combined, in women hospitalised with AN. It is possible that some of the metabolic or hormonal changes observed in AN could work as a protective factor for breast cancer. More experimental work is needed to identify and explain these factors. The new finding on the higher risk of salivary gland tumours could inform clinicians caring for patients with AN.

Shared and distinct white matter abnormalities in adolescent-onset schizophrenia and adolescent-onset psychotic bipolar disorder.

BACKGROUND: While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need. METHODS: Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FAT) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FAT and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence. RESULTS: Individuals with adolescent-onset psychosis exhibited pronounced FW and FAT abnormalities compared to HCs. FAT reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FAT was positively related to age. CONCLUSIONS: We observe evidence for cellular (FAT) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium.

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

Cognitive behavioural therapy for anxiety disorders in children and adolescents.

BACKGROUND: Previous Cochrane Reviews have shown that cognitive behavioural therapy (CBT) is effective in treating childhood anxiety disorders. However, questions remain regarding the following: up-to-date evidence of the relative efficacy and acceptability of CBT compared to waiting lists/no treatment, treatment as usual, attention controls, and alternative treatments; benefits across a range of outcomes; longer-term effects; outcomes for different delivery formats; and amongst children with autism spectrum disorders (ASD) and children with intellectual impairments. OBJECTIVES: To examine the effect of CBT for childhood anxiety disorders, in comparison with waitlist/no treatment, treatment as usual (TAU), attention control, alternative treatment, and medication. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (all years to 2016), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO (each to October 2019), international trial registries, and conducted grey literature searches. SELECTION CRITERIA: We included randomised controlled trials of CBT that involved direct contact with the child, parent, or both, and included non-CBT comparators (waitlist/no treatment, treatment as usual, attention control, alternative treatment, medication). Participants were younger than age 19, and met diagnostic criteria for an anxiety disorder diagnosis. Primary outcomes were remission of primary anxiety diagnosis post-treatment, and acceptability (number of participants lost to post-treatment assessment), and secondary outcomes included remission of all anxiety diagnoses, reduction in anxiety symptoms, reduction in depressive symptoms, improvement in global functioning, adverse effects, and longer-term effects. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. We used GRADE to assess the quality of the evidence. MAIN RESULTS: We included 87 studies and 5964 participants in quantitative analyses. Compared with waitlist/no treatment, CBT probably increases post-treatment remission of primary anxiety diagnoses (CBT: 49.4%, waitlist/no treatment: 17.8%; OR 5.45, 95% confidence interval (CI) 3.90 to 7.60; n = 2697, 39 studies, moderate quality); NNTB 3 (95% CI 2.25 to 3.57) and all anxiety diagnoses (OR 4.43, 95% CI 2.89 to 6.78; n = 2075, 28 studies, moderate quality). Low-quality evidence did not show a difference between CBT and TAU in post-treatment primary anxiety disorder remission (OR 3.19, 95% CI 0.90 to 11.29; n = 487, 8 studies), but did suggest CBT may increase remission from all anxiety disorders compared to TAU (OR 2.74, 95% CI 1.16 to 6.46; n = 203, 5 studies). Compared with attention control, CBT may increase post-treatment remission of primary anxiety disorders (OR 2.28, 95% CI 1.33 to 3.89; n = 822, 10 studies, low quality) and all anxiety disorders (OR 2.75, 95% CI 1.22 to 6.17; n = 378, 5 studies, low quality). There was insufficient available data to compare CBT to alternative treatments on post-treatment remission of primary anxiety disorders, and low-quality evidence showed there may be little to no difference between these groups on post-treatment remission of all anxiety disorders (OR 0.89, 95% CI 0.35 to 2.23; n = 401, 4 studies) Low-quality evidence did not show a difference for acceptability between CBT and waitlist/no treatment (OR 1.09, 95% CI 0.85 to 1.41; n=3158, 45 studies), treatment as usual (OR 1.37, 95% CI 0.73 to 2.56; n = 441, 8 studies), attention control (OR 1.00, 95% CI 0.68 to 1.49; n = 797, 12 studies) and alternative treatment (OR 1.58, 95% CI 0.61 to 4.13; n=515, 7 studies). No adverse effects were reported across all studies; however, in the small number of studies where any reference was made to adverse effects, it was not clear that these were systematically monitored. Results from the anxiety symptom outcomes, broader outcomes, longer-term outcomes and subgroup analyses are provided in the text. We did not find evidence of consistent differences in outcomes according to delivery formats (e.g. individual versus group; amount of therapist contact time) or amongst samples with and without ASD, and no studies included samples of children with intellectual impairments. AUTHORS' CONCLUSIONS: CBT is probably more effective in the short-term than waiting lists/no treatment, and may be more effective than attention control. We found little to no evidence across outcomes that CBT is superior to usual care or alternative treatments, but our confidence in these findings are limited due to concerns about the amount and quality of available evidence, and we still know little about how best to efficiently improve outcomes.

Disrupted brain structural connectivity in Pediatric Bipolar Disorder with psychosis.

Bipolar disorder (BD) has been linked to disrupted structural and functional connectivity between prefrontal networks and limbic brain regions. Studies of patients with pediatric bipolar disorder (PBD) can help elucidate the developmental origins of altered structural connectivity underlying BD and provide novel insights into the aetiology of BD. Here we compare the network properties of whole-brain structural connectomes of euthymic PBD patients with psychosis, a variant of PBD, and matched healthy controls. Our results show widespread changes in the structural connectivity of PBD patients with psychosis in both cortical and subcortical networks, notably affecting the orbitofrontal cortex, frontal gyrus, amygdala, hippocampus and basal ganglia. Graph theoretical analysis revealed that PBD connectomes have fewer hubs, weaker rich club organization, different modular fingerprint and inter-modular communication, compared to healthy participants. The relationship between network features and neurocognitive and psychotic scores was also assessed, revealing trends of association between patients' IQ and affective psychotic symptoms with the local efficiency of the orbitofrontal cortex. Our findings reveal that PBD with psychosis is associated with significant widespread changes in structural network topology, thus strengthening the hypothesis of a reduced capacity for integrative processing of information across brain regions. Localised network changes involve core regions for emotional processing and regulation, as well as memory and executive function, some of which show trends of association with neurocognitive faculties and symptoms. Together, our findings provide the first comprehensive characterisation of the alterations in local and global structural brain connectivity and network topology, which may contribute to the deficits in cognition and emotion processing and regulation found in PBD.

Determinants of inter-practice variation in ADHD diagnosis and stimulant prescribing: cross-sectional database study of a national surveillance network.

Early recognition, identification and treatment of children with attention deficit hyperactivity disorder (ADHD) can reduce detrimental outcomes and redirect their developmental trajectory. We aimed to describe variations in age of ADHD diagnosis and stimulant prescribing among general practitioner practices in a nationwide network and identify child, parental, household and general practice factors that might account for these variations. Cross-sectional study of children aged under 19 years registered within a general practice in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network in 2016, RCGP RSC has a household key allowing parent and child details to be linked. Data from 158 general practices and 353 774 children under 19 were included. The mean age of first ADHD diagnosis was 10.5 years (95% CI 10.1 to 10.9, median 10, IQR 9.0-11.9) and the mean percentage of children with ADHD prescribed stimulant medications among RCGP RSC practices was 41.2% (95% CI 38.7 to 43.6). There was wide inter-practice variation in the prevalence of diagnosis of ADHD, the age of diagnosis and stimulant prescribing. ADHD diagnosis is more likely to be made later in households with a greater number of children and with a larger age difference between adults and children. Stimulant prescribing for children with ADHD was higher in less deprived practices. Older parents and families with more children fail to recognise ADHD and may need more support. Practices in areas of higher socio-economic status are associated with greater prescribing of stimulants for children with ADHD.

Different Types and Acceptability of Psychotherapies for Acute Anxiety Disorders in Children and Adolescents: A Network Meta-analysis.

Importance: Anxiety disorders are common in children and adolescents, and uncertainty remains regarding the optimal strategy of psychotherapies in this population. Objective: To compare and rank the different types of psychotherapies and the different ways of delivering psychological treatments for anxiety disorders in children and adolescents. Data Sources: PubMed, Cochrane Central Register of Controlled Trials, EMBASE, PsycINFO, Web of Science, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ProQuest Dissertations, LILACS (Literatura Latino Americana em Ciências da Saúde), international trial registers, and US Food and Drug Administration reports were searched from inception to November 30, 2017. Study Selection: Randomized clinical trials that compared any structured psychotherapy with another psychotherapy or a control condition for anxiety disorders in children and adolescents were selected. Data Extraction and Synthesis: Four researchers independently performed data extraction and quality assessment. Pairwise meta-analyses and Bayesian network meta-analysis within the random-effects model were used to synthesize data. Main Outcomes and Measures: Efficacy (change in anxiety symptoms) posttreatment and at follow-up, acceptability (all-cause discontinuation), and quality of life and functional improvement were measured. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Results: A total of 101 unique trials including 6625 unique participants compared 11 different psychotherapies with 4 specific control conditions. The certainty of evidence was rated as low or very low for most comparisons. For efficacy, most psychotherapies were significantly more effective than the wait list condition posttreatment (standardized mean difference [SMD], -1.43 to -0.61) and at the longest follow-up (SMD, -1.84 to -1.64). However, only group cognitive behavioral therapy (CBT) was significantly more effective than the other psychotherapies and all control conditions posttreatment. For acceptability, bibliotherapy CBT had significantly more all-cause discontinuations than some psychotherapies and control conditions (range of odds ratios, 2.48-9.32). In terms of quality of life and functional improvement, CBT (delivered in different ways) was significantly beneficial compared with psychological placebo and the wait list condition (SMDs, 0.73 to 1.99). Conclusions and Relevance: Group CBT would be the more appropriate choice of psychotherapy for anxiety disorders in children and adolescents, based on these findings. Other types of psychotherapies and different ways of delivering psychological treatment can be alternative options. Further research is needed to explore specific anxiety disorders, disorder-specific psychotherapy, and moderators of treatment effect. Trial Registration: PROSPERO Identifier: CRD42015016283.

Patients with chronic bipolar disorder exhibit widespread increases in extracellular free water.

OBJECTIVES: Bipolar disorder (BP) is a debilitating psychiatric disease that is not well understood. Previous diffusion magnetic resonance imaging (dMRI) studies of BP patients found prominent microstructural white matter (WM) abnormalities of reduced fractional anisotropy (FA). Because FA is a nonspecific measure, relating these abnormalities to a specific pathology is difficult. Here, dMRI specificity was increased by free water (FW) imaging, which allows identification of changes in extracellular space (FW) from neuronal tissue (fractional anisotropy of tissue [FA-t]). Previous studies identified increased FW in early schizophrenia (SZ) stages which was replaced by widespread decreased FA-t in chronic stages. This is the first analysis utilizing this method to compare BP patients and controls. METHODS: 3 Tesla diffusion weighted imaging (3T DWI) data were acquired for 17 chronic BP and 28 healthy control (HC) participants at Oxford University. Tract-based spatial statistics was utilized to generate a WM skeleton. FW imaging deconstructed the diffusion signal into extracellular FW and tissue FA-t maps. These maps were projected onto the skeleton and FA, FA-t, and FW were compared between groups. RESULTS: We found significantly lower FA in BP patients when compared to HC in areas that overlapped with extensive FW increases. There were no FA-t differences. CONCLUSIONS: Our study suggests that chronic BP shows similar WM changes to early SZ, suggesting that extracellular FW increases could be a transient indication of recent psychotic episodes. Since FW increase in SZ has been suggested to be related to neuroinflammation, we theorize that neuroinflammation might be a shared pathology between chronic BP and early SZ.

A Systematic Review and Network Meta-Analysis to Assess the Relative Efficacy of Antipsychotics for the Treatment of Positive and Negative Symptoms in Early-Onset Schizophrenia.

INTRODUCTION: Early-onset schizophrenia (EOS) is a serious debilitating disorder with considerable morbidity and a reduced life expectancy; therefore, early diagnosis and effective treatments are particularly important. Negative symptoms are more prominent in adolescents and children (compared with adults), and are key predictors of worse functional and clinical outcomes in EOS. Therefore, this study aimed to explore the relative efficacy of antipsychotics used in the treatment of EOS, with a focus on studies reporting effectiveness using the Positive and Negative Syndrome scale (PANSS), a scale that includes an overall symptom measure, in addition to separate subscales for positive and, importantly, negative symptoms. METHODS: A systematic literature review was conducted using the MEDLINE and Cochrane Central Register of Controlled Trials databases to identify trials conducted in children and adolescents with schizophrenia, and symptom control was reported using the PANSS. A Bayesian random-effects network meta-analysis was performed, synthesising data for a number of outcomes, including mean change from baseline in PANSS scores, treatment discontinuation and weight gain. RESULTS: Eleven studies were included in the evidence synthesis, comprising 1714 patients across eight active interventions (aripiprazole, haloperidol, molindone, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone) and placebo. All treatments showed a greater reduction in total PANSS scores vs placebo; however, only three interventions (molindone, olanzapine and risperidone) were associated with a statistically significant reduction in total PANSS scores at 6 weeks vs placebo. Haloperidol had the greatest reduction vs placebo; however, this result was not statistically significant [mean difference, -15.6, 95% credible interval (-35.4, 4.1)]. Haloperidol, olanzapine and risperidone showed a statistically significant reduction in positive PANSS scores vs placebo; however, whilst all interventions showed a trend of reduction in negative PANSS scores vs placebo, no comparisons were statistically significant. CONCLUSIONS: Many of the treatments are efficacious in controlling symptoms, and all showed a trend of superiority vs placebo for total, positive and negative PANSS scores, although only olanzapine and risperidone yielded statistically significant results vs placebo for both total and positive PANSS scores. Varying results for discontinuation and weight gain demonstrate a need to balance efficacy with side-effect profiles.

Comparative efficacy and acceptability of psychotherapies for acute anxiety disorders in children and adolescents: study protocol for a network meta-analysis.

INTRODUCTION: Anxiety disorders are associated with significant public health burden in young individuals. Cognitive-behavioural therapy (CBT) is the most commonly used psychotherapy for anxiety disorders in children and adolescents, but previous reviews were hindered by a limited number of trials with direct comparisons between different psychotherapies and their deliveries. Consequently, the main aim of this research was to investigate the comparative efficacy and acceptability of various types and deliveries of psychotherapies for anxiety disorders in children and adolescents. METHODS AND ANALYSIS: We will systematically search PubMed, EMBASE, Cochrane, Web of Science, PsycINFO, CINAHL, ProQuest Dissertations and LiLACS for randomised controlled trials, regardless of whether participants received blinding or not, published from 1 January 1966 to 30 January 2015 (updated to 1 July 2015), that compared any psychotherapy with either a control condition or an active comparator with different types and/or different delivery formats for the acute treatment of anxiety disorders in children and adolescents. Data extraction, risk of bias and quality assessments will be independently extracted by two reviewers. The primary outcome for efficacy will be mean overall change scores in anxiety symptoms (self-rated or assessor-rated) from baseline to post-treatment between two groups. The acceptability of treatment will be measured as the proportion of patients who discontinued treatment during the acute phase of treatment. We will assess efficacy, based on the standardised mean difference (SMD), and acceptability, based on the OR, using a random-effects network meta-analysis within a Bayesian framework. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. The results will be published in a peer-reviewed journal and will be disseminated electronically and in print. The meta-analysis may be updated to inform and guide management of anxiety in children and adolescents. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015016283.

Fear responses to safety cues in anxious adolescents: Preliminary evidence for atypical age-associated trajectories of functional neural circuits.

Adolescent anxiety is common and impairing and often persists into adulthood. There is growing evidence that adult anxiety is characterized by abnormal fear responses to threat and safety cues, along with perturbations in fear-related neural circuits. Although some of this work has been extended to adolescents, with promising results, it is not yet clear whether changes in these circuits across developmental age varies between anxious and non-anxious adolescents. Here we used fMRI to examine how age modulates neural responses as adolescents are exposed to threat and safety cues. Participants were 15 anxious and 11 non-anxious adolescents (age 12-17) who completed a fear conditioning paradigm. The paradigm incorporated a threat cue comprising a neutral face which was paired with a fearful, screaming face, a safety cue comprising a different neutral face, and a control stimulus. Across the whole sample, neural activation to the threat cue (relative to the control cue) correlated positively with age in a number of regions, including the dorsal anterior cingulate and bilateral dorsolateral prefrontal cortex (PFC). However, neural activation to the safety cue (relative to the control cue) was modulated differently by age in the two groups: a more positive association between activation and age was observed in the control group compared to the anxious group in various regions including medial and dorsolateral PFC, anterior insula, and amygdala. These findings suggest that maturation of the neural substrates of fear responses to safety cues may be perturbed in anxious adolescents, potentially contributing to the emergence and maintenance of anxiety disorders in adulthood.

Cognitive behavioural therapy for anxiety disorders in children and adolescents.

BACKGROUND: A previous Cochrane review (James 2005) showed that cognitive behavioural therapy (CBT) was effective in treating childhood anxiety disorders; however, questions remain regarding (1) the relative efficacy of CBT versus non-CBT active treatments; (2) the relative efficacy of CBT versus medication and the combination of CBT and medication versus placebo; and (3) the long-term effects of CBT.  OBJECTIVES: To examine (1) whether CBT is an effective treatment for childhood and adolescent anxiety disorders in comparison with (a) wait-list controls; (b) active non-CBT treatments (i.e. psychological placebo, bibliotherapy and treatment as usual (TAU)); and (c) medication and the combination of medication and CBT versus placebo; and (2) the long-term effects of CBT. SEARCH METHODS: Searches for this review included the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Depression, Anxiety and Neurosis Group Register, which consists of relevant randomised controlled trials from the bibliographic databases－The Cochrane Library (1970 to July 2012), EMBASE, (1970 to July 2012) MEDLINE (1970 to July 2012) and PsycINFO (1970 to July 2012). SELECTION CRITERIA: All randomised controlled trials (RCTs) of CBT versus waiting list, active control conditions, TAU or medication were reviewed. All participants must have met the criteria of the Diagnostic and Statistical Manual (DSM) or the International Classification of Diseases (ICD) for an anxiety diagnosis, excluding simple phobia, obsessive-compulsive disorder, post-traumatic stress disorder and elective mutism. DATA COLLECTION AND ANALYSIS: The methodological quality of included trials was assessed by three reviewers independently. For the dichotomous outcome of remission of anxiety diagnosis, the odds ratio (OR) with 95% confidence interval (CI) based on the random-effects model, with pooling of data via the inverse variance method of weighting, was used. Significance was set at P < 0.05. Continuous data on each child's anxiety symptoms were pooled using the standardised mean difference (SMD). MAIN RESULTS: Forty-one studies consisting of 1806 participants were included in the analyses. The studies involved children and adolescents with anxiety of mild to moderate severity in university and community clinics and school settings. For the primary outcome of remission of any anxiety diagnosis for CBT versus waiting list controls, intention-to-treat (ITT) analyses with 26 studies and 1350 participants showed an OR of 7.85 (95% CI 5.31 to 11.60, Z = 10.26, P < 0.0001), but with evidence of moderate heterogeneity (P = 0.04, I² = 33%). The number needed to treat (NNT) was 6.0 (95% CI 7.5 to 4.6). No difference in outcome was noted between individual, group and family/parental formats. ITT analyses revealed that CBT was no more effective than non-CBT active control treatments (six studies, 426 participants) or TAU in reducing anxiety diagnoses (two studies, 88 participants). The few controlled follow-up studies (n = 4) indicate that treatment gains in the remission of anxiety diagnosis are not statistically significant. AUTHORS' CONCLUSIONS: Cognitive behavioural therapy is an effective treatment for childhood and adolescent anxiety disorders; however, the evidence suggesting that CBT is more effective than active controls or TAU or medication at follow-up, is limited and inconclusive.

Cognitive reappraisal of peer rejection in depressed versus non-depressed adolescents: functional connectivity differences.

BACKGROUND: Depression is the most common psychiatric disorder in adolescence, and is characterised by an inability to down-regulate negative emotional responses to stress. Adult studies suggest this may be associated with reduced functional connectivity between prefrontal and subcortical regions, yet the neurological mechanisms in adolescence remain unclear. METHODS: We developed a novel, age-appropriate, reappraisal paradigm to investigate functional connectivity during reappraisal of a real-life source of stress in 15 depressed and 15 non-depressed adolescents. During fMRI, participants i) attended to, and ii) implemented reappraisal techniques (learnt prior to fMRI) in response to, rejection. RESULTS: Reappraisal reduced negative mood and belief in negative thoughts in both groups alike, however during reappraisal (versus attend) trials, depressed adolescents showed greater connectivity between the right frontal pole and numerous subcortical and cortical regions than non-depressed adolescents. CONCLUSIONS: These findings tentatively suggest that, when instructed, depressed adolescents do have the ability to engage neural networks involved in emotion regulation, possibly because adolescence reflects a period of heightened plasticity. These data support the value of cognitive reappraisal as a treatment tool, identify neural markers that could be used to optimise current therapies, and lay the foundations for developing novel neuroscientific techniques for the treatment of adolescent depression.

Laterality interacts with sex across the schizophrenia/bipolarity continuum: an interpretation of meta-analyses of structural MRI.

Review of the first comprehensive meta-analysis of VBM (voxel-based morphometry) studies in schizophrenia indicates asymmetrical reductions of anterior cingulate gyrus to the right, and medial temporal lobe (including the uncus) and para-hippocampal gyrus to the left. In subsequent meta-analyses of schizophrenia and bipolar disorder change in these limbic structures is systematically related to change in the insula. Deficits in insula (and para-hippocampal gyrus) to the left, and dorsal anterior cingulate gyrus to the right are greater in schizophrenic psychoses whereas deficits in anterior cingulate to the left and insula to the right are greater in bipolar illness. Thus (1) brain structures implicated in schizophrenia include those implicated in bipolar disorder, (2) the variation that separates the prototypical psychoses may be a subset of that relating to the structural asymmetry (the "torque") characteristic of the human brain, and (3) the meta-analysis of Bora et al. (2012) indicates that laterality of involvement of the insula and cingulate gyrus across the spectrum of bipolar and schizophrenic psychoses is critically dependent upon the sex ratio. Thus structural change underlying the continuum of psychosis relates to the interaction of laterality and sex.

Cognitive behavioural therapy for anxiety disorders in children and adolescents.

BACKGROUND: A previous Cochrane review (James 2005) showed that cognitive behavioural therapy (CBT) was effective in treating childhood anxiety disorders; however, questions remain regarding (1) the relative efficacy of CBT versus non-CBT active treatments; (2) the relative efficacy of CBT versus medication and the combination of CBT and medication versus placebo; and (3) the long-term effects of CBT.  OBJECTIVES: To examine (1) whether CBT is an effective treatment for childhood and adolescent anxiety disorders in comparison with (a) wait-list controls; (b) active non-CBT treatments (i.e. psychological placebo, bibliotherapy and treatment as usual (TAU)); and (c) medication and the combination of medication and CBT versus placebo; and (2) the long-term effects of CBT. SEARCH METHODS: Searches for this review included the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Depression, Anxiety and Neurosis Group Register, which consists of relevant randomised controlled trials from the bibliographic databases－The Cochrane Library (1970 to July 2012), EMBASE, (1970 to July 2012) MEDLINE (1970 to July 2012) and PsycINFO (1970 to July 2012). SELECTION CRITERIA: All randomised controlled trials (RCTs) of CBT versus waiting list, active control conditions, TAU or medication were reviewed. All participants must have met the criteria of the Diagnostic and Statistical Manual (DSM) or the International Classification of Diseases (ICD) for an anxiety diagnosis, excluding simple phobia, obsessive-compulsive disorder, post-traumatic stress disorder and elective mutism. DATA COLLECTION AND ANALYSIS: The methodological quality of included trials was assessed by three reviewers independently. For the dichotomous outcome of remission of anxiety diagnosis, the odds ratio (OR) with 95% confidence interval (CI) based on the random-effects model, with pooling of data via the inverse variance method of weighting, was used. Significance was set at P < 0.05. Continuous data on each child's anxiety symptoms were pooled using the standardised mean difference (SMD). MAIN RESULTS: Forty-one studies consisting of 1806 participants were included in the analyses. The studies involved children and adolescents with anxiety of mild to moderate severity in university and community clinics and school settings. For the primary outcome of remission of any anxiety diagnosis for CBT versus waiting list controls, intention-to-treat (ITT) analyses with 26 studies and 1350 participants showed an OR of 0.13 (95% CI 0.09 to 0.19, Z = 10.26, P < 0.0001), but with evidence of moderate heterogeneity (P = 0.04, I² = 33%). The number needed to treat (NNT) was 6.0 (95% CI 7.5 to 4.6). No difference in outcome was noted between individual, group and family/parental formats. ITT analyses revealed that CBT was no more effective than non-CBT active control treatments (six studies, 426 participants) or TAU in reducing anxiety diagnoses (two studies, 88 participants). The few controlled follow-up studies (n = 4) indicate that treatment gains in the remission of anxiety diagnosis are not statistically significant. AUTHORS' CONCLUSIONS: Cognitive behavioural therapy is an effective treatment for childhood and adolescent anxiety disorders; however, the evidence suggesting that CBT is more effective than active controls or TAU or medication at follow-up, is limited and inconclusive.

Anxious and non-anxious adolescents' experiences of non-clinical magnetic resonance imaging research.

Magnetic resonance imaging (MRI) has become a ubiquitous research tool for developmental neuroscientists interested in brain structure and function in children and adolescents. However, ethical concerns are sometimes raised about using MRI with children and adolescents, especially when participants have anxiety. We asked 17 clinically/sub-clinically anxious and 19 non-anxious adolescents about their experiences of taking part in MRI for research purposes. Although the anxious group reported experiencing more anxiety during the scan, these differences had attenuated by the time participants got home. We found no evidence that anxious adolescents would be less likely to choose to have another scan or would feel more nervous during another scan. There was some evidence that more trait anxious adolescents found the MRI study enjoyable. These findings should give ethics committees, clinicians, and parents confidence that so long as researchers exercise appropriate care, MRI research is acceptable to adolescents, including those with clinical anxiety.

Structural connectivity in schizophrenia and its impact on the dynamics of spontaneous functional networks.

The neuropathology of schizophrenia remains unclear. Some insight has come from modern neuroimaging techniques, which offer an unparalleled opportunity to explore in vivo the structure and function of the brain. Using functional magnetic resonance imaging, it has been found that the large-scale resting-state functional connectivity (rsFC) in schizophrenia--measured as the temporal correlations of the blood-oxygen-level-dependent (BOLD) signal--exhibit altered network topology, with lower small-world index. The origin of these rsFC alterations and link with the underlying structural connectivity remain unclear. In this work, we used a computational model of spontaneous large-scale brain activity to explore the role of the structural connectivity in the large-scale dynamics of the brain in health and schizophrenia. The structural connectomes from 15 adolescent patients with early-onset schizophrenia and 15 age- and gender-matched controls were built from diffusion tensor imaging data to detect the white matter tracts between 90 brain areas. Brain areas, simulated using a reduced dynamic mean-field model, receive excitatory input from other areas in proportion to the number of fibre tracts between them. The simulated mean field activity was transformed into BOLD signal, and the properties of the simulated functional networks were analyzed. Our results suggest that the functional alterations observed in schizophrenia are not directly linked to alterations in the structural topology. Instead, subtly randomized and less small-world functional networks appear when the brain operates with lower global coupling, which shifts the dynamics from the optimal healthy regime.

Microdistribution and long-term retention of 239Pu (NO3)4 in the respiratory tracts of an acutely exposed plutonium worker and experimental beagle dogs.

The long-term retention of inhaled soluble forms of plutonium raises concerns as to the potential health effects in persons working in nuclear energy or the nuclear weapons program. The distributions of long-term retained inhaled plutonium-nitrate [(239)Pu (NO(3))(4)] deposited in the lungs of an accidentally exposed nuclear worker (Human Case 0269) and in the lungs of experimentally exposed beagle dogs with varying initial lung depositions were determined via autoradiographs of selected histologic lung, lymph node, trachea, and nasal turbinate tissue sections. These studies showed that both the human and dogs had a nonuniform distribution of plutonium throughout the lung tissue. Fibrotic scar tissue effectively encapsulated a portion of the plutonium and prevented its clearance from the body or translocation to other tissues and diminished dose to organ parenchyma. Alpha radiation activity from deposited plutonium in Human Case 0269 was observed primarily along the subpleural regions while no alpha activity was seen in the tracheobronchial lymph nodes of this individual. However, relatively high activity levels in the tracheobronchial lymph nodes of the beagles indicated the lymphatic system was effective in clearing deposited plutonium from the lung tissues. In both the human case and beagle dogs, the appearance of retained plutonium within the respiratory tract was inconsistent with current biokinetic models of clearance for soluble forms of plutonium. Bound plutonium can have a marked effect on the dose to the lungs and subsequent radiation exposure has the potential to increase cancer risk.