Oxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers.

Blood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period.

Compared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness.

Plasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies.

Meta-analyses suggest that reboxetine may be less effective than other antidepressants. Such comparisons may be biased by lower adherence to reboxetine and subsequent handling of missing outcome data. This study illustrates how to adjust for differential non-adherence and hence derive an unbiased estimate of the efficacy of reboxetine compared with citalopram in primary care patients with depression.

A structural mean modelling (SMM) approach was used to generate adherence-adjusted estimates of the efficacy of reboxetine compared with citalopram using GENetic and clinical Predictors Of treatment response in Depression (GENPOD) trial data. Intention-to-treat (ITT) analyses were performed to compare estimates of effectiveness with results from previous meta-analyses.

At 6 weeks, 92% of those randomized to citalopram were still taking their medication, compared with 72% of those randomized to reboxetine. In ITT analysis, there was only weak evidence that those on reboxetine had a slightly worse outcome than those on citalopram [adjusted difference in mean Beck Depression Inventory (BDI) scores: 1.19, 95% confidence interval (CI) –0.52 to 2.90, p = 0.17]. There was no evidence of a difference in efficacy when differential non-adherence was accounted for using the SMM approach for mean BDI (–0.29, 95% CI –3.04 to 2.46, p = 0.84) or the other mental health outcomes.

There was no evidence of a difference in the efficacy of reboxetine and citalopram when these drugs are taken and tolerated by depressed patients. The SMM approach can be implemented in standard statistical software to adjust for differential non-adherence and generate unbiased estimates of treatment efficacy for comparisons of two (or more) active interventions.

Sleep benefits memory consolidation. Here, we tested the beneficial effect of sleep on memory consolidation following exposure psychotherapy of phobic anxiety.

A total of 40 individuals afflicted with spider phobia according to DSM-IV underwent a one-session virtual reality exposure treatment and either slept for 90 min or stayed awake afterwards.

Sleep following exposure therapy compared with wakefulness led to better reductions in self-reported fear (p = 0.045, d = 0.47) and catastrophic spider-related cognitions (p = 0.026, d = 0.53) during approaching a live spider, both tested after 1 week. Both reductions were associated with greater percentages of stage 2 sleep.

Our results indicate that sleep following successful psychotherapy, such as exposure therapy, improves therapeutic effectiveness, possibly by strengthening new non-fearful memory traces established during therapy. These findings offer an important non-invasive alternative to recent attempts to facilitate therapeutic memory extinction and consolidation processes with pharmacological or behavioral interventions.

Psychotic-like experiences (PLEs) and juvenile mania in adolescence index risk for severe psychopathology in adulthood. The importance of childhood problems with communication, reading, speech and mathematics for the development of PLEs and juvenile mania is not well understood.

Through the Child and Adolescent Twin Study in Sweden, we identified 5812 children. The parents were interviewed about their children's development at age 9 or 12 years. At age 15 or 18 years, children and parents completed questionnaires targeting current PLEs and juvenile mania symptoms. Logistic regressions were used to assess associations between problems with communication, reading, speech and mathematics and PLEs/juvenile mania symptoms. To evaluate the relative importance of genes and environment in these associations, we used bivariate twin analyses based on structural equation models.

Children with parent-endorsed childhood problems with communication, reading and mathematics had an increased risk of developing auditory hallucinations and parental-reported juvenile mania symptoms in adolescence. The most consistent finding was that children with childhood problems with communication, reading and mathematics had an increased risk of developing auditory hallucinations [for example, the risk for self-reported auditory hallucinations at age 15 was increased by 96% for children with communication problems: OR (odds ratio) 1.96, 95% confidence interval (CI) 1.33–2.88]. The twin analyses showed that genetic effects accounted for the increased risk of PLEs and juvenile mania symptoms among children with communication problems.

Childhood problems with communication, reading and mathematics predict PLEs and juvenile mania symptoms in adolescence. Similar to the case for schizophrenia and bipolar disorder, PLEs and juvenile mania may share genetic aetiological factors.

Previous research on impulsivity in borderline personality disorder (BPD) has revealed inconsistent findings. Impulsive behaviour is often observed during states of emotional distress and might be exaggerated by current attention deficit hyperactivity disorder (ADHD) symptoms in individuals with BPD. We aimed to investigate different components of impulsivity dependent on stress induction controlling for self-reported ADHD symptoms in BPD.

A total of 31 unmedicated women with BPD and 30 healthy women (healthy controls; HCs), matched for age, education and intelligence, completed self-reports and behavioural tasks measuring response inhibition (go/stop task) and feedback-driven decision making (Iowa Gambling Task) under resting conditions and after experimental stress induction. ADHD symptoms were included as a covariate in the analyses of behavioural impulsivity. Additionally, self-reported emotion-regulation capacities were assessed.

BPD patients reported higher impulsive traits than HCs. During stress conditions – compared with resting conditions – self-reported impulsivity was elevated in both groups. Patients with BPD reported higher state impulsivity under both conditions and a significantly stronger stress-dependent increase in state impulsivity. On the behavioural level, BPD patients showed significantly impaired performance on the go/stop task under stress conditions, even when considering ADHD symptoms as a covariate, but not under resting conditions. No group differences on the Iowa Gambling Task were observed. Correlations between impulsivity measures and emotion-regulation capacities were observed in BPD patients.

Findings suggest a significant impact of stress on self-perceived state impulsivity and on response disinhibition (even when considering current ADHD symptoms) in females with BPD.

Victims of bullying are at risk for psychotic experiences in early adolescence. It is unclear if this elevated risk extends into late adolescence. The aim of this study was to test whether bullying perpetration and victimization in elementary school predict psychotic experiences in late adolescence.

The current study is based on the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective community-based study. A total of 4720 subjects with bullying perpetration and victimization were repeatedly assessed between the ages of 8 and 11 years by child and mother reports. Suspected or definite psychotic experiences were assessed with the Psychosis-Like Symptoms semi-structured interview at age 18 years.

Controlling for child's gender, intelligence quotient at age 8 years, childhood behavioural and emotional problems, and also depression symptoms and psychotic experiences in early adolescence, victims [child report at 10 years: odds ratio (OR) 2.4, 95% confidence interval (CI) 1.6–3.4; mother report: OR 1.6, 95% CI 1.1–2.3], bully/victims (child report at 10 years: OR 3.1, 95% CI 1.7–5.8; mother: OR 2.9, 95% CI 1.7–5.0) and bullies (child report at 10 years: OR 4.9, 95% CI 1.3–17.7; mother: OR 1.2, 95% CI 0.46–3.1, n.s.) had a higher prevalence of psychotic experiences at age 18 years. Path analysis revealed that the association between peer victimization in childhood and psychotic experiences at age 18 years was only partially mediated by psychotic or depression symptoms in early adolescence.

Involvement in bullying, whether as victim, bully/victim or bully, may increase the risk of developing psychotic experiences in adolescence. Health professionals should ask routinely during consultations with children about their bullying of and by peers.

Bipolar disorder (BD) is associated with adverse childhood experiences (ACE), which worsen the lifetime course of illness, and with signs of widespread disruption of white matter (WM) integrity in adult life. ACE are associated with changes in WM microstructure in healthy humans.

We tested the effects of ACE on diffusion-tensor imaging (DTI) measures of WM integrity in 80 in-patients affected by a major depressive episode in the course of BD. We used whole-brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial and mean diffusivity, and fractional anisotropy.

ACE hastened the onset of illness. We observed an inverse correlation between the severity of ACE and DTI measures of axial diffusivity in several WM fibre tracts contributing to the functional integrity of the brain and including the corona radiata, thalamic radiations, corpus callosum, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and uncinate fasciculus.

Axial diffusivity reflects the integrity of axons and myelin sheaths, and correlates with functional connectivity and with higher-order abilities such as reasoning and experience of emotions. In patients with BD axial diffusivity is increased by lithium treatment. ACE might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.

Previous work reports an association between familial risk factors stemming from parental characteristics and offspring disruptive behavior disorders (DBDs). This association may reflect (a) the direct effects of familial environment and (b) a passive gene–environment correlation (rGE), wherein the parents provide both the genes and the environment. The current study examined the contributions of direct environmental influences and passive rGE by comparing the effects of familial risk factors on child DBDs in genetically related (biological) and non-related (adoptive) families.

Participants were 402 adoptive and 204 biological families. Familial environment was defined as maternal and paternal maladaptive parenting and antisociality, marital conflict and divorce; offspring DBDs included attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD). Mixed-level regressions estimated the main effects of familial environment, adoption status and the familial environment by adoption status interaction term, which tested for the presence of passive rGE.

There was a main effect of maternal and paternal maladaptive parenting and marital discord on child DBDs, indicating a direct environmental effect. There was no direct environmental effect of maternal or paternal antisociality, but maternal and paternal antisociality had stronger associations with child DBDs in biological families than adoptive families, indicating the presence of a passive rGE.

Many familial risk factors affected children equally across genetically related and non-related families, providing evidence for direct environmental effects. The relationship of parental antisociality and offspring DBDs was best explained by a passive rGE, where a general vulnerability toward externalizing psychopathology is passed down by the parents to the children.

The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM).

A total of 20 medication-naive ADHD boys underwent functional magnetic resonance imaging during a parametric WM n-back task three times, under a single clinical dose of either MPH, ATX or placebo in a randomized, double-blind, placebo-controlled, cross-over design. To test for normalization effects, brain activations in ADHD under each drug condition were compared with that of 20 age-matched healthy control boys.

Relative to healthy boys, ADHD boys under placebo showed impaired performance only under high WM load together with significant underactivation in the bilateral dorsolateral prefrontal cortex (DLPFC). Both drugs normalized the performance deficits relative to controls. ATX significantly enhanced right DLPFC activation relative to MPH within patients, and significantly normalized its underactivation relative to controls. MPH, by contrast, both relative to placebo and ATX, as well as relative to controls, upregulated the left inferior frontal cortex (IFC), but only during 2-back. Both drugs enhanced fronto-temporo-striatal activation in ADHD relative to control boys and deactivated the default-mode network, which were negatively associated with the reduced DLPFC activation and performance deficits, suggesting compensation effects.

The study shows both shared and drug-specific effects. ATX upregulated and normalized right DLPFC underactivation, while MPH upregulated left IFC activation, suggesting drug-specific laterality effects on prefrontal regions mediating WM.

Common chronic conditions, such as heart disease and cancer, are associated with increased psychological distress, functional limitations and shortened life expectancy, but whether these diseases alter aspects of personality remains unclear.

To examine whether the onset of heart disease, stroke, diabetes, cancer, hypertension, arthritis and respiratory disease is associated with subsequent changes in personality traits of the five-factor model, we pooled data from the Health and Retirement Study, the Midlife in the United States Survey, and the graduate and sibling samples of the Wisconsin Longitudinal Study for an individual-participant meta-analysis (total n = 17 493; mean age at baseline 55.8 years).

After adjustment for age, we observed consistent decreases in extraversion [−0.25 T-scores per one disease; 95% confidence interval (CI) −0.40 to −0.10], emotional stability (−0.40, 95% CI −0.61 to −0.19), conscientiousness (−0.44, 95% CI −0.57 to −0.30) and openness to experience (−0.25, 95% CI −0.37 to −0.13) but not in agreeableness (−0.05, 95% CI −0.19 to 0.08) after the onset of chronic diseases. The onset of each additional chronic disease accelerated the average age-related personality change by 2.5 years in decreasing extraversion, 5.5 years in decreasing conscientiousness, and 1.6 years in decreasing openness to experience, and attenuated the increasing levels of emotional stability by 1.9 years. Co-morbid conditions were associated with larger changes than single diseases, suggesting a dose–response association between morbidity and personality change.

These results support the hypothesis that chronic diseases influence personality development in adulthood.

Prior research has suggested that, consistent with the diathesis–stress model of gene–environment interaction (G × E), parent–child conflict activates genetic influences on antisocial/externalizing behaviors during adolescence. It remains unclear, however, whether this model is also important during childhood, or whether the moderation of child conduct problems by negative/conflictive parenting is better characterized as a bioecological interaction, in which environmental influences are enhanced in the presence of environmental risk whereas genetic influences are expressed most strongly in their absence. The current study sought to distinguish between these possibilities, evaluating how the parent–child relationship moderates the etiology of childhood-onset conduct problems.

We conducted a series of ‘latent G by measured E’ interaction analyses, in which a measured environmental variable was allowed to moderate both genetic and environmental influences on child conduct problems. Participants included 500 child twin pairs from the Michigan State University Twin Registry (MSUTR).

Shared environmental influences on conduct problems were found to be several-fold larger in those with high levels of parent–child conflict as compared with those with low levels. Genetic influences, by contrast, were proportionally more influential at lower levels of conflict than at higher levels.

Our findings suggest that, although the diathesis–stress form of G × E appears to underlie the relationship between parenting and conduct problems during adolescence, this pattern of moderation does not extend to childhood. Instead, results were more consistent with the bioecological form of G × E which postulates that, in some cases, genetic influences may be most fully manifested in the absence of environmental risk.

Increased intra-individual variability (IIV) in reaction time (RT) across various tasks is one ubiquitous neuropsychological finding in attention deficit hyperactivity disorder (ADHD). However, neurobiological underpinnings of IIV in individuals with ADHD have not yet been fully delineated. The ex-Gaussian distribution has been proved to capture IIV in RT. The authors explored the three parameters [μ (mu), σ (sigma), τ (tau)] of an ex-Gaussian RT distribution derived from the Conners' continuous performance test (CCPT) and their correlations with the microstructural integrity of the frontostriatal–caudate tracts and the cingulum bundles.

We assessed 28 youths with ADHD (8–17 years; 25 males) and 28 age-, sex-, IQ- and handedness-matched typically developing (TD) youths using the CCPT, Wechsler Intelligence Scale for Children, 3rd edition and magnetic resonance imaging (MRI). Microstructural integrity, indexed by generalized fractional anisotropy (GFA), was measured by diffusion spectrum imaging tractrography on a 3-T MRI system.

Youths with ADHD had larger σ (s.d. of Gaussian distribution) and τ (mean of exponential distribution) and reduced GFA in four bilateral frontostriatal tracts. With increased inter-stimulus intervals of CCPT, the magnitude of greater τ in ADHD than TD increased. In ADHD youths, the cingulum bundles and frontostriatal integrity were associated with three ex-Gaussian parameters and with μ (mean of Gaussian distribution) and τ, respectively; while only frontostriatal GFA was associated with μ and τ in TD youths.

Our findings suggest the crucial role of the integrity of the cingulum bundles in accounting for IIV in ADHD. Involvement of different brain systems in mediating IIV may relate to a distinctive pathophysiological processing and/or adaptive compensatory mechanism.

Deep brain stimulation (DBS) is increasingly being applied to psychiatric conditions such as obsessive–compulsive disorder (OCD), major depression and anorexia nervosa. Double-blind, randomized controlled trials (RCTs) of active versus sham treatment have been limited to small numbers. We therefore undertook a systematic review and meta-analysis of the effectiveness of DBS in psychiatric conditions to maximize study power.

We conducted a systematic literature search for double-blind, RCTs of active versus sham treatment using Pubmed/Medline and EMBASE up to April 2013. Where possible, we combined results from studies in a meta-analysis. We assessed differences in final values between the active and sham treatments for parallel-group studies and compared changes from baseline score for cross-over designs.

Inclusion criteria were met by five studies, all of which were of OCD. Forty-four subjects provided data for the meta-analysis. The main outcome was a reduction in obsessive symptoms as measured by the Yale–Brown Obsessive Compulsive Scale (YBOCS). Patients on active, as opposed to sham, treatment had a significantly lower mean score [mean difference (MD) −8.93, 95% confidence interval (CI) −13.35 to −5.76, p < 0.001], representing partial remission. However, one-third of patients experienced significant adverse effects (n = 16). There were no differences between the two groups in terms of other outcomes.

DBS may show promise for treatment-resistant OCD but there are insufficient randomized controlled data for other psychiatric conditions. DBS remains an experimental treatment in adults for severe, medically refractory conditions until further data are available.

Although cognitive subtypes have been suggested in schizophrenia patients, similar analyses have not been carried out in their non-affected siblings. Subtype classification may provide more insight into genetically driven variation in cognitive function. We investigated cognitive subtypes in siblings.

Cluster analyses were performed in 654 non-affected siblings, on a cognitive battery that included tests of attention, intellectual function and episodic memory. Resulting subtypes in the siblings were analyzed for cognitive, demographic and clinical characteristics and compared with those of their probands.

Three sibling subtypes of cognitive function were distinguished: ‘normal’, ‘mixed’ and ‘impaired’. Normal profile siblings (n = 192) were unimpaired on cognitive tests, in contrast to their proband (n = 184). Mixed profile siblings (n = 228) and their probands (n = 222) had a more similar performance pattern. Impaired profile siblings had poorer functional outcomes (n = 234) and their profile was almost identical to that of their proband (n = 223). Probands with cognitively impaired siblings could be distinguished from other schizophrenia patients by their own cognitive performance. They also had poorer clinical characteristics, including achievement of symptomatic remission.

Unaffected siblings of patients with schizophrenia are heterogeneous with respect to cognitive function. The poorer the cognitive profile of the sibling, the higher the level of correspondence with the proband. The sibling's cognitive subtype was predictive for disease course in the proband. Distinguishing cognitive subtypes of unaffected siblings may be of relevance for genetic studies.

Severe youth antisocial behaviour has been associated with increased risk of premature mortality in high-risk samples for many years, and some evidence now points to similar effects in representative samples. We set out to assess the prospective association between adolescent conduct problems and premature mortality in a population-based sample of men and women followed to the age of 65 years.

A total of 4158 members of the Medical Research Council National Survey of Health and Development (the British 1946 birth cohort) were assessed for conduct problems at the ages of 13 and 15 years. Follow-up to the age of 65 years via the UK National Health Service Central Register provided data on date and cause of death.

Dimensional measures of teacher-rated adolescent conduct problems were associated with increased hazards of death from cardiovascular disease by the age of 65 years in men [hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.04–1.32], and of all-cause and cancer mortality by the age of 65 years in women (all-cause HR 1.16, 95% CI 1.07–1.25). Adjustment for childhood cognition and family social class did little to attenuate these risks. Adolescent conduct problems were not associated with increased risks of unnatural/substance-related deaths in men or women in this representative sample.

Whereas previous studies of high-risk delinquent or offender samples have highlighted increased risks of unnatural and alcohol- or substance abuse-related deaths in early adulthood, we found marked differences in mortality risk from other causes emerging later in the life course among women as well as men.

Recent falls in suicide rates should be accompanied by a decline in the prevalence of suicidal ideation.

We used a pseudo-cohort analytic strategy to examine trends in suicidal ideation measured identically in 2000 and 2007, in nationally representative English probability samples of adults aged ⩾ 16 years. Suicidal ideation included tiredness of life, death wishes and thoughts of suicide. Logistic regression models were fitted to estimate trends in age-specific prevalence of suicidal ideation in the past year and past week between 2000 and 2007.

There were 6799 participants aged 16–71 years in 2000, and 6815 participants aged 16–78 years in 2007. There was little evidence of trends in prevalence of suicidal ideation, with the exception of women aged 44–50 years in 2007, whose prevalence was unusually high. Prevalence of suicidal ideation in the past year followed a W-shaped profile with age, with peaks at the transition to adulthood, in the forties, and in the oldest participants.

Despite falling suicide rates, suicidal ideation did not decline overall between 2000 and 2007. This may indicate the success of the National Suicide Prevention Strategy. Women aged 44–50 years in 2007 were, however, particularly prone to suicidal ideation. As they also have the highest age-adjusted prevalence of common mental disorders and the highest female suicide rate, there are clear implications for treatment access, availability and delivery in primary care.

An unhealthy body mass index (BMI) has been associated with depression but the direction of association is uncertain. Our aim was to estimate the co-morbidity and direction of association between BMI and depressive symptoms at several ages, from childhood to mid-adulthood.

The data were from 18 558 individuals born in 1 week in March 1958, in England, Scotland and Wales, with follow-up at ages 7, 11, 16, 23, 33, 42, 45 and 50 years. Depression (scores ⩾90th percentile) was identified from child/adolescent (teacher questionnaires) and adult (self-complete questionnaires and clinical interview) measures. BMI (kg/m2) measured in child/adolescence and adulthood was classified as underweight, normal, overweight or obese.

In cross-sectional analyses, obesity and underweight (not overweight) from 11 to 45 years were associated respectively with 1.3–2.1 and 1.5–2.3 times the risk of depression compared with normal weight. Using the time-lagged generalized estimating equation (GEE) approach, we tested (a) whether underweight or obesity at prior ages (7 to 45 years) predicted subsequent risk of depression (11 to 50 years), adjusting for baseline depression; and (b) whether depression at prior ages (7 to 42 years) predicted subsequent risk of underweight or obesity (11 to 45 years), adjusting for baseline BMI. In longitudinal analyses, underweight predicted subsequent depression in both sexes [odds ratio (OR) 1.25, 95% confidence interval (CI) 1.11–1.40] and depression predicted subsequent underweight in males only (OR 1.84, 95% CI 1.52–2.23). Obesity predicted subsequent depressive symptoms in females only (OR 1.34, 95% CI 1.14–1.56), but depression did not predict obesity.

Clinicians should consider screening routinely for depression patients with unhealthy BMI, namely underweight and obesity, and vice versa.

Previous studies have reported mixed results on neuropsychological deficits in attention deficit hyperactivity disorder (ADHD) and only a few studies have focused on adolescents. There is also a debate about whether the executive function (EF) impairments in ADHD are primary deficits or have some contribution from the underlying non-EF processes. The aim of this study was to investigate the impairments in EF and neuropsychological function with relatively low executive demand (low-EF) in adolescents with childhood diagnosis of ADHD as a function of current ADHD status.

Psychiatric diagnostic interviews and computerized neuropsychological tests classified into EF and low-EF tasks were completed by 435 adolescents with a childhood diagnosis of ADHD (300 adolescents classified as persistent ADHD, 109 as subsyndromal ADHD and 26 as remitted ADHD based on the current diagnosis) and 263 typically developing (TD) adolescents.

There were significant EF (spatial working memory, spatial planning and verbal working memory) and low-EF (signal detectability, spatial span and visual recognition memory) impairments in persistent and subsyndromal ADHD. The impairments in EF were independent of low-EF despite significant moderate correlations between any two of these tasks. Adolescents with remitted ADHD showed no deficit in either EF or low-EF.

This study suggests that adolescents with persistent and subsyndromal ADHD have EF and low-EF impairments that might contribute to ADHD independently.