The GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects.

We computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122).

Five polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex.

Multiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults.

In depression, non-remission, recurrence of depressive episodes after remission and conversion to bipolar disorder are crucial determinants of poor outcome. The present study aimed to determine the cumulative incidences and clinical predictors of these long-term outcomes after the first lifetime episode of depression.

A total of 301 in- or out-patients aged 18–70 years with a validated diagnosis of a single depressive episode were assessed from 2005 to 2007. At 5 years of follow-up, 262 patients were reassessed by means of the life chart method and diagnostic interviews from 2011 to 2013. Cumulative incidences and the influence of clinical variables on the rates of remission, recurrence and conversion to bipolar disorder, respectively, were estimated by survival analysis techniques.

Within 5 years, 83.3% obtained remission, 31.5% experienced recurrence of depression and 8.6% converted to bipolar disorder (6.3% within the first 2 years). Non-remission increased with younger age, co-morbid anxiety and suicidal ideations. Recurrence increased with severity and treatment resistance of the first depression, and conversion to bipolar disorder with treatment resistance, a family history of affective disorder and co-morbid alcohol or drug abuse.

The identified clinical characteristics of the first lifetime episode of depression should guide patients and clinicians for long-term individualized tailored treatment.

Maternal stress during pregnancy may increase the risk of preterm delivery (PD), but the associations between stress and subtypes of PD are not clear. We investigated maternal loss of a close relative and risks of very and moderately PD (<32 and 32–36 weeks, respectively) and spontaneous and medically indicated PD.

We studied 4 940 764 live singleton births in Denmark (1978–2008) and Sweden (1973–2006). We retrieved information on death of women's family members (children, partner, siblings, parents), birth outcomes and maternal characteristics from nationwide registries.

Overall, the death of a close family member the year before pregnancy or in the first 36 weeks of pregnancy was associated with a 7% increased risk of PD [95% confidence interval (CI) 1.04–1.10]. The highest hazard ratios (HR) for PD were found for death of an older child [HR (95% CI) 1.20 (1.10–1.31)] and for death of a partner [HR (95% CI) 1.31 (1.03–1.66)]. These losses were associated with higher risks of very preterm [HR (95% CI) 1.61 (1.29–2.01) and 2.07 (1.15–3.74), respectively] than of moderately preterm [HR (95% CI) 1.14 (1.03–1.26) and 1.22 (0.94–1.58), respectively] delivery. There were no substantial differences in the association between death of a child or partner and the risk of spontaneous v. medically indicated PD.

Death of a close family member the year before or during pregnancy was associated with an increased risk of PD, especially very PD. Possible mechanisms include both spontaneous and medically indicated preterm birth.

Empirical evidence on whether patients’ mental health and functioning will be more improved after long-term than short-term therapy is scarce. We addressed this question in a clinical trial with a long follow-up.

In the Helsinki Psychotherapy Study, 326 out-patients with mood or anxiety disorder were randomly assigned to long-term psychodynamic psychotherapy (LPP), short-term psychodynamic psychotherapy (SPP) or solution-focused therapy (SFT) and were followed for 10 years. The outcome measures were psychiatric symptoms, work ability, personality and social functioning, need for treatment, and remission.

At the end of the follow-up, altogether 74% of the patients were free from clinically elevated psychiatric symptoms. Compared with SPP, LPP showed greater reductions in symptoms, greater improvement in work ability and higher remission rates. A similar difference in symptoms and work ability was observed in comparison with SFT after adjustment for violations of treatment standards. No notable differences in effectiveness between SFT and SPP were observed. The prevalence of auxiliary treatment was relatively high, 47% in SFT, 58% in SPP and 33% in LPP, and, accordingly, the remission rates for general symptoms were 55, 45 and 62%, respectively.

After 10 years of follow-up, the benefits of LPP in comparison with the short-term therapies are rather small, though significant in symptoms and work ability, possibly due to more frequent use of auxiliary therapy in the short-term therapy groups. Further studies should focus on the choice of optimal length of therapy and the selection of factors predicting outcome of short- v. long-term therapy.

Whether the incidence of eating disorders in Western, industrialized countries has changed over time has been the subject of much debate. The purpose of this primary-care study was to examine changes in the incidence of eating disorders in The Netherlands during the 1980s, 1990s and 2000s.

A nationwide network of general practitioners (GPs), serving a representative sample (~1%) of the total Dutch population, recorded newly diagnosed patients with anorexia nervosa (AN) and bulimia nervosa (BN) in their practice during 1985–1989, 1995–1999, and 2005–2009. GPs are key players in the Dutch healthcare system, as their written referral is mandatory in order to get access to specialized (mental) healthcare, covered by health insurance. Health insurance is virtually universal in The Netherlands (99% of the population). A substantial number of GPs participated in all three study periods, during which the same case identification criteria were used and the same psychiatrist was responsible for making the final diagnoses. Incidence rates were calculated and for comparison between periods, incidence rate ratios.

The overall incidence rate of BN decreased significantly in the past three decades (from 8.6 per 100 000 person-years in 1985–1989 to 6.1 in 1995–1999, and 3.2 in 2005–2009). The overall incidence of AN remained fairly stable during three decades, i.e. 7.4 per 1 00 000 person-years in 1985–1989, 7.8 in 1995–1999, and 6.0 in 2005–2009.

The incidence rate of BN decreased significantly over the past three decades, while the overall incidence rate of AN remained stable.

Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD.

Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects.

Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo.

The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.

A large-scale network named the default mode network (DMN) dynamically cooperates and competes with an external attention system (EAS) to facilitate various cognitive functioning that is prominently impaired in schizophrenia. However, it is unclear whether the cognitive deficit in schizophrenia is related to the disrupted competition and/or cooperation between these two networks.

A total of 35 schizophrenia patients and 30 healthy controls were scanned using gradient-echo echo-planar imaging during n-back working memory (WM) processing. Brain activities of the DMN and EAS were measured using general linear modelling of the functional magnetic resonance imaging data. Dynamic interaction between the DMN and EAS was decomposed into two directions using Granger causality analysis.

We observed a significant failure of DMN suppression in patients with schizophrenia, which was significantly related to WM/attentional deficit. Granger causality modelling showed that in healthy controls, while the EAS inhibitorily influenced the DMN, the DMN exerted an ‘excitatory’ or cooperative influence back on the EAS, especially in those with lower WM accuracy. In schizophrenia, this ‘excitatory’ DMN→EAS influence within the reciprocal EAS–DMN loop was significantly reduced, especially in patients with WM/attentional deficit.

The dynamic interaction between the DMN and EAS is likely to be comprised of both competitive and cooperative influences. In healthy controls, both the ‘inhibitory’ EAS→DMN interaction and ‘excitatory’ DMN→EAS interaction are correlated with WM performance. In schizophrenia, reduced ‘cooperative’ influence from the DMN to dorsal nodes of the EAS occurs in the context of non-suppression of the DMN and may form a possible pathophysiological substrate of WM deficit and attention disorder.

The relationship between white-matter tracts and executive functions (EF) in attention deficit hyperactivity disorder (ADHD) has not been well studied and previous studies mainly focused on frontostriatal (FS) tracts. The authors explored the microstructural property of several fibre tracts hypothesized to be involved in EF, to correlate their microstructural property with EF, and to explore whether such associations differ between ADHD and typically developing (TD) youths.

We assessed 45 youths with ADHD and 45 individually matched TD youths with a computerized test battery for multiple dimensions of EF. From magnetic resonance imaging, FS tract, superior longitudinal fasciculus (SLF), arcuate fasciculus (AF) and cingulum bundle (CB) were reconstructed by diffusion spectrum imaging tractography. The generalized fractional anisotropy (GFA) values of white-matter tracts were computed to present microstructural property of each tract.

We found lower GFA in the left FS tract, left SLF, left AF and right CB, and poorer performance in set-shifting, sustained attention, cognitive inhibition and visuospatial planning in ADHD than TD. The ADHD and TD groups demonstrated different association patterns between EF and fibre tract microstructural property. Most of the EF were associated with microstructural integrity of the FS tract and CB in TD youths, while with that of the FS tract, SLF and AF in youths with ADHD.

Our findings support that the SLF, AF and CB also involve in a wide range of EF and that the main fibre tracts involved in EF are different in youths with ADHD.

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may be associated with lower heart rate variability (HRV), a condition associated with increased mortality risk. We aimed to investigate the association between TCAs, SSRIs and HRV in a population-based study.

In the prospective Rotterdam Study cohort, up to five electrocardiograms (ECGs) per participant were recorded (1991–2012). Two HRV variables were studied based on 10-s ECG recordings: standard deviation of normal-to-normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD). We compared the HRV on ECGs recorded during use of antidepressants with the HRV on ECGs recorded during non-use of any antidepressant. Additionally, we analysed the change in HRV on consecutive ECGs. Those who started or stopped using antidepressants before the second ECG were compared with non-users on two ECGs.

We included 23 647 ECGs from 11 729 participants (59% women, mean age 64.6 years at baseline). Compared to ECGs recorded during non-use of antidepressants (n = 22 971), SDNN and RMSSD were lower in ECGs recorded during use of TCAs (n = 296) and SSRIs (n = 380). Participants who started using TCAs before the second ECG had a decrease in HRV and those who stopped had an increase in HRV compared to consistent non-users (p < 0.001). Starting or stopping SSRIs was not associated with HRV changes.

TCAs were associated with a lower HRV in all analyses, indicating a real drug effect. For SSRIs the results are mixed, indicating a weaker association, possibly due to other factors.

Appraisals are suggested to play a determining role in the clinical outcome of psychotic experiences (PEs). We used experimental tasks that mimic PEs to investigate appraisals in individuals with PEs with and without a ‘need-for-clinical-care’, and psychosis patients whose symptoms have remitted. We predicted that patients would appraise the tasks as threatening regardless of current symptom level, while non-clinical and control groups would appraise them as non-threatening.

Appraisals following three anomalous experiences-inducing tasks [Telepath, Cards task, Virtual acoustic space paradigm (VASP)] were examined in 71 individuals: symptomatic (n = 18) and remitted (n = 16) psychosis patients; non-clinical group with PEs (n = 16); controls without PEs (n = 21).

As predicted, symptomatic patients endorsed more threatening appraisals for all tasks than non-clinical and control groups, who did not differ from each other. However, remitted patients were less likely to endorse threatening appraisals of the Cards and Telepath than their symptomatic counterparts, although they did not differ in global ratings of how striking, threatening and distressing they found the tasks. Moreover, remitted participants endorsed more threatening appraisals of the Telepath and VASP than non-clinical participants, and of the VASP than controls. Remitted participants also rated all three tasks as globally more threatening than the non-clinical group and controls.

Clinical outcome may not necessarily be driven by the presence of symptoms, with threatening appraisals of PEs representing a key factor. The remitted group's intermediate appraisal scores imply that the relationship between appraisal and clinical outcome is not straightforward, and potential mediating factors need to be determined.

A basic phenomenological question of much theoretical and empirical interest is whether the latent structure of depression is dimensional or categorical in nature. Prior taxometric studies of youth depression have yielded mixed findings. In a step towards resolving these contradictory findings, the current taxometric investigation is the first to utilize a recently developed objective index, the comparison curve fit index, to evaluate the latent structure of major depression in an epidemiological sample of children and adolescents.

Data were derived from Mental Health of Children and Young People in Great Britain surveys. Participants were administered a structured diagnostic interview to assess for current depression. Parents (n = 683) were interviewed for children aged 5–16 years, and child interviews (n = 605) were conducted for those aged 11–16 years.

MAMBAC (mean above minus below a cut), MAXEIG (maximum eigenvalue) and L-Mode (latent mode) analyses provided convergent support for a dimensional latent structure.

The current findings suggest that depression in youth is more accurately conceptualized as a continuous syndrome rather than a discrete diagnostic entity.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neuropsychiatric disorders in childhood. Besides inattention and hyperactivity, impulsivity is the third core symptom leading to diverse and serious problems. However, the neuronal mechanisms underlying impulsivity in ADHD are still not fully understood. This is all the more the case when patients with the ADHD combined subtype (ADHD-C) are considered who are characterized by both symptoms of inattention and hyperactivity/impulsivity.

Combining high-density electroencephalography (EEG) recordings with source localization analyses, we examined what information processing stages are dysfunctional in ADHD-C (n = 20) compared with controls (n = 18).

Patients with ADHD-C made more impulsive errors in a Go/No-go task than healthy controls. Neurophysiologically, different subprocesses from perceptual gating to attentional selection, resource allocation and response selection processes are altered in this patient group. Perceptual gating, stimulus-driven attention selection and resource allocation processes were more pronounced in ADHD-C, are related to activation differences in parieto-occipital networks and suggest attentional filtering deficits. However, only response selection processes, associated with medial prefrontal networks, predicted impulsive errors in ADHD-C.

Although the clinical picture of ADHD-C is complex and a multitude of processing steps are altered, only a subset of processes seems to directly modulate impulsive behaviour. The present findings improve the understanding of mechanisms underlying impulsivity in patients with ADHD-C and might help to refine treatment algorithms focusing on impulsivity.

Depression is a disabling disorder that significantly impacts on the interpersonal functioning of individuals. However, little is known about the neural substrates of such difficulties. In the last few years neuroeconomics, which combines imaging with multiplayer behavioural economic paradigms, has been used to study the neural substrates of normal and abnormal interpersonal interactions.

This study used functional magnetic resonance imaging to investigate neural activity in unmedicated depressed participants (n = 25) and matched healthy controls (n = 25). During scanning, participants played a behavioural economic game, the Prisoner's Dilemma. In this game, the participant and a co-player independently choose either to cooperate or not cooperate with each other.

Depressed participants reported higher levels of negative feelings (betrayal, guilt) during the game than did controls. Neural activation was compared between ‘imbalanced’ events [when one of the players cooperated and the other defected (‘CD’ and ‘DC’)] and ‘draw’ events [when both players either cooperated or defected (‘CC’ and ‘DD’)]. Participants preferentially activated the anterior insula and the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and regulation of emotions. Importantly, compared to controls depressed participants showed reduced activation in the left DLPFC, with the extent of signal reduction correlating with increased self-report feelings of guilt associated with DC outcomes.

Our findings suggest that depression is associated with reduced activation of the DLPFC during social events that involve unreciprocated cooperation. This abnormality may underlie anomalies in cognitive control and top-down regulation of emotions during challenging social exchanges.

Attention-deficit/hyperactivity disorder (ADHD) predisposes to drug abuse (DA) and twin studies suggest shared genetic effects. We here seek to determine, using adoption and adoption-like samples, the magnitude of the cross-generational transmission from DA in parents to ADHD in their children and clarify the degree to which this arises from genetic v. rearing effects.

We ascertained ADHD and DA from multiple Swedish registries. Statistical analysis was performed by Cox and path models.

Risk for ADHD was significantly and similarly increased in the offspring of biological mothers and fathers with DA who did v. did not rear their offspring. Risk for ADHD was not elevated in the offspring of adoptive or step-parents with DA.

Cross-generational transmission was observed from DA in parents to ADHD in their children. An analysis of adoptive and adoptive-like parent–offspring relationships suggested that this transmission results from genetic and not from rearing effects.

There has been considerable recent interest in possible causal linkages between exposure to bullying victimization and later psychotic symptomatology. Prior research in this area has had several limitations which make it difficult to ascertain causality, and to determine the extent to which these effects extend beyond adolescence.

Data were obtained from the Christchurch Health and Development Study, a 35-year study of a longitudinal birth cohort. This investigation used generalized estimating equation modelling to estimate the associations between bullying victimization (ages 13–16 years) and psychotic symptoms (ages 18–35 years), before and after controlling for possible confounding factors, including: gender; childhood socio-economic status; child intelligence quotient; exposure to sexual abuse in childhood; anxious/withdrawn behaviour and attention problems (ages 7–9 years); and adolescent psychotic symptoms and paranoid ideation (ages 15–16 years).

There was a significant (p < 0.0001) bivariate association between bullying victimization in adolescence and psychotic symptomatology in adulthood. Successive models controlling for covariation reduced this association to statistical non-significance. After controlling for covariates, those with the highest level of bullying victimization had rates of psychotic symptoms that were 1.21 (95% confidence interval 0.73–1.99) times higher than those who were not victimized.

The association between bullying victimization in adolescence and psychotic symptomatology in adulthood could be largely explained by childhood behavioural problems, and exposure to sexual abuse in childhood. The results suggest that bullying victimization was unlikely to have been a cause of adult psychotic symptoms, but bullying victimization remained a risk marker for these symptoms.

Studies have linked ethnic differences in depression rates with neighbourhood ethnic density although results have not been conclusive. We looked at this using a novel approach analysing whole population data covering just over one million GP patients in four London boroughs.

Using a dataset of GP records for all patients registered in Lambeth, Hackney, Tower Hamlets and Newham in 2013 we investigated new diagnoses of depression and antidepressant use for: Indian, Pakistani, Bangladeshi, black Caribbean and black African patients. Neighbourhood effects were assessed independently of GP practice using a cross-classified multilevel model.

Black and minority ethnic groups are up to four times less likely to be newly diagnosed with depression or prescribed antidepressants compared to white British patients. We found an inverse relationship between neighbourhood ethnic density and new depression diagnosis for some groups, where an increase of 10% own-ethnic density was associated with a statistically significant (p < 0.05) reduced odds of depression for Pakistani [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.70–0.93], Indian (OR 0.88, CI 0.81–0.95), African (OR 0.88, CI 0.78–0.99) and Bangladeshi (OR 0.94, CI 0.90–0.99) patients. Black Caribbean patients, however, showed the opposite effect (OR 1.26, CI 1.09–1.46). The results for antidepressant use were very similar although the corresponding effect for black Caribbeans was no longer statistically significant (p = 0.07).

New depression diagnosis and antidepressant use was shown to be less likely in areas of higher own-ethnic density for some, but not all, ethnic groups.

Psychiatric disorders commonly emerge during the first year following traumatic brain injury (TBI). However, it is not clear whether these disorders soon remit or persist for long periods post-injury. This study aimed to examine, prospectively: (1) the frequency, (2) patterns of co-morbidity, (3) trajectory, and (4) risk factors for psychiatric disorders during the first 5 years following TBI.

Participants were 161 individuals (78.3% male) with moderate (31.2%) or severe (68.8%) TBI. Psychiatric disorders were diagnosed using the Structured Clinical Interview for DSM-IV, administered soon after injury and 3, 6 and 12 months, and 2, 3, 4 and 5 years post-injury. Disorder frequencies and generalized estimating equations were used to identify temporal relationships and risk factors.

In the first 5 years post-injury, 75.2% received a psychiatric diagnosis, commonly emerging within the first year (77.7%). Anxiety, mood and substance-use disorders were the most common diagnostic classes, often presenting co-morbidly. Many (56.5%) experienced a novel diagnostic class not present prior to injury. Disorder frequency ranged between 61.8 and 35.6% over time, decreasing by 27% [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.65–0.83] with each year post-injury. Anxiety disorders declined significantly over time (OR 0.73, 95% CI 0.63–0.84), whilst mood and substance-use disorder rates remained stable. The strongest predictors of post-injury disorder were pre-injury disorder (OR 2.44, 95% CI 1.41–4.25) and accident-related limb injury (OR 1.78, 95% CI 1.03–3.07).

Findings suggest the first year post-injury is a critical period for the emergence of psychiatric disorders. Disorder frequency declines thereafter, with anxiety disorders showing greater resolution than mood and substance-use disorders.