Meta-analyses have shown that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) has antidepressant properties when compared with sham rTMS. However, its overall response and remission rates in major depression (MD) remain unclear. Thus, we have systematically and quantitatively assessed the efficacy of HF-rTMS for MD based on randomized, double-blind and sham-controlled trials (RCTs).

We searched the literature from 1995 through to July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses. We used a random-effects model, odds ratios (ORs) and the number needed to treat (NNT).

Data from 29 RCTs were included, totaling 1371 subjects with MD. Following approximately 13 sessions, 29.3% and 18.6% of subjects receiving HF-rTMS were classified as responders and remitters, respectively (compared with 10.4% and 5% of those receiving sham rTMS). The pooled OR was 3.3 (p < 0.0001) for both response and remission rates (with associated NNTs of 6 and 8, respectively). Furthermore, we found HF-rTMS to be equally effective as an augmentation strategy or as a monotherapy for MD, and when used in samples with primary unipolar MD or in mixed samples with unipolar and bipolar MD. Also, alternative stimulation parameters were not associated with differential efficacy estimates. Moreover, baseline depression severity and drop-out rates at study end were comparable between the HF-rTMS and sham rTMS groups. Finally, heterogeneity between the included RCTs was not statistically significant.

HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile.

Short-term antidepressant administration has been reported to decrease amygdala response to threat in healthy volunteers and depressed patients. Neuroticism (N) is a risk factor for depression but has also been associated with slow or incomplete remission with antidepressant drug treatment. Our aim was to investigate early selective serotonin reuptake inhibitor (SSRI) administration neural effects on implicit processing of fearful facial expressions in volunteers with high levels of N.

Highly neurotic subjects received 20 mg/day citalopram versus placebo for 7 days in a double-blind, between-groups design. On the last day haemoperfusion and functional magnetic resonance imaging (fMRI) data during a gender discrimination task with fearful and happy faces were acquired. A control group of non-neurotic volunteers was also tested.

High-N volunteers had reduced responses to threatening facial expressions across key neural circuits compared to low-N volunteers. SSRI treatment was found to elevate resting perfusion in the right amygdala, increase bilateral amygdalae activation to positive and negative facial expressions and increase activation to fearful versus happy facial expressions in occipital, parietal, temporal and prefrontal cortical areas.

These results suggest that 7 days of SSRI administration can increase neural markers of fear reactivity in subjects at the high end of the N dimension and may be related to early increases in anxiety and agitation seen early in treatment. Such processes may be involved in the later therapeutic effects through decreased avoidance and increased learning about social ‘threat’ cues.

Leptin is thought to act as an important mediator in stress reactions. To date, no study has examined the association between psychological stress and leptin levels in children. This study aimed to assess the association between emotional symptoms and peer problems and serum leptin levels in children aged 10 years of the two population-based GINI-plus and LISA-plus birth cohorts.

Cross-sectional data from 2827 children aged 10 years were assessed with regard to leptin concentrations in serum and behavioral problems using the parent-reported Strengths and Difficulties Questionnaire (SDQ). Linear regression modeling was applied to determine the likelihood of elevated leptin levels in children with emotional symptoms and peer problems, controlling for socio-economic status (SES), body mass index (BMI), fasting serum leptin levels, pubertal development and sex hormones.

We found that increases in emotional symptoms (exp βadj = 1.03, s.e. = 0.02, p < 0.04) and peer problems (exp βadj = 1.05, s.e. = 0.01, p = 0.0001) were significantly associated with higher serum leptin levels controlled for BMI and sociodemographic factors. Similar results were found when the fasting serum leptin sample was examined (exp βadj = 1.08, s.e. = 0.04, p = 0.0294). Gender-stratified analyses showed a significant relationship between serum leptin and peer problems in girls (exp βadj = 1.05, s.e. = 0.02, p = 0.03), and a borderline significant association in boys (exp βadj = 1.04, s.e. = 0.02, p = 0.05).

Children with peer problems have higher stress and eat more, acquire a higher body fat mass and thus, through increased leptin resistance, exhibit higher leptin levels.

Characteristics related to the areas where people live have been associated with suicide risk, although these might reflect aggregation into these communities of individuals with mental health or social problems. No studies have examined whether area characteristics during childhood are associated with subsequent suicide, or whether risk associated with individual characteristics varies according to childhood neighbourhood context.

We conducted a longitudinal study of 204 323 individuals born in Sweden in 1972 and 1977 with childhood data linked to suicide (n = 314; 0.15%) up to age 26–31 years. Multilevel modelling was used to examine: (i) whether school-, municipality- or county-level characteristics during childhood are associated with later suicide, independently of individual effects, and (ii) whether associations between individual characteristics and suicide vary according to school context (reflecting both peer group and neighbourhood effects).

Associations between suicide and most contextual measures, except for school-level gender composition, were explained by individual characteristics. There was some evidence of cross-level effects of individual- and school-level markers of ethnicity and deprivation on suicide risk, with qualitative interaction patterns. For example, having foreign-born parents increased the risk for individuals raised in areas where they were in a relative minority, but protected against suicide in areas where larger proportions of the population had foreign-born parents.

Characteristics that define individuals as being different from most people in their local environment as they grow up may increase suicide risk. If robustly replicated, these findings have potentially important implications for understanding the aetiology of suicide and informing social policy.

More effective prevention of suicide requires a comprehensive understanding of sociodemographic, psychiatric and somatic risk factors. Previous studies have been limited by incomplete ascertainment of these factors. We conducted the first study of this issue using sociodemographic and out-patient and in-patient health data for a national population.

We used data from a national cohort study of 7140589 Swedish adults followed for 8 years for suicide mortality (2001–2008). Sociodemographic factors were identified from national census data, and psychiatric and somatic disorders were identified from all out-patient and in-patient diagnoses nationwide.

There were 8721 (0.12%) deaths from suicide during 2001–2008. All psychiatric disorders were strong risk factors for suicide among both women and men. Depression was the strongest risk factor, with a greater than 15-fold risk among women or men and even higher risks (up to 32-fold) within the first 3 months of diagnosis. Chronic obstructive pulmonary disease (COPD), cancer, spine disorders, asthma and stroke were significant risk factors among both women and men (1.4–2.1-fold risks) whereas diabetes and ischemic heart disease were modest risk factors only among men (1.2–1.4-fold risks). Sociodemographic risk factors included male sex, unmarried status or non-employment; and low education or income among men.

All psychiatric disorders, COPD, cancer, spine disorders, asthma, stroke, diabetes, ischemic heart disease and specific sociodemographic factors were independent risk factors for suicide during 8 years of follow-up. Effective prevention of suicide requires a multifaceted approach in both psychiatric and primary care settings, targeting mental disorders (especially depression), specific somatic disorders and indicators of social support.

No previous study has prospectively investigated incidence and risk factors for suicide attempts among primary care patients with depression.

In the Vantaa Primary Care Depression Study, a stratified random sample of 1119 patients was screened for depression, and Structured Clinical Interviews for DSM-IV used to diagnose Axis I and II disorders. A total of 137 patients were diagnosed with a DSM-IV depressive disorder. Altogether, 82% of patients completed the 5-year follow-up. Information on timing of suicide attempts, plus major depressive episodes (MDEs) and partial or full remission, or periods of substance abuse were examined with life charts. Incidence of suicide attempts and their stable and time-varying risk factors (phases of depression/substance abuse) were investigated using Cox proportional hazard and Poisson regression models.

During the follow-up there were 22 discrete suicide attempts by 14/134 (10.4%) patients. The incidence rates were 0, 5.8 and 107 during full or partial remission or MDEs, or 22.2 and 142 per 1000 patient-years during no or active substance abuse, respectively. In Cox models, current MDE (hazard ratio 33.5, 95% confidence interval 3.6–309.7) was the only significant independent risk factor. Primary care doctors were rarely aware of the suicide attempts.

Of the primary care patients with depressive disorders, one-tenth attempted suicide in 5 years. However, risk of suicidal acts was almost exclusively confined to MDEs, with or without concurrent active substance abuse. Suicide prevention among primary care patients with depression should focus on active treatment of major depressive disorder and co-morbid substance use, and awareness of suicide risk.

There is an ongoing debate whether biological illness explanations improve tolerance towards persons with mental illness or not. Several theoretical models have been proposed to predict the relationship between causal beliefs and social acceptance. This study uses path models to compare different theoretical predictions regarding attitudes towards persons with schizophrenia, depression and alcohol dependence.

In a representative population survey in Germany (n = 3642), we elicited agreement with belief in biogenetic causes, current stress and childhood adversities as causes of either disorder as described in an unlabelled case vignette. We further elicited potentially mediating attitudes related to different theories about the consequences of biogenetic causal beliefs (attribution theory: onset responsibility, offset responsibility; genetic essentialism: differentness, dangerousness; genetic optimism: treatability) and social acceptance. For each vignette condition, we calculated a multiple mediator path model containing all variables.

Biogenetic beliefs were associated with lower social acceptance in schizophrenia and depression, and with higher acceptance in alcohol dependence. In schizophrenia and depression, perceived differentness and dangerousness mediated the largest indirect effects, the consequences of biogenetic causal explanations thus being in accordance with the predictions of genetic essentialism. Psychosocial causal beliefs had differential effects: belief in current stress as a cause was associated with higher acceptance in schizophrenia, while belief in childhood adversities resulted in lower acceptance of a person with depression.

Biological causal explanations seem beneficial in alcohol dependence, but harmful in schizophrenia and depression. The negative correlates of believing in childhood adversities as a cause of depression merit further exploration.

Epidemiological research is believed to underestimate the lifetime prevalence of mental illness due to recall failure and a lack of rapport between researchers and participants.

In this prospective study, we examined lifetime prevalence and co-morbidity rates of substance use disorders, antisocial personality disorder (ASPD) and major depressive disorder (MDD) in a representative, statewide Minnesota sample (n = 1252) assessed four times between the ages of 17 and 29 years with very low attrition.

Lifetime prevalence rates of all disorders more than doubled between the ages of 17 and 29 years in both men and women, and our prospective rates at the age of 29 years were consistently higher than rates from leading epidemiological surveys. Although there was some variation, the general trend was for lifetime co-morbidity to increase between the ages of 17 and 29 years, and this trend was significant for MDD–alcohol dependence, MDD–nicotine dependence, and ASPD–nicotine dependence.

Overall, our results show that emerging adulthood is a high-risk period for the development of mental illness, with increases in the lifetime prevalence and co-morbidity of mental disorders during this time. More than a quarter of individuals had met criteria for MDD and over a fifth had experienced alcohol dependence by the age of 29 years, indicating that mental illness is more common than is estimated in cross-sectional mental health surveys. These findings have important implications for the measurement of economic burden, resource allocation toward mental health services and research, advocacy organizations for the mentally ill, and etiological theories of mental disorders.

Subthreshold psychotic and bipolar experiences are common in major depressive disorder (MDD). However, it is unknown if effectiveness of psychotherapy is altered in depressed patients who display such features compared with those without. The current paper aimed to investigate the impact of the co-presence of subclinical psychotic experiences and subclinical bipolar symptoms on the effectiveness of psychological treatment, alone or in combination with pharmacotherapy.

In a naturalistic study, patients with MDD (n = 116) received psychological treatment (cognitive behavioural therapy or interpersonal psychotherapy) alone or in combination with pharmacotherapy. Depression and functioning were assessed six times over 2 years. Lifetime psychotic experiences and bipolar symptoms were assessed at the second time point.

Subclinical psychotic experiences predicted more depression over time (β = 0.20, p < 0.002), non-remission [odds ratio (OR) 7.51, p < 0.016] and relapse (OR 3.85, p < 0.034). Subthreshold bipolar symptoms predicted relapse (OR 1.16, p < 0.037).

In general, subclinical psychotic experiences have a negative impact on the course and outcome of psychotherapy in MDD. Effects of subclinical bipolar experiences were less prominent.

Cross-sectional studies show that neuroticism is strongly associated with affective disorders. We investigated whether neuroticism and affective disorders mutually reinforce each other over time, setting off a potential downward spiral.

A total of 2981 adults aged 18–65 years, consisting of healthy controls, persons with a prior history of affective disorders and persons with a current affective disorder were assessed at baseline (T1) and 2 (T2) and 4 years (T3) later. At each wave, affective disorders according to DSM-IV criteria were assessed with the Composite Interview Diagnostic Instrument (CIDI) version 2.1 and neuroticism with the Neuroticism–Extraversion–Openness Five Factor Inventory (NEO-FFI).

Using structural equation models the association of distress disorders (i.e. dysthymia, depressive disorder, generalized anxiety disorder) and fear disorders (i.e. social anxiety disorder, panic disorder, agoraphobia without panic) with neuroticism could be attributed to three components: (a) a strong correlation of the stable components of distress and fear disorders with the stable trait component of neuroticism; (b) a modest contemporaneous association of change in distress and fear disorders with change in neuroticism; (c) a small to modest delayed effect of change in distress and fear disorders on change in neuroticism. Moreover, neuroticism scores in participants newly affected at T2 but remitted at T3 did not differ from their pre-morbid scores at T1.

Our results do not support a positive feedback cycle of changes in psychopathology and changes in neuroticism. In the context of a relative stability of neuroticism and affective disorders, only modest contemporaneous and small to modest delayed effects of psychopathology on neuroticism were observed.

Stressful life events have long been suspected to contribute to multiple sclerosis (MS) disease activity. The few studies examining the relationship between stressful events and neuroimaging markers have been small and inconsistent. This study examined whether different types of stressful events and perceived stress could predict the development of brain lesions.

This was a secondary analysis of 121 patients with MS followed for 48 weeks during a randomized controlled trial comparing stress management therapy for MS (SMT-MS) to a waitlist control (WLC). Patients underwent magnetic resonance imaging (MRI) scans every 8 weeks. Every month, patients completed an interview measure assessing stressful life events and self-report measures of perceived stress, anxiety and depressive symptoms, which were used to predict the presence of gadolinium-enhancing (Gd+) and T2 lesions on MRI scans 29–62 days later. Participants classified stressful events as positive or negative. Negative events were considered ‘major’ if they involved physical threat or threat to the patient's family structure, and ‘moderate’ otherwise.

Positive stressful events predicted decreased risk for subsequent Gd+ lesions in the control group [odds ratio (OR) 0.53 for each additional positive stressful event, 95% confidence interval (CI) 0.30–0.91] and less risk for new or enlarging T2 lesions regardless of group assignment (OR 0.74, 95% CI 0.55–0.99). Across groups, major negative stressful events predicted Gd+ lesions (OR 1.77, 95% CI 1.18–2.64) and new or enlarging T2 lesions (OR 1.57, 95% CI 1.11–2.23) whereas moderate negative stressful events, perceived stress, anxiety and depressive symptoms did not.

Major negative stressful events predict increased risk for Gd+ and T2 lesions whereas positive stressful events predict decreased risk.

Despite its high prevalence and associated levels of impairment, the latent structure of social anxiety disorder (SAD) is not well understood, with published studies reporting inconsistent results. Furthermore, it is unknown whether the latent structure of social fears in individuals with and without SAD is the same.

Exploratory factor analysis (EFA) and confirmatory factor analysis followed by multiple indicators multiple causes (MIMIC) analysis were conducted on 13 commonly feared social situations assessed in a nationally representative sample including individuals with SAD and those with social fears but who did not meet DSM-IV criteria for SAD.

An EFA conducted in the full sample, including individuals with no social fears (88% of the sample), yielded only one factor. When the sample was restricted to those with at least one social fear, the EFA yielded three factors, in both the subsample with at least one social fear but no SAD and the subsample with SAD. The three factors represented feared situations related to public performance, close scrutiny and social interaction. The MIMIC analyses further indicated that the three-factor structure was able to explain differences in prevalence of social fears across a broad range of sociodemographic covariates.

Among individuals with at least one social fear and those with DSM-IV SAD the latent structure of social fears appears to be best described by three factors, although this may partially depend on how the sample is specified. These results may help reconcile the findings of different numbers of factors identified in previous studies.

Using three independent methods, prior studies in Swedish sibling pairs indicate that environmental factors contribute substantially to familial aggregation for drug abuse (DA). Could we replicate these results in cousin pairs?

Using multiple Swedish public databases (1964–2011), we defined DA using medical, legal or pharmacy registry records and examined concordance in full cousin pairs as a function of age differences, younger–older relationships and geographical proximity while growing up.

Replicating prior results in siblings, cousin pairs were significantly more similar in their history of DA if they were (i) closer versus more distant in age and (ii) grew up in high versus low geographical proximity to one another. Furthermore, controlling for background factors, having an older cousin with DA conveys a greater risk for DA than having a younger drug-abusing cousin. The greater transmission of DA from older to younger versus younger to older cousin was more prominent in pairs who grew up close to one another. In age difference and geographical proximity analyses, effects were consistently strongest in male–male cousin pairs. In analyses of older → younger versus younger → older transmission, effects were stronger in male–male and male–female than in female–female or female–male relative pairs.

In accord with prior results in siblings, environmental factors contribute substantially to the familial aggregation of DA in cousins and these effects are, in general, stronger in males than in females.

Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients.

The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls.

Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation.

The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

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.

There is evidence that a range of socio-environmental exposures is associated with an increased risk of psychosis. However, despite the fact that such factors probably combine in complex ways to increase risk, the majority of studies have tended to consider each exposure separately. In light of this, we sought to extend previous analyses of data from the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study on childhood and adult markers of disadvantage to examine how they combine to increase risk of psychosis, testing both mediation (path) models and synergistic effects.

All patients with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK (n = 390) and a series of community controls (n = 391) were included in the AESOP study. Data relating to clinical and social variables, including parental separation and loss, education and adult disadvantage, were collected from cases and controls.

There was evidence that the effect of separation from, but not death of, a parent in childhood on risk of psychosis was partially mediated through subsequent poor educational attainment (no qualifications), adult social disadvantage and, to a lesser degree, low self-esteem. In addition, there was strong evidence that separation from, but not death of, a parent combined synergistically with subsequent disadvantage to increase risk. These effects held for all ethnic groups in the sample.

Exposure to childhood and adult disadvantage may combine in complex ways to push some individuals along a predominantly sociodevelopmental pathway to psychosis.

Ethnic minority position is associated with increased risk for psychotic outcomes, which may be mediated by experiences of social exclusion, defeat and discrimination. Sexual minorities are subject to similar stressors. The aim of this study is to examine whether sexual minorities are at increased risk for psychotic symptoms and to explore mediating pathways.

A cross-sectional survey was performed assessing cumulative incidence of psychotic symptoms with the Composite International Diagnostic Interview in two separate random general population samples (NEMESIS-1 and NEMESIS-2). Participants were sexually active and aged 18–64 years (n = 5927, n = 5308). Being lesbian, gay or bisexual (LGB) was defined as having sexual relations with at least one same-sex partner during the past year. Lifetime experience of any psychotic symptom was analysed using logistic regression, adjusted for gender, educational level, urbanicity, foreign-born parents, living without a partner, cannabis use and other drug use.

The rate of any psychotic symptom was elevated in the LGB population as compared with the heterosexual population both in NEMESIS-1 [odds ratio (OR) 2.56, 95% confidence interval (CI) 1.71–3.84] and NEMESIS-2 (OR 2.30, 95% CI 1.42–3.71). Childhood trauma, bullying and experience of discrimination partly mediated the association.

The finding that LGB orientation is associated with psychotic symptoms adds to the growing body of literature linking minority status with psychosis and other mental health problems, and suggests that exposure to minority stress represents an important mechanism.

Deficits in sustained attention and reaction time are core features of attention deficit hyperactivity disorder (ADHD). However, little is known about attention performance in unaffected siblings. Hence, we examined sustained attention and reaction time in youths with ADHD, unaffected siblings and controls to test whether impaired performance in attention tasks can be a potential endophenotype of ADHD.

We recruited 438 probands with clinical diagnosis of ADHD according to DSM-IV criteria, 180 unaffected siblings, and 173 healthy controls without lifetime ADHD. They were assessed using psychiatric interviews, Conners’ Continuous Performance Test, and the tasks involving attention performance of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Rapid Visual Information Processing (RVP), Reaction Time (RTI) and Match to Sample Visual Search (MTS). Multi-level models were used for data analysis.

Compared with the controls, probands with ADHD and unaffected siblings had significantly higher total misses, lower probability of hits in the RVP task and probands with ADHD performed worse in the RTI and MTS tasks after controlling for sex, age, co-morbidity, parental educational levels and IQ. The duration of methylphenidate use and IQ but not psychiatric co-morbidity or current use of methylphenidate were associated with deficits in sustained attention in probands with ADHD.

Our findings suggest that attention performance assessed by the RVP task, but not the RTI or MTS tasks, of the CANTAB may be a useful cognitive endophenotype for ADHD genetic studies.