Draft DSM-5 criteria for a mixed major depressive episode have been proposed, but their predictive validity has not yet been established. We hypothesized that such symptoms would be associated with poorer antidepressant treatment outcomes.

We examined outcomes among individuals with major depressive disorder participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, an effectiveness study conducted at primary and specialty care centers in the USA. Mixed features were derived from the six self-report items of the mania subscale of the Psychiatric Diagnosis Screening Questionnaire. Primary analyses examined the association between the presence of at least two of these in the 6 months before study entry, and remission across up to four sequential treatment trials, as well as adverse outcomes.

Of the 2397 subjects with a major depressive episode of at least 6 months' duration, 449 (18.7%) reported at least two mixed symptoms. The presence of such symptoms was associated with a greater likelihood of remission across up to four sequential treatments, which persisted after adjustment for potential confounding clinical and demographic variables (adjusted hazard ratio 1.16, 95% confidence interval 1.03–1.28). Two individual items, expansive mood and cheerfulness, were strongly associated with a greater likelihood of remission.

Proposed DSM-5 mixed state features were associated with a greater rather than a lesser likelihood of remission. While unexpected, this result suggests the potential utility of further investigation of depressive mixed states in major depression.

Primary health care provides treatment for most patients with depression. Despite their importance for organizing services, long-term course of depression and risk factors for poor outcome in primary care are not well known.

In the Vantaa Primary Care Depression Study, a stratified random sample of 1119 patients representing primary care patients in a Finnish city was screened for depression with the Primary Care Evaluation of Mental Disorders. SCID-I/P and SCID-II interviews were used to diagnose Axis I and II disorders. The 137 patients with DSM-IV depressive disorder were prospectively followed up at 3, 6, 18 and 60 months. Altogether, 82% of patients completed the 5-year follow-up, including 102 patients with a research diagnosis of major depressive disorder (MDD) at baseline. Duration of the index episode, recurrences, time spent in major depressive episodes (MDEs) and partial or full remission were examined with a life-chart.

Of the MDD patients, 70% reached full remission, in a median time of 20 months. One-third had at least one recurrence. The patients spent 34% of the follow-up time in MDEs, 24% in partial remission and 42% in full remission. Baseline severity of depression and substance use co-morbidity predicted time spent in MDEs.

This prospective, naturalistic, long-term study of a representative cohort of primary care patients with depression indicated slow or incomplete recovery and a commonly recurrent course, which need to be taken into account when developing primary care services. Severity of depressive symptoms and substance use co-morbidity should be systematically evaluated in planning treatment.

The prevention of depression is a key public health policy priority. PredictD is the first risk algorithm for the prediction of the onset of major depression. Our aim in this study was to model the cost-effectiveness of PredictD in depression prevention in general practice (GP).

A decision analytical model was developed to determine the cost-effectiveness of two approaches, each of which was compared to treatment as usual (TAU) over 12 months: (1) the PredictD risk algorithm plus a low-intensity depression prevention programme; and (2) a universal prevention programme in which there was no initial identification of those at risk. The model simulates the incidence of depression and disease progression over 12 months and calculates the net monetary benefit (NMB) from the National Health Service (NHS) perspective.

Providing patients with PredictD and a depression prevention programme prevented 15 (17%) cases of depression in a cohort of 1000 patients over 12 months and had the highest probability of being the optimal choice at a willingness to pay (WTP) of £20 000 for a quality-adjusted life year (QALY). Universal prevention was strongly dominated by PredictD plus a depression prevention programme in that universal prevention resulted in less QALYs than PredictD plus prevention for a greater cost.

Using PredictD to identify primary-care patients at high risk of depression and providing them with a low-intensity prevention programme is potentially cost-effective at a WTP of £20 000 per QALY.

The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome?

Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples.

The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety.

MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.

Endothelial dysfunction (ED), low-grade inflammation (LGI) and oxidative stress (OxS) may be involved in the pathobiology of depression. Previous studies on the association of these processes in depression have yielded contradictory results. We therefore investigated comprehensively, in a population-based cohort study, the association between ED, LGI and OxS on the one hand and depressive symptoms on the other.

We used data from the Hoorn Study and determined biomarkers of ED [flow-mediated dilatation (FMD), von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble thrombomodulin and soluble endothelial selectin], LGI [C-reactive protein, tumour necrosis factor-α, interleukin 6, interleukin 8, serum amyloid A, myeloperoxidase (MPO) and sICAM-1] and OxS (oxidized low density lipoprotein and MPO). Depressive symptoms were quantified by the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire (n = 493; age 68 years; 49.9% female). Regression analyses were performed with the use of biomarker Z scores. Adjustments were made for age, sex and glucose metabolism status (cohort stratification variables) and prior cardiovascular disease, hypertension, waist-to-hip ratio, cholesterol levels, education level, physical activity, dietary habits, and the use of antihypertensive and/or lipid-lowering medication and/or metformin (potential confounders).

After adjustment for age, sex and glucose metabolism status, one standard deviation increase in the ED Z score was associated with a 1.9 [95% confidence interval (CI) 0.7–3.1] higher CES-D score. Additional adjustments did not materially change this result. LGI and OxS were not associated with the CES-D score.

ED, as quantified by an array of circulating biomarkers and FMD, was independently associated with depressive symptoms. This study supports the hypothesis that ED plays an important role in the pathobiology of depression.

Most knowledge regarding the effects of antidepressant drugs is at the receptor level, distal from the nervous system effects that mediate their clinical efficacy. Using functional magnetic resonance imaging (fMRI), this study investigated the effects of escitalopram, a selective serotonin reuptake inhibitor (SSRI), on resting-state brain function in patients with major depressive disorder (MDD).

Fourteen first-episode drug-naive MDD patients completed two fMRI scans before and after 8 weeks of escitalopram therapy. Scans were also acquired in 14 matched healthy subjects. Data were analyzed using the regional homogeneity (ReHo) approach.

Compared to controls, MDD patients before treatment demonstrated decreased ReHo in the frontal (right superior frontal gyrus), temporal (left middle and right inferior temporal gyri), parietal (right precuneus) and occipital (left superior occipital gyrus and right cuneus) cortices, and increased ReHo in the left dorsal medial prefrontal gyrus and left anterior lobe of the cerebellum. Compared to the unmedicated state, ReHo in the patients after treatment was decreased in the left dorsal medial prefrontal gyrus, the right insula and the bilateral thalamus, and increased in the right superior frontal gyrus. Compared to controls, patients after treatment displayed a ReHo decrease in the right precuneus and a ReHo increase in the left anterior lobe of the cerebellum.

Successful treatment with escitalopram may be associated with modulation of resting-state brain activity in regions within the fronto-limbic circuit. This study provides new insight into the effects of antidepressants on functional brain systems in MDD.

Although significant changes in both gray and white matter have been noted in late-life depression (LLD), the pathophysiology of implicated white-matter tracts has not been fully described. In this study we examined the integrity of specific white-matter tracts in LLD versus healthy controls (HC).

Participants aged ⩾60 years were recruited from the community. The sample included 23 clinically diagnosed individuals with LLD and 23 HC. White-matter integrity metrics [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD)] were calculated in the bilateral cingulum and uncinate fasciculus. Depression severity was measured using the Center for Epidemiological Studies Depression Scale (CESD). Composite scores for learning and memory and executive function were created using standardized neuropsychological assessments.

White-matter integrity was lower in LLD versus HC in the bilateral cingulum and right uncinate fasciculus (p⩽0.05). In the whole sample, depression severity correlated with integrity in the bilateral cingulum and right uncinate fasciculus (p ⩽0.05). In patients, depression severity correlated with the integrity of the left uncinate fasciculus (p = 0.03); this tract also correlated with executive function (p = 0.02). Among HC, tract integrity did not correlate with depression scores; however, learning and memory correlated with integrity of the bilateral uncinate fasciculus and bilateral cingulum; executive function correlated with the right uncinate and left cingulum (p ⩽0.05).

White-matter tract integrity was lower in LLD than in HC and was associated with depression severity across all participants. Tract integrity was associated with cognition in both groups but more robustly among HC.

Depression is commonly co-morbid with obsessive–compulsive disorder (OCD). However, it is unknown whether depression is a functional consequence of OCD or whether these disorders share a common genetic aetiology. This longitudinal twin study compared these two hypotheses.

Data were drawn from a longitudinal sample of adolescent twins and siblings (n = 2651; Genesis 12–19 study) and from a cross-sectional sample of adult twins (n = 4920). The longitudinal phenotypic associations between OCD symptoms (OCS) and depressive symptoms were examined using a cross-lag model. Multivariate twin analyses were performed to explore the genetic and environmental contributions to the cross-sectional and longitudinal relationship between OCS and depressive symptoms.

In the longitudinal phenotypic analyses, OCS at time 1 (wave 2 of the Genesis 12–19 study) predicted depressive symptoms at time 2 (wave 3 of the Genesis 12–19 study) to a similar extent to which depressive symptoms at time 1 predicted OCS at time 2. Cross-sectional twin analyses in both samples indicated that common genetic factors explained 52–65% of the phenotypic correlation between OCS and depressive symptoms. The proportion of the phenotypic correlation due to common non-shared environmental factors was considerably smaller (35%). In the adolescent sample, the longitudinal association between OCS at time 1 and subsequent depressive symptoms was accounted for by the genetic association between OCS and depressive symptoms at time 1. There was no significant environmental association between OCS and later depressive symptoms.

The present findings show that OCS and depressive symptoms co-occur primarily due to shared genetic factors and suggest that genetic, rather than environmental, effects account for the longitudinal relationship between OCS and depressive symptoms.

Co-morbid major depression occurs in approximately 10% of people suffering from a chronic medical condition such as cancer. Systematic integrated management that includes both identification and treatment has been advocated. However, we lack information on the cost-effectiveness of this combined approach, as published evaluations have focused solely on the systematic (collaborative care) treatment stage. We therefore aimed to use the best available evidence to estimate the cost-effectiveness of systematic integrated management (both identification and treatment) compared with usual practice, for patients attending specialist cancer clinics.

We conducted a cost-effectiveness analysis using a decision analytic model structured to reflect both the identification and treatment processes. Evidence was taken from reviews of relevant clinical trials and from observational studies, together with data from a large depression screening service. Sensitivity and scenario analyses were undertaken to determine the effects of variations in depression incidence rates, time horizons and patient characteristics.

Systematic integrated depression management generated more costs than usual practice, but also more quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) was £11 765 per QALY. This finding was robust to tests of uncertainty and variation in key model parameters.

Systematic integrated management of co-morbid major depression in cancer patients is likely to be cost-effective at widely accepted threshold values and may be a better way of generating QALYs for cancer patients than some existing medical and surgical treatments. It could usefully be applied to other chronic medical conditions.

Cognitive behavioural therapy (CBT) is a successful treatment of obsessive compulsive disorder (OCD). It is known to induce changes in cerebral metabolism; however, the dynamics of these changes and their relation to clinical change remain largely unknown, precluding the identification of individualized response biomarkers.

In order to study the dynamics of treatment response, we performed systematic clinical and functional magnetic resonance imaging (fMRI) evaluation of 35 OCD patients immediately before a 3-month course of CBT, halfway through and at its end, as well as 6 months after. To sensitize fMRI probing, we used an original exposure task using neutral, generic and personalized obsession-inducing images.

As expected, CBT produced a significant improvement in OCD. This improvement was continuous over the course of the therapy; therefore, outcome could be predicted by response at mid-therapy (r2 = 0.67, p < 0.001). Haemodynamic response to the task was located in the anterior cingulate and orbitofrontal cortices and was stronger during exposure to personalized obsession-inducing images. In addition, both the anxiety ratings and the haemodynamic response to the obsession-inducing images in the anterior cingulate and the left but not the right orbitofrontal clusters decreased with symptom improvement. Interestingly, haemodynamic activity continued to decrease after stabilization of clinical symptoms.

Using an innovative and highly sensitive exposure paradigm in fMRI, we showed that clinical and haemodynamic phenotypes have similar time courses during CBT. Our results, which suggest that the initial CBT sessions are crucial, prompt us to investigate the anatomo-functional modifications underlying the very first weeks of the therapy.

Aberrant functional connectivity within the default network is generally assumed to be involved in the pathophysiology of obsessive compulsive disorder (OCD); however, the genetic risk of default network connectivity in OCD remains largely unknown.

Here, we systematically investigated default network connectivity in 15 OCD patients, 15 paired unaffected siblings and 28 healthy controls. We sought to examine the profiles of default network connectivity in OCD patients and their siblings, exploring the correlation between abnormal default network connectivity and genetic risk for this population.

Compared with healthy controls, OCD patients exhibited reduced strength of default network functional connectivity with the posterior cingulate cortex (PCC), and increased functional connectivity in the right inferior frontal lobe, insula, superior parietal cortex and superior temporal cortex, while their unaffected first-degree siblings only showed reduced local connectivity in the PCC.

These findings suggest that the disruptions of default network functional connectivity might be associated with family history of OCD. The decreased default network connectivity in both OCD patients and their unaffected siblings may serve as a potential marker of OCD.

Few studies have been published on the association between mental disorders and violence based on general population studies. Here we focus on different types of violence, adjusting for violent victimization and taking account of the limitations of previous population studies.

Data were used from the first two waves of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2), a nationally representative face-to-face survey of the general population aged 18–64 years (n = 6646). Violence was differentiated into physical and psychological violence against intimate partner(s), children or any person(s) in general. DSM-IV diagnoses were assessed with the Composite International Diagnostic Interview Version 3.0 (CIDI 3.0).

Psychological violence occurs considerably more frequently than physical violence, but both showed almost identical associations with mental disorders. After adjustment for sociodemographic characteristics, most of the main categories of common mental disorders were associated with violence. The strongest associations were found for externalizing disorders (substance use, impulse-control, antisocial personality disorder). After additional adjustment for violent victimization, negative life events and social support, most diagnostic correlates lost their significance whereas substance use (in particular alcohol) disorders were still associated with most types of violence.

The increased risk of violent offending among people with common mental disorders, other than substance use disorders, can be attributed to factors other than their mental illness.

Twin studies of veterans and adults suggest that approximately 30–46% of the variance in post-traumatic stress disorder (PTSD) is attributable to genetic factors. The remaining variance is attributable to the non-shared environment, which, by definition, includes combat exposure. This study used a gene by measured environment twin design to determine whether the effects of genetic and environmental factors that contribute to the etiology of PTSD are dependent on the level of combat exposure.

The sample was drawn from the Vietnam Era Twin Registry (VETR) and included 620 male–male twin pairs who served in the US Military in South East Asia during the Vietnam War era. Analyses were based on data from a clinical diagnostic interview of lifetime PTSD symptoms and a self-report measure of combat exposure.

Biometric modeling revealed that the effects of genetic and non-shared environment factors on PTSD varied as a function of level of combat exposure such that the association between these factors and PTSD was stronger at higher levels of combat exposure.

Combat exposure may act as a catalyst that augments the impact of hereditary and environmental contributions to PTSD. Individuals with the greatest exposure to combat trauma were at increased risk for PTSD as a function of both genetic and environmental factors. Additional work is needed to determine the biological and environmental mechanisms driving these associations.

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.

Insomnia is a prevalent problem with a high burden of disease (e.g. reduced quality of life, reduced work capacity) and a high co-morbidity with other mental and somatic disorders. Cognitive behavioural therapy (CBT) is effective in the treatment of insomnia but is seldom offered. CBT delivered through the Internet might be a more accessible alternative. In this study we examined the effectiveness of a guided Internet-delivered CBT for adults with insomnia using a randomized controlled trial (RCT).

A total of 118 patients, recruited from the general population, were randomized to the 6-week guided Internet intervention (n = 59) or to a wait-list control group (n = 59). Patients filled out an online questionnaire and a 7-day sleep diary before (T0) and after (T1) the 6-week period. The intervention group received a follow-up questionnaire 3 months after baseline (T2).

Almost three-quarters (72.9%) of the patients completed the whole intervention. Intention-to-treat (ITT) analysis showed that the treatment had statistically significant medium to large effects (p < 0.05; Cohen's d between 0.40 and 1.06), and resulted more often in clinically relevant changes, on all sleep and secondary outcomes with the exception of sleep onset latency (SOL) and number of awakenings (NA). There was a non-significant difference in the reduction in sleep medication between the intervention (a decrease of 6.8%) and control (an increase of 1.8%) groups (p = 0.20). Data on longer-term effects were inconclusive.

This study adds to the growing body of literature that indicates that guided CBT for insomnia can be delivered through the Internet. Patients accept the format and their sleep improves.

Preterm birth confers risk for poor outcome, including mental health problems. Survival of extremely preterm (EP; <28 weeks' gestation) or extremely low birthweight (ELBW; <1000 g) infants increased in the 1990s but psychiatric outcomes in older adolescents born preterm since 1990 are not well documented. This study aimed to characterize mental health and personality traits in a prospective geographical cohort of adolescents born EP/ELBW in Victoria, Australia in 1991 and 1992.

At age 18 years, 215 EP/ELBW and 157 normal birthweight (>2499 g) control adolescents completed the Structured Clinical Interview for DSM-IV Disorders, Axis 1 Non-Patient version (SCID-I/NP), the Children's Interview for Psychiatric Syndromes (ChIPS) attention deficit hyperactivity disorder (ADHD) module, and questionnaires assessing recent depression and anxiety symptoms and personality traits.

ADHD prevalence was significantly elevated in EP/ELBW adolescents compared with controls [15% v. 7%; odds ratio (OR) 2.67, 95% confidence interval (CI) 1.08–6.58]. Aside from ADHD, however, EP/ELBW and control adolescents reported very similar outcomes, with other lifetime diagnoses identified in 23% of EP/ELBW and 21% of controls. These were predominantly mood and anxiety disorders (21% EP/ELBW, 20% controls). The groups did not differ in recent depression or anxiety symptoms assessed using questionnaires, and personality traits were also similar.

ADHD was more prevalent in EP/ELBW adolescents than controls, which is consistent with some, but not all, reports on preterm survivors born before the 1990s, and younger preterm children born in the 1990s. The high rates of anxiety and mood disorders were similar in both groups, and comparable with population-based estimates.

Pain is a common symptom of chronic fatigue syndrome (CFS). We investigated the effects of the treatments used in the PACE trial [cognitive behavioural therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy (APT) and specialist medical care (SMC)] on pain in CFS.

We compared pain outcomes including individual painful symptoms, taken from the CDC criteria for CFS and co-morbid fibromyalgia. We modelled outcomes adjusting for baseline variables with multiple linear regression.

Significantly less frequent muscle pain was reported by patients following treatment with CBT compared to SMC (mean difference = 0.38 unit change in frequency, p = 0.02), GET versus SMC (0.42, p = 0.01) and GET versus APT (0.37, p = 0.01). Significantly less joint pain was reported following CBT versus APT (0.35, p = 0.02) and GET versus APT (0.36, p = 0.02). Co-morbid fibromyalgia was less frequent following GET versus SMC (0.03, p = 0.03). The effect sizes of these differences varied between 0.25 and 0.31 for muscle pain and 0.24 and 0.26 for joint pain. Treatment effects on pain were independent of ‘change in fatigue’.

CBT and GET were more effective in reducing the frequency of both muscle and joint pain than APT and SMC. When compared to SMC, GET also reduced the frequency of co-morbid fibromyalgia; the size of this effect on pain was small.

Central nervous system (CNS) dysfunction is a prominent feature of the functional gastrointestinal (GI) disorder, irritable bowel syndrome (IBS). However, the neurobiological and cognitive consequences of key pathophysiological features of IBS, such as stress-induced changes in hypothalamic–pituitary–adrenal (HPA)-axis functioning, is unknown. Our aim was to determine whether IBS is associated with cognitive impairment, independently of psychiatric co-morbidity, and whether cognitive performance is related to HPA-axis function.

A cross-sectional sample of 39 patients with IBS, a disease control group of 18 patients with Crohn's disease (CD) in clinical remission and 40 healthy age- and IQ-matched control participants were assessed using the Paired Associates Learning (PAL), Intra-Extra Dimensional Set Shift (IED) and Spatial Working Memory (SWM) tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and a computerized Stroop test. HPA-axis function was determined by measuring the cortisol awakening response (CAR).

IBS patients exhibited a subtle visuospatial memory deficit at the PAL six- pattern stage (p = 0.03), which remained after psychiatric co-morbidity was controlled for (p = 0.04). Morning cortisol levels were lower in IBS (p = 0.04) and significantly associated with visuospatial memory performance within IBS only (p = 0.02).

For the first time, altered cognitive function on a hippocampal-mediated test of visuospatial memory, which was related to cortisol levels and independent of psychiatric co-morbidity, has been identified in IBS. Visuospatial memory impairment may be a common, but currently neglected, component of IBS. Further elucidation of the nature of this impairment may lead to a greater understanding of the underlying pathophysiology of IBS, and may provide novel therapeutic approaches.