Previous studies suggest that the relationship between genetic risk and depression may be moderated by stressful life events (SLEs). The goal of this study was to assess whether SLEs moderate the association between polygenic risk of major depressive disorder (MDD) and depressive symptoms in older adults.

We used logistic and negative binomial regressions to assess the associations between polygenic risk, SLEs and depressive symptoms in a sample of 8761 participants from the Health and Retirement Study. Polygenic scores were derived from the Psychiatric Genomics Consortium genome-wide association study of MDD. SLEs were operationalized as a dichotomous variable indicating whether participants had experienced at least one stressful event during the previous 2 years. Depressive symptoms were measured using an eight-item Center for Epidemiologic Studies Depression Scale subscale and operationalized as both a dichotomous and a count variable.

The odds of reporting four or more depressive symptoms were over twice as high among individuals who experienced at least one SLE (odds ratio 2.19, 95% confidence interval 1.86–2.58). Polygenic scores were significantly associated with depressive symptoms (β = 0.21, p ⩽ 0.0001), although the variance explained was modest (pseudo r2 = 0.0095). None of the interaction terms for polygenic scores and SLEs was statistically significant.

Polygenic risk and SLEs are robust, independent predictors of depressive symptoms in older adults. Consistent with an additive model, we found no evidence that SLEs moderated the association between common variant polygenic risk and depressive symptoms.

Impaired emotion regulation may underlie exaggerated emotional reactivity in patients with obsessive compulsive disorder (OCD), yet instructed emotion regulation has never been studied in the disorder.

This study aimed to assess the neural correlates of emotion processing and regulation in 43 medication-free OCD patients and 38 matched healthy controls, and additionally test if these can be modulated by stimulatory (patients) and inhibitory (controls) repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (dlPFC). Participants performed an emotion regulation task during functional magnetic resonance imaging before and after a single session of randomly assigned real or sham rTMS. Effect of group and rTMS were assessed on self-reported distress ratings and brain activity in frontal-limbic regions of interest.

Patients had higher distress ratings than controls during emotion provocation, but similar rates of distress reduction after voluntary emotion regulation. OCD patients compared with controls showed altered amygdala responsiveness during symptom provocation and diminished left dlPFC activity and frontal-amygdala connectivity during emotion regulation. Real v. sham dlPFC stimulation differentially modulated frontal-amygdala connectivity during emotion regulation in OCD patients.

We propose that the increased emotional reactivity in OCD may be due to a deficit in emotion regulation caused by a failure of cognitive control exerted by the dorsal frontal cortex. Modulatory rTMS over the left dlPFC may influence automatic emotion regulation capabilities by influencing frontal-limbic connectivity.

It has been suggested that the structure of psychopathology is best described as a complex network of components that interact in dynamic ways. The goal of the present paper was to examine the concept of psychopathology from a network perspective, combining complementary top-down and bottom-up approaches using momentary assessment techniques.

A pooled Experience Sampling Method (ESM) dataset of three groups (individuals with a diagnosis of depression, psychotic disorder or no diagnosis) was used (pooled N = 599). The top-down approach explored the network structure of mental states across different diagnostic categories. For this purpose, networks of five momentary mental states (‘cheerful’, ‘content’, ‘down’, ‘insecure’ and ‘suspicious’) were compared between the three groups. The complementary bottom-up approach used principal component analysis to explore whether empirically derived network structures yield meaningful higher order clusters.

Individuals with a clinical diagnosis had more strongly connected moment-to-moment network structures, especially the depressed group. This group also showed more interconnections specifically between positive and negative mental states than the psychotic group. In the bottom-up approach, all possible connections between mental states were clustered into seven main components that together captured the main characteristics of the network dynamics.

Our combination of (i) comparing network structure of mental states across three diagnostically different groups and (ii) searching for trans-diagnostic network components across all pooled individuals showed that these two approaches yield different, complementary perspectives in the field of psychopathology. The network paradigm therefore may be useful to map transdiagnostic processes.

A growing body of research has investigated associations between insecure attachment styles and psychosis. However, despite good theoretical and epidemiological reasons for hypothesising that insecure attachment may be specifically implicated in paranoid delusions, few studies have considered the role it plays in specific symptoms.

We examined the relationship between attachment style, paranoid beliefs and hallucinatory experiences in a sample of 176 people with a diagnosis of schizophrenia spectrum disorders and 113 healthy controls. We also investigated the possible role of negative self-esteem in mediating this association.

Insecure attachment predicted paranoia but not hallucinations after co-morbidity between the symptoms was controlled for. Negative self-esteem partially mediated the association between attachment anxiety and clinical paranoia, and fully mediated the relationship between attachment avoidance and clinical paranoia.

It may be fruitful to explore attachment representations in psychological treatments for paranoid patients. If future research confirms the importance of disrupted attachment as a risk factor for persecutory delusions, consideration might be given to how to protect vulnerable young people, for example those raised in children's homes.

Abnormalities in the anterior inter-hemispheric connectivity have previously been implicated in major depressive disorder. Disruptions in fractional anisotropy in the callosum and fornix have been reported in schizophrenia and major depressive disorder. Oligodendrocyte density and overall size of the callosum and fornix show no alteration in either illness, suggesting that gross morphology is unchanged but more subtle organizational disruption may exist within these brain regions in mood and affective disorders.

Using high-resolution oil-immersion microscopy we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath, and using standard high-resolution light microscopy we measured the density of myelinated axons. These measurements were made in the genu of the corpus callosum and the medial body of the fornix at its most dorsal point. Measures were taken in the sagittal plane in the callosal genu and in the coronal plane at the most dorsal part of the fornix body.

Cases of major depressive disorder had significantly greater mean myelin cross-sectional area (p = 0.017) and myelin thickness (p = 0.004) per axon in the genu than in control or schizophrenia groups. There was no significant change in the density of myelinated axons, and no changes observed in the fornix.

The results suggest a clear increase of myelin in the axons of the callosal genu in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin.

Several studies have reported smaller hippocampal volume (HcV) in depression patients; however, the temporality of the association remains unknown. One proposed hypothesis is that depression may cause HcV loss. This study evaluates whether previous depression and recent depressive symptoms are associated with HcV and HcV loss.

We used a prospective cohort of older adults (n = 1328; age = 65–80 years) with two cerebral magnetic resonance imaging examinations at baseline and 4-year follow-up. Using multivariable linear regression models, we estimated, in stratified analyses by gender, the association between indicators of history of depression and its severity (age at onset, recurrence, hospitalization for depression), proximal depressive symptoms [Center for Epidemiologic Studies-Depression (CES-D) scale], baseline antidepressant use, and the outcomes: baseline HcV and annual percentage change in HcV.

At baseline, women with more depressive symptoms had smaller HcV [−0.05 cm3, 95% confidence interval (CI) −0.1 to −0.01 cm3 per 10-unit increase in CES-D scores]. History of depression was associated with a 0.2% faster annual HcV loss in women (95% CI 0.01–0.36%). More baseline depressive symptoms and worsening of these symptoms were also associated with accelerated HcV loss in women. No associations were observed in men. Treatment for depression was associated with slower HcV loss in women and men.

While only concomitant depressive symptoms were associated with HcV, both previous depression and more proximal depressive symptoms were associated with faster HcV loss in women.

The salience of a visual stimulus is often reduced by nearby stimuli, an effect known as surround suppression of perceived contrast, which may help in locating the borders of an object. Weaker surround suppression has been observed in schizophrenia but it is unclear whether this abnormality is present in other mental disorders with similar symptomatology, or is evident in people with genetic liability for schizophrenia.

By examining surround suppression among subjects with schizophrenia or bipolar affective disorder, their unaffected biological relatives and healthy controls we sought to determine whether diminished surround suppression was specific to schizophrenia, and if subjects with a genetic risk for either disorder would show similar deficits. Measuring perceived contrast in different surround conditions also allowed us to investigate how this suppression depends on the similarity of target and surrounding stimuli.

Surround suppression was weaker among schizophrenia patients regardless of surround configuration. Subjects with bipolar affective disorder showed an intermediate deficit, with stronger suppression than in schizophrenia but weaker than control subjects. Surround suppression was normal in relatives of both patient groups. Findings support a deficit in broadly tuned (rather than sharply orientation- or direction-selective) suppression mechanisms.

Weak broadly tuned suppression during visual perception is evident in schizophrenia and bipolar affective disorder, consistent with impaired gain control related to the clinical expression of these conditions.

Stress and vulnerability likely interact to play a major role in psychosis. While much has been written about the neural diathesis-stress model in psychosis and its clinical risk states, little is known about HPA axis biomarkers in non-help-seeking individuals at familial high risk (FHR). We sought to prospectively measure pituitary volume (PV) in adolescents and young adults at FHR for schizophrenia and to follow their emerging sub-clinical psychotic symptoms and clinical trajectories.

Forty healthy controls and 38 relatives of patients with schizophrenia or schizoaffective disorder were identified in Pittsburgh, USA. PV was derived from baseline 1.5 T magnetic resonance imaging. Chapman's schizotypy scales were acquired at baseline, and structured clinical interviews for DSM-IV-TR Axis I diagnoses were attempted annually for up to 3 years.

Seven individuals converted to psychosis. PV did not differ between FHR and control groups overall. Within the FHR group, PV was positively correlated with Chapman's positive schizotypy (Magical Ideation and Perceptual Aberration) scores, and there was a significant group × PV interaction with schizotypy. PV was significantly higher in FHR subjects carrying any baseline Axis I diagnosis (p = 0.004), and higher still in individuals who went on to convert to psychosis (p = 0.0007).

Increased PV is a correlate of early positive schizotypy, and may predict trait vulnerability to subsequent psychosis in FHR relatives. These preliminary findings support a model of stress-vulnerability and HPA axis activation in the early phases of psychosis.

There is growing interest in the role of childhood adversities, including parental death and separation, in the etiology of psychotic disorders. However, few studies have used prospectively collected data to specifically investigate parental separation across development, or assessed the importance of duration of separation, and family characteristics.

We measured three types of separation not due to death: maternal, paternal, and from both parents, across the ages of 1–15 years among a cohort of 985 058 individuals born in Denmark 1971–1991 and followed to 2011. Associations with narrowly and broadly defined schizophrenia and bipolar disorder in the psychiatric register were assessed in terms of separation occurrence, age of separation, and number of years separated. Interactions with parental history of mental disorder were assessed.

Each type of separation was associated with all three outcomes, adjusting for age, sex, birth period, calendar year, family history of mental disorder, urbanicity at birth and parental age. Number of years of paternal separation was positively associated with both schizophrenia and bipolar disorder. Associations between separation from both parents and schizophrenia were stronger when separation occurred at later ages, while those with bipolar disorder remained stable across development. The first occurrence of paternal separation appeared to increase risk more when it occurred earlier in childhood. Associations differed according to parental history of mental disorder, although in no situation was separation protective.

Effects of parental separation may differ by type, developmental timing and family characteristics. These findings highlight the importance of considering such factors in studies of childhood adversity.

Cognitive deficits are well documented in ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, with such deficits being taken as evidence of dysregulation of the serotonin (5-hydroxytryptamine; 5-HT) system. More recently neuroimaging has been used to corroborate these deficits. The present study aimed to assess multitasking performance in ecstasy polydrug users, polydrug users and drug-naive individuals. It was predicted that ecstasy polydrug users would perform worse than non-users on the behavioural measure and this would be supported by differences in cortical blood oxygenation.

In the study, 20 ecstasy-polydrug users, 17 polydrug users and 19 drug-naive individuals took part. On day 1, drug use history was taken and questionnaire measures were completed. On day 2, participants completed a 20-min multitasking stressor while brain blood oxygenation was measured using functional near infrared spectroscopy (fNIRS).

There were no significant differences between the three groups on the subscales of the multitasking stressor. In addition, there were no significant differences on self-report measures of perceived workload (NASA Task Load Index). In terms of mood, ecstasy users were significantly less calm and less relaxed compared with drug-naive controls. There were also significant differences at three voxels on the fNIRS, indicating decreased blood oxygenation in ecstasy users compared with drug-naive controls at voxel 2 (left dorsolateral prefrontal cortex), voxel 14 and voxel 16 (right dorsolateral prefrontal cortex), and compared with polydrug controls at V14.

The results of the present study provide support for changes in brain activation during performance of demanding tasks in ecstasy polydrug users, which could be related to cerebral vasoconstriction.

Evidence suggests that in affective, non-psychotic disorders: (i) environmental exposures increase risk of subthreshold psychotic experiences (PEs) and strengthen connectivity between domains of affective and subthreshold psychotic psychopathology; and (ii) PEs are a marker of illness severity.

In 3021 adolescents from the Early Developmental Stages of Psychopathology cohort, we tested whether the association between PEs and presence of DSM-IV mood disorder (MD)/obsessive–compulsive disorder (OCD) would be moderated by risk factors for psychosis (cannabis use, childhood trauma and urbanicity), using the interaction contrast ratio (ICR) method. Furthermore, we analysed whether the interaction between environment and PEs was mediated by non-psychotic psychopathology.

The association between PEs and MD/OCD was moderated by urbanicity (ICR = 2.46, p = 0.005), cannabis use (ICR = 3.76, p = 0.010) and, suggestively, trauma (ICR = 1.91, p = 0.063). Exposure to more than one environmental risk factor increased the likelihood of co-expression of PEs in a dose–response fashion. Moderating effects of environmental exposures were largely mediated by the severity of general non-psychotic psychopathology (percentage explained 56–68%, all p < 0.001). Within individuals with MD/OCD, the association between PEs and help-seeking behaviour, as an index of severity, was moderated by trauma (ICR = 1.87, p = 0.009) and urbanicity (ICR = 1.48, p = 0.005), but not by cannabis use.

In non-psychotic disorder, environmental factors increase the likelihood of psychosis admixture and help-seeking behaviour through an increase in general psychopathology. The findings are compatible with a relational model of psychopathology in which more severe clinical states are the result of environment-induced disturbances spreading through a psychopathology network.

The past two decades have seen a great improvement in the care of people with Prader–Willi syndrome (PWS), particularly with regard to control of diet and behaviour management. Has this affected mortality rates or thrown up new issues regarding premature ageing or dementia? We investigated two aspects of ageing in people with PWS: (1) an estimate of mortality over 9 years in a cohort of people with PWS, originally recruited in 1998–2000; and (2) premature ageing or dementia in people aged ⩾40 years.

(1) A follow-up of the population-based 1998–2000 cohort to investigate the subsequent mortality rate; and (2) the recruitment and structured assessment of all members of the Prader–Willi Syndrome Association UK (PWSA-UK) aged ⩾40 years who agreed to participate.

Follow-up of the population-based 1998–2000 cohort gave a mortality rate of at least 7/62 over 9 years (1.25% per annum; 20 untraced), age at death was between 13 and 59 years. Twenty-six members of the PWSA-UK aged ⩾40 years were recruited, 18 of whom had a genetic diagnosis (gd) of PWS. Twenty-two (14 gd) showed no evidence of dementia. Four, with possible symptoms, are described in more detail; all are female, of maternal uniparental disomy (mUPD) genetic subtype, or have a disomic region, and all have a long history of psychotic illness.

The mortality rate in people with PWS seems to be declining. The subgroup of people with PWS due to UPD or disomic region with female gender and a history of psychosis may be at risk of early onset dementia.

There is increasing recognition that, in addition to negative psychological consequences of trauma such as post-traumatic stress disorder (PTSD), some individuals may develop post-traumatic growth (PTG) following such experiences. To date, however, data regarding the prevalence, correlates and functional significance of PTG in population-based samples are lacking.

Data were analysed from the National Health and Resilience in Veterans Study, a contemporary, nationally representative survey of 3157 US veterans. Veterans completed a survey containing measures of sociodemographic, military, health and psychosocial characteristics, and the Posttraumatic Growth Inventory-Short Form.

We found that 50.1% of all veterans and 72.0% of veterans who screened positive for PTSD reported at least ‘moderate’ PTG in relation to their worst traumatic event. An inverted U-shaped relationship was found to best explain the relationship between PTSD symptoms and PTG. Among veterans with PTSD, those with PTSD reported better mental functioning and general health than those without PTG. Experiencing a life-threatening illness or injury and re-experiencing symptoms were most strongly associated with PTG. In multivariable analysis, greater social connectedness, intrinsic religiosity and purpose in life were independently associated with greater PTG.

PTG is prevalent among US veterans, particularly among those who screen positive for PTSD. These results suggest that there may be a ‘positive legacy’ of trauma that has functional significance for veterans. They further suggest that interventions geared toward helping trauma-exposed US veterans process their re-experiencing symptoms, and to develop greater social connections, sense of purpose and intrinsic religiosity may help promote PTG in this population.

We investigated the course of decline in multiple cognitive domains in non-demented subjects from a memory clinic setting, and compared pattern, onset and magnitude of decline between subjects who progressed to Alzheimer's disease (AD) dementia at follow-up and subjects who did not progress.

In this retrospective cohort study 819 consecutive non-demented patients who visited the memory clinics in Maastricht or Amsterdam between 1987 and 2010 were followed until they became demented or for a maximum of 10 years (range 0.5–10 years). Differences in trajectories of episodic memory, executive functioning, verbal fluency, and information processing speed/attention between converters to AD dementia and subjects remaining non-demented were compared by means of random effects modelling.

The cognitive performance of converters and non-converters could already be differentiated seven (episodic memory) to three (verbal fluency and executive functioning) years prior to dementia diagnosis. Converters declined in these three domains, while non-converters remained stable on episodic memory and executive functioning and showed modest decline in verbal fluency. There was no evidence of decline in information processing speed/attention in either group.

Differences in cognitive performance between converters to AD dementia and subjects remaining non-demented could be established 7 years prior to diagnosis for episodic memory, with verbal fluency and executive functioning following several years later. Therefore, in addition to early episodic memory decline, decline in executive functions may also flag incident AD dementia. By contrast, change in information processing speed/attention seems less informative.

Children with somatic complaints are at increased risk for emotional disorders during childhood. Whether this elevated risk extends into young adulthood – and to which specific disorders – has rarely been tested with long-term prospective-longitudinal community samples. Here we test whether frequent and recurring stomach aches, headaches, and muscle aches during childhood predict emotional disorders in adulthood after accounting for childhood psychiatric and physical health status and psychosocial adversity.

The Great Smoky Mountains Study is a community representative sample with 1420 participants. Children/adolescents were assessed 4–7 times between ages 9–16 years. They were assessed again up to three times between ages 19–26 years. Childhood somatic complaints were coded when subjects or their parents reported frequent and recurrent headaches, stomach aches, or muscular/joint aches at some point when children were aged 9–16 years. Psychiatric disorders were assessed with the Child and Adolescent Psychiatric Assessment and the Young Adult Psychiatric Assessment.

Frequent and recurrent somatic complaints in childhood predicted adulthood emotional disorders. After controlling for potential confounders, predictions from childhood somatic complaints were specific to later depression and generalized anxiety disorder. Long-term predictions did not differ by sex. Somatic complaints that persisted across developmental periods were associated with the highest risk for young adult emotional distress disorders.

Children from the community with frequent and recurrent physical distress are at substantially increased risk for emotional distress disorders during young adulthood. Preventions and interventions for somatic complaints could help alleviate this risk.

Pituitary volume enlargements have been observed among individuals with first-episode psychosis. These abnormalities are suggestive of hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, which may contribute to the development of psychosis. However, the extent to which these abnormalities characterize individuals at elevated risk for schizophrenia prior to illness onset is currently unclear, as volume increases, decreases and no volume differences have all been reported relative to controls. The current study aimed to determine whether antipsychotic-naive, putatively at-risk children who present multiple antecedents of schizophrenia (ASz) or a family history of illness (FHx) show pituitary volume abnormalities relative to typically developing (TD) children. An additional aim was to explore the association between pituitary volume and experiences of psychosocial stress.

ASz (n = 30), FHx (n = 22) and TD (n = 32) children were identified at age 9–12 years using a novel community-screening procedure or as relatives of individuals with schizophrenia. Measures of pituitary volume and psychosocial stress were obtained at age 11–14 years.

Neither ASz nor FHx children showed differences in pituitary volume relative to TD children. Among FHx children only, pituitary volume was negatively associated with current distress relating to negative life events and exposure to physical punishment.

The lack of pituitary volume abnormalities among ASz and FHx children is consistent with our previous work demonstrating that these children are not characterized by elevated diurnal cortisol levels. The findings imply that these biological markers of HPA axis hyperactivity, observed in some older samples of high-risk individuals, may emerge later, more proximally to disease onset.

Altered dopaminergic neurotransmission in the mesocorticolimbic (MCL) system may mediate psychotic symptoms. In addition, pharmacological dopaminergic manipulation may coincide with altered functional connectivity (fc) ‘in rest’. We set out to test whether MCL-fc is conditional on (familial risk for) psychotic disorder and/or interactions with environmental exposures.

Resting-state functional magnetic resonance imaging data were obtained from 63 patients with psychotic disorder, 73 non-psychotic siblings of patients with psychotic disorder and 59 healthy controls. With the nucleus accumbens (NAcc) as seed region, fc within the MCL system was estimated. Regression analyses adjusting for a priori hypothesized confounders were used to assess group differences in MCL connectivity as well as gene (group) × environmental exposure interactions (G × E) (i.e. to cannabis, developmental trauma and urbanicity).

Compared with controls, patients and siblings had decreased fc between the right NAcc seed and the right orbitofrontal cortex (OFC) as well as the left middle cingulate cortex (MCC). Siblings showed decreased connectivity between the NAcc seed and lentiform nucleus compared with patients and controls. In addition, patients had decreased left NAcc connectivity compared with siblings in the left middle frontal gyrus. There was no evidence for a significant interaction between group and the three environmental exposures in the model of MCL-fc.

Reduced NAcc–OFC/MCC connectivity was seen in patients and siblings, suggesting that altered OFC connectivity and MCC connectivity are vulnerability markers for psychotic disorder. Differential exposure to environmental risk factors did not make an impact on the association between familial risk and MCL connectivity.

Do DSM-IV diagnostic criteria for major depression (MD) in Chinese and Western women perform in a similar manner?

The CONVERGE study included interview-based assessments of women of Han Chinese descent with treated recurrent MD. Using Mplus software, we investigated the overall degree of between-sample measurement invariance (MI) for DSM-IV diagnostic criteria for MD in the CONVERGE sample and samples selected from four major Western studies from the USA and Europe matched to the inclusion criteria of CONVERGE. These analyses were performed one pair at a time. We then compared the results from CONVERGE paired with Western samples to those obtained when examining levels of MI between pairs of the Western samples.

Assuming a single factor model for the nine diagnostic criteria for MD, the level of MI based on global fit indexes observed between the CONVERGE and the four Western samples was very similar to that seen between the Western samples. Comparable results were obtained when using a two-factor structure for MI testing when applied to the 14 diagnostic criteria for MD disaggregated for weight, appetite, sleep, and psychomotor changes.

Despite differences in language, ethnicity and culture, DSM criteria for MD perform similarly in Chinese women with recurrent MD and comparable subjects from the USA and Europe. The DSM criteria for MD may assess depressive symptoms that are relatively insensitive to cultural and ethnic differences. These results support efforts to compare findings from depressed patients in China and Western countries.

Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism.

Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed.

A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum.

Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

Mixed anxiety–depression (MAD) has been under scrutiny to determine its potential place in psychiatric nosology. The current study sought to investigate its prevalence, clinical characteristics, course and potential validators.

Restricted latent-class analyses were fit to 12-month self-reports of depression and anxiety symptom criteria in a large population-based sample of twins. Classes were examined across an array of relevant indicators (demographics, co-morbidity, adverse life events, clinical significance and twin concordance). Longitudinal analyses investigated the stability of, and transitions between, these classes for two time periods approximately 1.5 years apart.

In all analyses, a class exhibiting levels of MAD symptomatology distinctly above the unaffected subjects yet having low prevalence of either major depression (MD) or generalized anxiety disorder (GAD) was identified. A restricted four-class model, constraining two classes to have no prior disorder history to distinguish residual or recurrent symptoms from new onsets in the last year, provided an interpretable classification: two groups with no prior history that were unaffected or had MAD and two with prior history having relatively low or high symptom levels. Prevalence of MAD was substantial (9–11%), and subjects with MAD differed quantitatively but not qualitatively from those with lifetime MD or GAD across the clinical validators examined.

Our findings suggest that MAD is a commonly occurring, identifiable syndromal subtype that warrants further study and consideration for inclusion in future nosologic systems.