Sample size planning (SSP) is vital for efficient studies that yield reliable outcomes. Hence, guidelines, emphasize the importance of SSP. The present study investigates the practice of SSP in current trials for depression.

Seventy-eight randomized controlled trials published between 2013 and 2017 were examined. Impact of study design (e.g. number of randomized conditions) and study context (e.g. funding) on sample size was analyzed using multiple regression.

Overall, sample size during pre-registration, during SSP, and in published articles was highly correlated (r's ≥ 0.887). Simultaneously, only 7–18% of explained variance related to study design (p = 0.055–0.155). This proportion increased to 30–42% by adding study context (p = 0.002–0.005). The median sample size was N = 106, with higher numbers for internet interventions (N = 181; p = 0.021) compared to face-to-face therapy. In total, 59% of studies included SSP, with 28% providing basic determinants and 8–10% providing information for comprehensible SSP. Expected effect sizes exhibited a sharp peak at d = 0.5. Depending on the definition, 10.2–20.4% implemented intense assessment to improve statistical power.

Findings suggest that investigators achieve their determined sample size and pre-registration rates are increasing. During study planning, however, study context appears more important than study design. Study context, therefore, needs to be emphasized in the present discussion, as it can help understand the relatively stable trial numbers of the past decades. Acknowledging this situation, indications exist that digital psychiatry (e.g. Internet interventions or intense assessment) can help to mitigate the challenge of underpowered studies. The article includes a short guide for efficient study planning.

Racial and ethnic groups in the USA differ in the prevalence of posttraumatic stress disorder (PTSD). Recent research however has not observed consistent racial/ethnic differences in posttraumatic stress in the early aftermath of trauma, suggesting that such differences in chronic PTSD rates may be related to differences in recovery over time.

As part of the multisite, longitudinal AURORA study, we investigated racial/ethnic differences in PTSD and related outcomes within 3 months after trauma. Participants (n = 930) were recruited from emergency departments across the USA and provided periodic (2 weeks, 8 weeks, and 3 months after trauma) self-report assessments of PTSD, depression, dissociation, anxiety, and resilience. Linear models were completed to investigate racial/ethnic differences in posttraumatic dysfunction with subsequent follow-up models assessing potential effects of prior life stressors.

Racial/ethnic groups did not differ in symptoms over time; however, Black participants showed reduced posttraumatic depression and anxiety symptoms overall compared to Hispanic participants and White participants. Racial/ethnic differences were not attenuated after accounting for differences in sociodemographic factors. However, racial/ethnic differences in depression and anxiety were no longer significant after accounting for greater prior trauma exposure and childhood emotional abuse in White participants.

The present findings suggest prior differences in previous trauma exposure partially mediate the observed racial/ethnic differences in posttraumatic depression and anxiety symptoms following a recent trauma. Our findings further demonstrate that racial/ethnic groups show similar rates of symptom recovery over time. Future work utilizing longer time-scale data is needed to elucidate potential racial/ethnic differences in long-term symptom trajectories.

Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.

Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.

Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.

Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.

It is unclear if psychiatric morbidity among parents bereaved of a child is related to major loss in general or if the cause of death matters. Whether such a link is consistent with a causal explanation also remains uncertain.

We identified 3 114 564 parents through linkage of Swedish nationwide registers. Risk of psychiatric hospitalization was assessed with log-linear Poisson regression and family-based analyses were used to explore familial confounding.

A total of 3284 suicides and 14 095 any-cause deaths were identified in offspring between 12 and 25 years of age. Parents exposed to offspring suicide had considerably higher risk of subsequent psychiatric hospitalization than unexposed parents [relative risk (RR) 1.90, 95% confidence interval (CI) 1.72–2.09], higher than parents exposed to offspring non-suicide death relative to controls (RR 1.18, 95% CI 1.11–1.26). We found no risk increase among stepfathers differentially exposed to biologically unrelated stepchildren's death or suicide, and the relative risk was notably lower among full siblings differentially exposed to offspring death or suicide.

Parental psychiatric hospitalization following offspring death was primarily found in offspring suicide. Familial (e.g. shared genetic) effects seemed important, judging from both lack of psychiatric hospitalization in bereaved stepfathers and attenuated risk when bereaved parents were contrasted to their non-bereaved siblings. We conclude that offspring suicide does not ‘cause’ psychiatric hospitalization in bereaved parents.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, yet the search for definite genetic etiologies remains elusive. Delineating ASD endophenotypes can boost the statistical power to identify the genetic etiologies and pathophysiology of ASD. We aimed to test for endophenotypes of neuroanatomy and associated intrinsic functional connectivity (iFC) via contrasting male youth with ASD, their unaffected brothers and typically developing (TD) males.

The 94 participants (aged 9–19 years) – 20 male youth with ASD, 20 unaffected brothers and 54 TD males – received clinical assessments, and undertook structural and resting-state functional magnetic resonance imaging scans. Voxel-based morphometry was performed to obtain regional gray and white matter volumes. A seed-based approach, with seeds defined by the regions demonstrating atypical neuroanatomy shared by youth with ASD and unaffected brothers, was implemented to derive iFC. General linear models were used to compare brain structures and iFC among the three groups. Assessment of familiality was investigated by permutation tests for variance of the within-family pair difference.

We found that atypical gray matter volume in the mid-cingulate cortex was shared between male youth with ASD and their unaffected brothers as compared with TD males. Moreover, reduced iFC between the mid-cingulate cortex and the right inferior frontal gyrus, and increased iFC between the mid-cingulate cortex and bilateral middle occipital gyrus were the shared features of male ASD youth and unaffected brothers.

Atypical neuroanatomy and iFC surrounding the mid-cingulate cortex may be a potential endophenotypic marker for ASD in males.

Schizophrenia (SZ) is associated with thalamic dysconnectivity. Compared to healthy controls (HCs), individuals with SZ have hyperconnectivity with sensory regions, and hypoconnectivity with cerebellar, thalamic, and prefrontal regions. Despite replication of this pattern in chronically ill individuals, less is known about when these abnormalities emerge in the illness course and if they are present prior to illness onset.

Resting-state functional magnetic resonance imaging data were collected from psychosis risk syndrome (PRS) youth (n = 45), early illness SZ (ESZ) (n = 74) patients, and HCs (n = 85). Age-adjusted functional connectivity, seeded from the thalamus, was compared among the groups.

Significant effects of group were observed in left and right middle temporal regions, left and right superior temporal regions, left cerebellum, and bilateral thalamus. Compared to HCs, ESZ demonstrated hyperconnectivity to all temporal lobe regions and reduced connectivity with cerebellar, anterior cingulate, and thalamic regions. Compared to HCs, PRS demonstrated hyperconnectivity with the left and right middle temporal regions, and hypoconnectivity with the cerebellar and other thalamic regions. Compared to PRS participants, ESZ participants were hyperconnected to temporal regions, but did not differ from PRS in hypoconnectivity with cerebellar and thalamic regions. Thalamic dysconnectivity was unrelated to positive symptom severity in ESZ or PRS groups.

PRS individuals demonstrated an intermediate level of thalamic dysconnectivity, whereas ESZ showed a pattern consistent with prior observations in chronic samples. These cross-sectional findings suggest that thalamic dysconnectivity may occur prior to illness onset and become more pronounced in early illness stages.

Second-generation immigrants have an increased risk of schizophrenia, a finding that still lacks a satisfactory explanation. Various operational definitions of second-generation immigrants have been used, including foreign parental country of birth. However, with increasing global migration, it is not clear that parental country of birth necessarily is informative with regard to ethnicity. We compare two independently collected measures of parental foreign ethnicity, parental foreign country of birth versus genetic divergence, based on genome-wide genotypic data, to access which measure most efficiently captures the increased risk of schizophrenia among second-generation immigrants residing in Denmark.

A case–control study covering all children born in Denmark since 1981 included 892 cases of schizophrenia and 883 matched controls. Genetic divergence was assessed using principal component analyses of the genotypic data. Independently, parental foreign country of birth was assessed using information recorded prospectively in the Danish Civil Registration System. We compared incidence rate ratios of schizophrenia associated with these two independently collected measures of parental foreign ethnicity.

People with foreign-born parents had a significantly increased risk of schizophrenia [relative risk (RR) 1.94 (95% confidence intervals (CI) 1.41–2.65)]. Genetically divergent persons also had a significant increased risk [RR 2.43 (95% CI 1.55–3.82)]. Mutual adjustment of parental foreign country of birth and genetic divergence showed no difference between these measures with regard to their potential impact on the results.

In terms of RR of schizophrenia, genetic divergence and parental foreign country of birth are interchangeable entities, and both entities have validity with regard to identifying second-generation immigrants.

Relapse from drug abuse (DA) is common, but has rarely been studied in general population samples using a wide range of objective predictors.

Using nationwide registries, we ascertained 44 523 subjects first registered for DA between the ages of 15 and 40 in 1998 to 2004 and followed for 8 years. We predicted relapse in subjects defined as a second DA registration. We also predicted DA relapse in relative pairs concordant for DA but discordant for relapse.

In multivariate regression analyses, the strongest predictors for relapse were prior criminal behavior, male sex, being on social welfare, low school achievement, prior alcoholism, and a high-risk father. A risk index trained from these analyses on random split-halves demonstrated a risk ratio of 1.11 [95% confidence intervals (CIs) 1.10–1.11] per decile and an ROC value of 0.70 (0.69–0.71). Co-relative analyses indicated that a modest proportion of this association was causal, with the remainder arising from familial confounders. A developmental structural equation model revealed a complex interviewing of risk pathways to DA with three key mediational hubs: low educational attainment, early age at first registration, and being on social welfare.

In a general population sample, using objective registry information, DA relapse is substantially predictable. However, the identified risk factors may not be valid targets for interventions because many index familial risk and may not impact causally on probability of relapse. Risk for DA relapse may reflect an inter-weaving, over developmental time, of genetic–temperamental vulnerability, indices of externalizing behaviors and social factors reflecting deprivation.

Social anxiety disorder involves fear of social objects or situations. Social referencing may play an important role in the acquisition of this fear and could be a key determinant in future biomarkers and treatment pathways. However, the neural underpinnings mediating such learning in social anxiety are unknown. Using event-related functional magnetic resonance imaging, we examined social reference learning in social anxiety disorder. Specifically, would patients with the disorder show increased amygdala activity during social reference learning, and further, following social reference learning, show particularly increased response to objects associated with other people's negative reactions?

A total of 32 unmedicated patients with social anxiety disorder and 22 age-, intelligence quotient- and gender-matched healthy individuals responded to objects that had become associated with others’ fearful, angry, happy or neutral reactions.

During the social reference learning phase, a significant group × social context interaction revealed that, relative to the comparison group, the social anxiety group showed a significantly greater response in the amygdala, as well as rostral, dorsomedial and lateral frontal and parietal cortices during the social, relative to non-social, referencing trials. In addition, during the object test phase, relative to the comparison group, the social anxiety group showed increased bilateral amygdala activation to objects associated with others’ fearful reactions, and a trend towards decreased amygdala activation to objects associated with others’ happy and neutral reactions.

These results suggest perturbed observational learning in social anxiety disorder. In addition, they further implicate the amygdala and dorsomedial prefrontal cortex in the disorder, and underscore their importance in future biomarker developments.

Self-efficacy is a pivotal factor in the etiology and prognosis of major depression. However, longitudinal studies on the relationship between self-efficacy and major depressive disorder (MDD) are scarce. The objectives were to investigate: (1) the associations between self-efficacy and the 1-year and 2-year risks of first onset of MDD and (2) the associations between self-efficacy and the 1-year and 2-year risks of the persistence/recurrence of MDD, in a sample of first-year university students.

We followed 8079 first-year university students for 2 years from April 2018 to October 2020. MDD was ascertained by the Chinese version of the Composite International Diagnostic Interview (CIDI-3.0) based on self-report. Self-efficacy was measured by the 10-item General Self-efficacy (GSE) scale. Random effect logistic regression modeling was used to estimate the associations.

Among participants without a lifetime MDD, the data showed that participants with high baseline GSE scores were associated with a higher risk of first onset of MDD over 2 years [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01–1.08]. Among those with a lifetime MDD, participants with high baseline GSE scores were less likely to have had a MDD over 2 years (OR 0.93, 95% CI 0.88–0.99) compared to others.

A high level of GSE may be protective of the risk of persistent or recurrent MDD. More longitudinal studies in university students are needed to further investigate the impact of GSE on the first onset of MDD.

There is increasing evidence that the frequently reported working memory impairments in schizophrenia might be partly due to an alteration in the functional connectivity between task-relevant areas. However, little is known about the functional connectivity patterns in schizophrenia patients during learning processes. In a previous study, Koch et al. [Neuroscience (2007) 146, 1474–1483] have demonstrated stronger exponential activation decreases in schizophrenia patients during overlearning of short-term memory material. The question arises whether these differential temporal patterns of activation in schizophrenia patients and controls are going along with changes in task-related functional connectivity.

Therefore, in the current study, 13 patients with schizophrenia and 13 controls were studied while performing a short-term memory task associated with increasing overlearning of verbal stimulus material. Functional connectivity was investigated by analyses of psychophysiological interactions (PPI).

Results revealed significant task-related modulation of functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and a network including the right DLPFC, left ventrolateral prefrontal cortex, premotor cortex, right inferior parietal cortex, left and right cerebellum as well as the left occipital lobe in patients during the course of overlearning and practice. No significant PPI results were detectable in controls.

Activation changes with practice were associated with high functional connectivity between task-relevant areas in schizophrenia patients. This could be interpreted as a compensatory resource allocation and network integration in the context of cortical inefficiency and may be a specific neurophysiological signature underlying the pathophysiology of schizophrenia.

There is increasing evidence that blood oxygenation level-dependent signaling in white matter (WM) reflects WM functional activity. Whether this activity is altered in schizophrenia remains uncertain, as does whether it is related to established alterations of gray matter (GM) or the microstructure of WM tracts.

A total of 153 antipsychotic-naïve schizophrenia patients and 153 healthy comparison subjects were assessed by resting-state functional magnetic resonance imaging, diffusion tensor imaging, and high-resolution T1-weighted imaging. We tested for case–control differences in the functional activity of WM, and examined their relation to the functional activity of GM and WM microstructure. The relations between fractional anisotropy (FA) in WM and GM–WM functional synchrony were investigated as well. Then, we examined the associations of identified abnormalities to age, duration of untreated psychosis (DUP), and symptom severity.

Schizophrenia patients displayed reductions of the amplitude of low-frequency fluctuations (ALFF), GM–WM functional synchrony, and FA in widespread regions. Specifically, the genu of corpus callosum not only had weakening in the synchrony of functional activity but also had reduced ALFF and FA. Positive associations were found between FA and functional synchrony in the genu of corpus callosum as well. No significant association was found between identified abnormalities and DUP, and symptom severity.

The widespread weakening in the synchrony of functional activity of GM and WM provided novel evidence for functional alterations in schizophrenia. Regarding the WM function as a component of brain systems and investigating its alternation represent a promising direction for future research.