Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data.

We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors.

The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms).

The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.

Higher thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population (Boedhoe et al. 2017, Weeland et al. 2021a). Functionally distinct thalamic nuclei are an integral part of OCD-relevant brain circuitry.

We aimed to study the thalamic nuclei volume in relation to subclinical and clinical OCD across different age ranges. Understanding the role of thalamic nuclei and their associated circuits in pediatric OCD could lead towards treatment strategies specifically targeting these circuits.

We studied the relationship between thalamic nuclei and obsessive-compulsive symptoms (OCS) in a large sample of school-aged children from the Generation R Study (N = 2500) (Weeland et al. 2021b). Using the data from the ENIGMA-OCD working group we conducted mega-analyses to study thalamic subregional volume in OCD across the lifespan in 2,649 OCD patients and 2,774 healthy controls across 29 sites (Weeland et al. 2021c). Thalamic nuclei were grouped into five subregions: anterior, ventral, intralaminar/medial, lateral and pulvinar (Figure 1).

Both children with subclinical and clinical OCD compared with controls show increased volume across multiple thalamic subregions. Adult OCD patients have decreased volume across all subregions (Figure 2), which was mostly driven by medicated and adult-onset patients.

Our results suggests that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

No significant relationships.

Childhood adversities have been associated with long-lasting brain morphological differences and poor psychological outcomes over the lifespan. Evidence with regard to protective factors counteracting the detrimental effect of childhood adversity on neurobiology is scarce.

Therefore, we examined the interplay of childhood adversity with multiple protective factors in relation to brain morphology in a child and an adult cohort.

We analyzed data from two epidemiological longitudinal birth cohorts, the Generation R Study (N=3,008) and the Mannheim Study of Children at Risk (MARS) (N=179). Cumulative exposure to 12 adverse events (such as physical and sexual abuse), and the presence of protective factors, including child temperament, cognition, self-esteem, friendship quality and maternal sensitivity were assessed at different time points during childhood. Anatomical scans were acquired at the ages of 9-11 years in Generation R and at 25 years in MARS.

Childhood adversity was related to smaller global brain volumes in Generation R, with similar effect sizes observed for the cerebellar volume in MARS. While small interaction effects between adversity and protective factors were found on the medial orbitofrontal cortex, the cerebellum and the amygdala in either cohort study, no interactions were consistent across cohorts or survived correction for multiple comparisons.

We found no consistent or strong evidence for interaction effects between multiple protective factors and childhood adversities on brain structure in a child and an adult cohort study. Instead, small interaction effects were found in either children or adults warranting further investigation and more fine-grained analyses.

TB:consultancy for Actelion, Hexal Pharma, Lilly, Lundbeck, Medice, Novartis, Shire; conference support by Lilly, Medice, Novartis, Shire; clinical trials by Shire and Viforpharma; royalties by Hogrefe, Kohlhammer, CIP Medien, Oxford University Press

Psychotic experiences predict adverse health outcomes, particularly if they are persistent. However, it is unclear what distinguishes persistent from transient psychotic experiences.

In a large population-based cohort, we aimed to (a) describe the course of hallucinatory experiences from childhood to adolescence, (b) compare characteristics of youth with persistent and remittent hallucinatory experiences, and (c) examine prediction models for persistence.

Youth were assessed longitudinally for hallucinatory experiences at mean ages of 10 and 14 years (n = 3473). Multi-informant-rated mental health problems, stressful life events, self-esteem, non-verbal IQ and parental psychopathology were examined in relation to absent, persistent, remittent and incident hallucinatory experiences. We evaluated two prediction models for persistence with logistic regression and assessed discrimination using the area under the curve (AUC).

The persistence rate of hallucinatory experiences was 20.5%. Adolescents with persistent hallucinatory experiences had higher baseline levels of hallucinatory experiences, emotional and behavioural problems, as well as lower self-esteem and non-verbal IQ scores than youth with remittent hallucinatory experiences. Although the prediction model for persistence versus absence of hallucinatory experiences demonstrated excellent discriminatory power (AUC-corrected = 0.80), the prediction model for persistence versus remittance demonstrated poor accuracy (AUC-corrected = 0.61).

This study provides support for the dynamic expression of childhood hallucinatory experiences and suggests increased neurodevelopmental vulnerability in youth with persistent hallucinatory experiences. Despite the inclusion of a wide array of psychosocial parameters, a prediction model discriminated poorly between youth with persistent versus remittent hallucinatory experiences, confirming that persistent hallucinatory experiences are a complex multifactorial trait.

Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment.

Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses.

Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10−07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4.

These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

In middle-aged and older patients in whom antidepressant use increased in last decades, patterns of use might be of concern The objective of this study was to investigate the patterns of prevalence, incidence and duration of antidepressant use in an ageing population.

All participants (aged > 45 years) from the population-based Rotterdam Study were followed from January 1st 1991 until death, loss to follow-up, or end of the study period (December 31st 2011). Antidepressant drug dispensing, based on pharmacy records, were subdivided into Tricyclic Antidepressants (TCAs), Selective Serotonin Reuptake Inhibitors (SSRIs) and other antidepressants. One-year prevalence, 5-year incidence and duration of antidepressant use were calculated.

Yearly prevalence of antidepressant use increased from 3.9% in 1991 to 8.3% of the population in 2011. The increase in SSRI use was 5.8-fold, whereas use of other antidepressants doubled and TCA use remained stable over time. Incidence of all antidepressants decreased from 23.9 to 14.2 per 1000 person-years between 1992 and 2011. The duration of a first treatment episode increased over time.

Despite the prevalence of antidepressant use increased over time, incidence did not, which is most likely explained by a longer treatment duration and recurrent episodes.

Previous studies have examined associations of cardiometabolic factors with depression and cognition separately.

To determine if depressive symptoms mediate the association between cardiometabolic factors and cognitive decline in two community studies.

Data for the analyses were drawn from the Rotterdam Study, the Netherlands (n = 2940) and the Whitehall II study, UK (n = 4469).

Mediation analyses suggested a direct association between cardiometabolic factors and cognitive decline and an indirect association through depression: poorer cardiometabolic status at time 1 was associated with a higher level of depressive symptoms at time 2 (standardised regression coefficient 0.07 and 0.06, respectively), which, in turn, was associated with greater cognitive decline between time 2 and time 3 (standardised regression coefficient of −0.15 and −0.41, respectively).

Evidence from two independent cohort studies suggest an association between cardiometabolic dysregulation and cognitive decline and that depressive symptoms tend to precede this decline.

None.

There is growing interest in linking vitamin D deficiency with autism spectrum disorders (ASDs). The association between vitamin D deficiency during gestation, a critical period in neurodevelopment, and ASD is not well understood.

To determine the association between gestational vitamin D status and ASD.

Based on a birth cohort (n=4334), we examined the association between 25-hydroxyvitamin D (25OHD), assessed from both maternal mid-gestation sera and neonatal sera, and ASD (defined by clinical records; n=68 cases).

Individuals in the 25OHD-deficient group at mid-gestation had more than twofold increased risk of ASD (odds ratio (OR)=2.42, 95% confidence interval (CI) 1.09 to 5.07, P=0.03) compared with the sufficient group. The findings persisted in analyses including children of European ethnicity only.

Mid-gestational vitamin D deficiency was associated with an increased risk of ASD. Because gestational vitamin D deficiency is readily preventable with safe, inexpensive and readily available supplementation, this risk factor warrants closer scrutiny.

Subjectively assessed health is related to mortality. Various subjective indicators of health have been studied, but it is unclear whether perceived physical functioning or mental health best accounts for the relation with mortality.

We studied the relation of subjective measures of health with all-cause mortality in 5538 participants of age 55 to 96 years at baseline from the Rotterdam Study. Various instruments of subjectively assessed health were used, that included basic activities of daily living (BADL), instrumental activities of daily living (IADL), quality of life (QoL), positive affect, somatic symptoms and negative affect. All participants completed questionnaires for each subjective measure of health and were followed for mortality for a mean of 12.2 (s.e. = 0.09) years. Cox regression analysis was conducted in the total sample.

In this cohort, 2021 persons died during 48 534 person-years of follow-up. All measures of subjective health were related to mortality after adjusting for age, gender, education, cognition, prevalent chronic diseases and cardiovascular risk [BADL hazard ratio (HR, calculated per Z-score) = 1.35, 95% confidence interval (CI) 1.29–1.41; IADL HR = 1.27, 95% CI 1.22–1.32; QoL HR = 0.85, 95% CI 0.81–0.89; positive affect HR = 0.92, 95% CI 0.88–0.96; somatic symptoms HR = 1.11, 95% CI 1.06–1.16; and negative affect HR = 1.05, 95% CI 1.01–1.10]. In the mutually adjusted model, only BADL (HR = 1.24, 95% CI 1.16–1.32) and IADL (HR = 1.10, 95% CI 1.04–1.17) remained independently associated with mortality.

Measures of subjectively assessed health are important indicators of mortality. Our study shows that of the different measures of subjective health, perceived physical health predicts mortality over and above mental health. Conversely, the association between mental health and mortality may partly be explained by poor perceived physical health.

Problem behavior of young children is generally not assessed with structured child interviews. This paper examined how information about problem behavior, obtained by structured interviews with six-year-old children, relates to DSM-disorders obtained from parents and to treatment referral.

In a population-based cohort, caregivers of 1084 young children (mean age 6.7 years) were interviewed with the DSM-based Diagnostic Interview Schedule-Young Child version (DISC-YC), and they scored the Child Behavior Checklist (CBCL). Children themselves were interviewed about problem behavior using the semi-structured Berkeley Puppet Interview (BPI). Information regarding treatment referral to mental health services was obtained by parent-reported questionnaire when children were on average eight years old.

DSM-disorders and CBCL problems in the clinical range were cross-sectionally associated with higher levels of child self-reported problems. Associations were strongest in the externalizing domain (e.g. DISC-YC externalizing disorders with BPI externalizing scores: F(1, 416) = 19.39, P < 0.001; DISC-YC internalizing disorders with BPI internalizing scores: F(1, 312) = 3.75, P = 0.054). Moreover, higher BPI internalizing and externalizing problem scores predicted treatment referral two years later.

We conclude that systematically interviewing preschool and young elementary school-aged children should be an integral part of child assessment. This approach may contribute to a better understanding of child development and may predict future problems.

Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset.

Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA.

Education, but not ethnicity/race, influenced the reporting of postpartum depression [difference between robust comparative fit indexes (∆*CFI) < 0.01]. The structure of EPDS responses significantly differed between Europe and the USA (∆*CFI > 0.01), but not between European countries (∆*CFI < 0.01).

Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.

The association between myocardial infarction (MI) and depression is well described. Yet, the underlying mechanisms are unclear and the contribution of psychological factors is uncertain. We aimed to determine the risk of recognized (RMI) and unrecognized (UMI) myocardial infections on depression, as both have a similar impact on cardiovascular health but differ in psychological epiphenomena.

Participants of the Rotterdam Study, 1823 men aged ⩾55 years, were followed for the occurrence of depression. RMI and UMI were ascertained using electrocardiography and medical history at baseline. We determined the strength of the association of RMI and UMI with mortality, and we studied the relationship of RMI and UMI with depressive symptoms and the occurrence of major depression.

The risk of mortality was similar in men with RMI [adjusted hazard ratio (aHR) 1.71, 95% confidence interval (CI) 1.45–2.03] and UMI (aHR 1.58, 95% CI 1.27–1.97). Men with RMI had on average [unstandardized regression coefficient (B) 1.14, 95% CI 0.07–2.21] higher scores for depressive symptoms. By contrast, we found no clear association between UMI and depressive symptoms (B 0.55, 95% CI −0.51 to 1.62) in men. Analysis including occurrence of major depression as the outcome were consistent with the pattern of association.

The discrepant association of RMI and UMI with mortality compared to depression suggests that the psychological burden of having experienced an MI contributes to the long-term risk of depression.

Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.

We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).

One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.

Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

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

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

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

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

Several psychosocial risk factors for complicated grief have been described. However, the association of complicated grief with cognitive and biological risk factors is unclear. The present study examined whether complicated grief and normal grief are related to cognitive performance or structural brain volumes in a large population-based study.

The present research comprised cross-sectional analyses embedded in the Rotterdam Study. The study included 5501 non-demented persons. Participants were classified as experiencing no grief (n = 4731), normal grief (n = 615) or complicated grief (n = 155) as assessed with the Inventory of Complicated Grief. All persons underwent cognitive testing (Mini-Mental State Examination, Letter–Digit Substitution Test, Stroop Test, Word Fluency Task, word learning test – immediate and delayed recall), and magnetic resonance imaging to measure general brain parameters (white matter, gray matter), and white matter lesions. Total brain volume was defined as the sum of gray matter plus normal white matter and white matter lesion volume. Persons with depressive disorders were excluded and analyses were adjusted for depressive symptoms.

Compared with no-grief participants, participants with complicated grief had lower scores for the Letter–Digit Substitution Test [Z-score −0.16 v. 0.04, 95% confidence interval (CI) −0.36 to −0.04, p = 0.01] and Word Fluency Task (Z-score −0.15 v. 0.03, 95% CI −0.35 to −0.02, p = 0.02) and smaller total volumes of brain matter (933.53 ml v. 952.42 ml, 95% CI −37.6 to −0.10, p = 0.04).

Participants with complicated grief performed poorly in cognitive tests and had a smaller total brain volume. Although the effect sizes were small, these findings suggest that there may be a neurological correlate of complicated grief, but not of normal grief, in the general population.

Selective serotonin reuptake inhibitors (SSRIs) are considered safe and are frequently used during pregnancy. However, two case–control studies suggested an association between prenatal SSRI exposure with childhood autism.

To prospectively determine whether intra-uterine SSSRI exposure is associated with childhood autistic symptoms in a population-based study.

A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included. Child pervasive developmental and affective problems were assessed by parental report with the Child Behavior Checklist at ages 1.5, 3 and 6. At age 6, we assessed autistic traits using the Social Responsiveness Scale (n = 4264).

Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07–1.93) and affective problems (OR = 1.44, 95% CI 1.15–1.81). Compared with unexposed children, those prenatally exposed to SSRIs also were at higher risk for developing pervasive developmental problems (OR = 1.91, 95% CI 1.13–3.47), but not for affective problems. Children prenatally exposed to SSRIs also had more autistic traits (B = 0.15, 95% CI 0.08–0.22) compared with those exposed to depressive symptoms only.

Our results suggest an association between prenatal SSRI exposure and autistic traits in children. Prenatal depressive symptoms without SSRI use were also associated with autistic traits, albeit this was weaker and less specific. Long-term drug safety trials are needed before evidence-based recommendations are possible.

While many neuroimaging studies have investigated the neurobiological basis of attention deficit hyperactivity disorder (ADHD), few have studied the neurobiology of attention problems in the general population. The ability to pay attention falls along a continuum within the population, with children with ADHD at one extreme of the spectrum and, therefore, a dimensional perspective of evaluating attention problems has an added value to the existing literature. Our goal was to investigate the relationship between cortical thickness and inattention and hyperactivity symptoms in a large population of young children.

This study is embedded within the Generation R Study and includes 6- to 8-year-old children (n = 444) with parent-reported attention and hyperactivity measures and high-resolution structural imaging data. We investigated the relationship between cortical thickness across the entire brain and the Child Behavior Checklist Attention Deficit Hyperactivity Problems score.

We found that greater attention problems and hyperactivity were associated with a thinner right and left postcentral gyrus. When correcting for potential confounding factors and multiple testing, these associations remained significant.

In a large, population-based sample we showed that young (6- to 8-year-old) children who show more attention problems and hyperactivity have a thinner cortex in the region of the right and left postcentral gyrus. The postcentral gyrus, being the primary somatosensory cortex, reaches its peak growth early in development. Therefore, the thinner cortex in this region may reflect either a deviation in cortical maturation or a failure to reach the same peak cortical thickness compared with children without attention or hyperactivity problems.