Five-year follow-up of the iBerry Study: screening in early adolescence to identify those at risk of psychopathology in emerging adulthood.

The iBerry Study, a Dutch population-based high-risk cohort (n = 1022) examines the transition from subclinical symptoms to psychiatric disorders in adolescents. Here, we present the first follow-up measurement, approximately 3 years after baseline assessment and 5 years after the screening based on self-reported emotional and behavioral problems (SDQ-Y). We give an update on the data collection, details on the (non)response, and the results on psychopathology outcomes. The first follow-up (2019-2022) had a response rate of 79% (n = 807). Our results at baseline (mean age 15.0 years) have shown the effectiveness of using the SDQ-Y to select a cohort oversampled for the risk of psychopathology. At first follow-up (mean age 18.1 years), the previously administered SDQ-Y remains predictive for selecting adolescents at risk. At follow-up, 47% of the high-risk adolescents showed significant mental health problems based on self- and parent reports and 46% of the high-risk adolescents met the criteria for multiple DSM-5 diagnoses. Compared to low-risk adolescents, high-risk adolescents had a sevenfold higher odds of significant emotional and behavioral problems at follow-up. Comprehensive assessment on psychopathology, substance abuse, psychotic symptoms, suicidality, nonsuicidal self-injury, addiction to social media and/or video gaming, and delinquency, as well as social development, and the utilization of healthcare and social services were conducted. This wave, as well as the ones to follow, track these adolescents into their young adulthood to identify risk factors, elucidate causal mechanisms, and discern pathways leading to both common and severe mental disorders. Results from the iBerry Study will provide leads for preventive interventions.

Adolescent Nonsuicidal Self-Injury and Suicidality: A Latent Class Analysis and Associations with Clinical Characteristics in an At-Risk Cohort.

Nonsuicidal self-injury (NSSI) is frequently encountered in adolescents, but its predictive value for suicidality or other clinical characteristics is challenging due to its heterogeneous nature. This study used latent class analysis to identify subgroups of NSSI and compared these on sociodemographic characteristics, adverse outcomes and protective factors. The study included 966 high-risk adolescents, Mage 14.9 y, SD 0.9 y, 51.8% female. Four classes emerged: (1) "Low NSSI-Low suicidality", (2) "Moderate NSSI-Low suicidality", (3) "Moderate NSSI-High suicidality", and (4) "High NSSI-High suicidality". Girls predominated in the high suicidality classes. Generally, Class 4 had the poorest outcomes: more internalizing and externalizing problems, less social support from friends and families and worst self-esteem. These findings emphasize the need for interventions tailored to specific phenotypes of adolescents engaging in NSSI.

A longitudinal study of mental health in at-risk adolescents before and during the COVID-19 pandemic.

Although cross-sectional studies have shown that the COVID-19 pandemic has negatively affected the mental health of adolescents, the effect of the pandemic on adolescents with pre-pandemic symptoms is unclear. We, therefore, tested the hypothesis that adolescents had increased emotional and behavioral problems during the lockdowns imposed during the pandemic.This study included three measurements in a prospective cohort of 1022 adolescents who were oversampled based on their high risk of developing psychopathology. Before the pandemic, we assessed depressive, anxiety, stress, oppositional defiant problems, psychotic experiences and suicidality, using the Youth Self-Report; 445 and 333 of these 1,022 adolescents subsequently completed the online questionnaire in the first lockdown (in April 2020) and in the second lockdown (in January 2021), respectively. Multilevel random intercept regression models were used to determine the change in psychiatric symptoms, including an interaction term to assess whether these changes differed based on the severity of symptoms prior to the pandemic. Throughout the pandemic, the majority of the participating adolescents reported having emotional and behavioral symptoms that were within the normal range. Moreover, the mean symptom scores for all six outcomes decreased significantly among adolescents with high clinical severity prior to the pandemic.In contrast to our original hypothesis, the effects of the COVID-19 pandemic may not necessarily be detrimental, at least among a specific subgroup of adolescents with pre-existing mental health problems. Moreover, our finding that most adolescents in this at-risk sample did not report experiencing clinically relevant symptoms during the pandemic reflects their resilience during the pandemic.

[Psychosis as an evolutionary adaptive mechanism to environmental changes; A plea for a functional explanatory model]. / Psychose als evolutionair adaptief mechanisme bij omgevingsverandering; pleidooi voor een functioneel verklaringsmodel.

BACKGROUND: From an evolutionary perspective it is remarkable that psychotic disorders, mostly occurring during fertile age and decreasing fecundity, maintain in the human population.
AIM: To argue the hypothesis that psychotic symptoms may not be viewed as an illness but as an adaptation phenomenon.
METHOD: Philosophical consideration and literature study.
RESULTS: Until now, biomedical research has not unraveled the definitive etiology of psychotic disorders. Findings are inconsistent and show non-specific brain anomalies and genetic variation with small effect sizes. However, compelling evidence was found for a relation between psychosis and stressful environmental factors, particularly those influencing social interaction. Psychotic symptoms may be explained as a natural defense mechanism or protective response to stressful environments. This is in line with the fact that psychotic symptoms most often develop during adolescence. In this phase of life, it is important for an individual's development to leave the familiar and safe home environment, and to build new social networks. This could cause symptoms of 'hyperconsciousness' and calls on the capacity for social adaptation. This mechanism can become out of control due to different underlying brain vulnerabilities and external stressors, leading to social exclusion. CONCLUSIONS There is theoretical ground to consider psychotic symptoms as an evolutionary maintained phenomenon. Research investigating psychotic disorders may benefit from a focus on underlying general brain vulnerabilities or prevention of social exclusion, instead of regarding psychotic symptoms as abnormal phenomena.

A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells.

Progress in elucidating the molecular and cellular pathophysiology of neuropsychiatric disorders has been hindered by the limited availability of living human brain tissue. The emergence of induced pluripotent stem cells (iPSCs) has offered a unique alternative strategy using patient-derived functional neuronal networks. However, methods for reliably generating iPSC-derived neurons with mature electrophysiological characteristics have been difficult to develop. Here, we report a simplified differentiation protocol that yields electrophysiologically mature iPSC-derived cortical lineage neuronal networks without the need for astrocyte co-culture or specialized media. This protocol generates a consistent 60:40 ratio of neurons and astrocytes that arise from a common forebrain neural progenitor. Whole-cell patch-clamp recordings of 114 neurons derived from three independent iPSC lines confirmed their electrophysiological maturity, including resting membrane potential (-58.2±1.0 mV), capacitance (49.1±2.9 pF), action potential (AP) threshold (-50.9±0.5 mV) and AP amplitude (66.5±1.3 mV). Nearly 100% of neurons were capable of firing APs, of which 79% had sustained trains of mature APs with minimal accommodation (peak AP frequency: 11.9±0.5 Hz) and 74% exhibited spontaneous synaptic activity (amplitude, 16.03±0.82 pA; frequency, 1.09±0.17 Hz). We expect this protocol to be of broad applicability for implementing iPSC-based neuronal network models of neuropsychiatric disorders.

Need analysis for a new high acuity medical psychiatry unit: which patients are considered for admission?

BACKGROUND: The study aims were: to estimate the proportion of patients with an indication for admission to a new high acuity Medical Psychiatric Unit (MPU), to explore the reasons for MPU-admission according to different health disciplines, and to check for differences in patient characteristics. The results of this study are to be utilized in the proposed establishment of a high-acuity MPU in a University Medical Center. Such a unit currently does not exist at Erasmus MC. METHODS: Hospital in-patients were included if they received psychiatric consultation from the Psychiatric Consultative Service (PCS). As part of the study protocol, psychiatrists, other medical specialists, and nurses determined the need for admission to the proposed MPU. Patient groups were compared with respect to diagnoses, socio-demographic characteristics and patient routing. RESULTS: One hundred and fifty-one patients were included, 43% had an indication for MPU-admission, for the other patients PCS involvement was sufficient. There was agreement on suicide attempts as a reason for MPU-admission. For psychiatrists, the need for further diagnostic evaluation was a common reason for MPU admission, while other medical specialists more often emphasized the need for safety measures. Patients with an unplanned hospital admission had a higher chance of MPU eligibility (OR = 2.72, 95% CI 1.10-6.70). The main psychiatric diagnoses of MPU-eligible patients were organic disorders (including delirium), mood disorders, and disorders related to substance abuse. The most common diagnoses found were similar to those in previous research on MPU populations. CONCLUSION: Different medical disciplines have different views on the advantages of MPUs, while all see the need for such facilities. The proposed MPU should be able to accommodate patients directly from the Emergency Unit, and the MPU should provide specialized diagnostic care in an extra safe environment.

A randomized clinical trial comparing two two-phase treatment strategies for in-patients with severe depression.

OBJECTIVE: To compare the efficacy of two antidepressant treatment strategies in severely depressed in-patients, that is, imipramine vs. venlafaxine, both with subsequent lithium addition in non-responders. METHOD: In-patients (n = 88) with major depressive disorder were randomized to 7-week treatment with imipramine or venlafaxine (phase I). All non-responders (n = 44) received 4-week plasma level-targeted dose lithium addition (phase II). Efficacy was evaluated after 11 weeks of treatment. RESULTS: Analyzing phases I and II combined, non-inferiority was established and the difference in the proportion of responders (HAM-D score reduction ≥50%) by the end of phase II demonstrated the venlafaxine-lithium treatment strategy to be significantly superior to the imipramine-lithium treatment strategy (77% vs. 52%) (χ2 (1) = 6.03; P = 0.01). Regarding remission (HAM-D score ≤ 7), 15 of 44 (34%) patients in the imipramine-lithium treatment group were remitters compared to 22 of 44 (50%) patients in the venlafaxine-lithium treatment group, a non-significant difference. Patients in the venlafaxine-lithium treatment group had a non-significant larger mean HAM-D score reduction compared with patients in the imipramine-lithium treatment group (16.1 vs. 13.5 points, respectively; Cohen's d = 0.30). CONCLUSION: The venlafaxine-lithium treatment strategy can be considered a valuable alternative for the imipramine-lithium treatment strategy in the treatment of severely depressed in-patients.

A common polymorphism in the ABCB1 gene is associated with side effects of PGP-dependent antidepressants in a large naturalistic Dutch cohort.

The drug efflux transporter permeability glycoprotein (PGP) and cytochrome P450 (CYP) 2C19 are important for eliminating antidepressants from the brain and body. The ABCB1 gene, encoding for PGP, and CYP2C19 gene have several variants that could influence enzyme function and thereby the effect of PGP- and 2C19-dependent antidepressants. We investigated the association of antidepressant side effect and common genetic variation in 789 antidepressant users. In PGP-dependent antidepressant users, the A-allele of the rs2032588 single-nucleotide polymorphism (SNP) was associated with a lower number of side effects after adjusting for gender, age, dosage and duration of use, (B=-0.44, q=4.6 × 10(-3)). This association was different from and absent in non-PGP-dependent antidepressant users. Other SNP associations as well as an interaction analysis between the rs2032588 SNP and the CYP2C19 SNPs were not statistically significant after adjusting for covariates and multiple comparisons. The association of rs2032588 with antidepressant side effects suggests the involvement of the ABCB1 genotype in the clinical pharmacology of PGP-dependent antidepressants.

ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder.

P-glycoprotein (P-gp), an ATP-driven efflux pump in the blood-brain barrier, has a major impact on the delivery of antidepressant drugs in the brain. Genetic variants in the gene ABCB1 encoding for P-gp have inconsistently been associated with adverse effects. In order to resolve these inconsistencies, we conducted a study in a large cohort of patients with major depressive disorder with the aim to unravel the association of ABCB1 variants with adverse effects of antidepressants and in particular with selective serotonin reuptake inhibitors (SSRIs), which display affinity as substrate for P-gp. The Netherlands Study of Depression and Anxiety (NESDA) study was used as a clinical sample. For 424 patients data were available on drug use, side effects. We selected six ABCB1 gene variants (1236T>C, 2677G>T/A, 3435T>C, rs2032583, rs2235040 and rs2235015) and analyzed them for association with adverse drug effects using multinomial regression analysis for both single variants and haplotypes. We found a significant association between the number of SSRI-related adverse drug effects and rs2032583 (P=0.001), rs2235040 (P=0.002) and a haplotype (P=0.002). Moreover, serotonergic effects (sleeplessness, gastrointestinal complaints and sexual effects) were significantly predicted by these variants and haplotype (P=0.002/0.003). We conclude that adverse drug effects with SSRI treatment, in particular serotonergic effects, are predicted by two common polymorphisms of the ABCB1 gene.

Associations between the urban environment and psychotic experiences in adolescents.

OBJECTIVE: In 2050 two-thirds of the world's population is predicted to live in cities, which asks for a better understanding of how the urban environment affects mental health. Urbanicity has repeatedly been found to be a risk factor, in particular for psychosis. Here, we explored what factors of the urban exposome underlie the association between urban characteristics and psychotic experiences (PE) in adolescents. METHODS: Participants were 815 adolescents (mean age 14.84 years, SD 0.78) from an at-risk cohort (greater Rotterdam area, the Netherlands) oversampled on their self-reported emotional and behavioral problems. We used linear regression analysis to examine the association with detailed geodata on urbanicity (surrounding address density), green space density (high and low vegetation), and mixed noise levels (road, rail, air, industry, and wind power) with PE in adolescents. Analyses were adjusted for multiple socio-economic and parental confounders. Furthermore, we explored sex-interaction effects. RESULTS: Higher surrounding address density and low greenspace density were each independently associated with more PE (B = 0.18, 95 % CI 0.02; 0.34 and B = 0.17, 95 % CI 0.01; 0.32, respectively). High mixed noise levels were only associated with more PE in boys (B = 0.23, 95 % CI 0.01; 0.46). A sex-interaction effect was found for high urbanicity (B = -0.46, 95 % CI -0.77; -0.14) and low greenspace density (B = -0.49, 95 % CI -0.73; -0.11), illustrating that these associations with PE were specific for boys. CONCLUSION: Multiple characteristics of living in an urban area are associated with more PE in adolescent boys. Our observations provide leads for prevention of mental health problems via urban designing.

Poor replication of candidate genes for major depressive disorder using genome-wide association data.

Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

[Chronotherapy for affective disorders]. / Chronotherapie bij stemmingsstoornissen.

BACKGROUND: In the literature there is increasing interest in the chronobiology of affective disorders and in the most important chronotherapies for treating these disorders. AIM: To discuss the background to and the main features of the most important therapies for affective disorders. METHOD: Using PubMed, we performed a concise review of the literature on the use of chronotherapeutics in affective disorders and we also studied the standard textbooks on the subject. RESULTS: Light therapy is the type of chronotherapy that has been studied most. Chronotherapies show interesting and promising results in open label studies, but so far there have been no randomized double-blind placebo controlled trials. CONCLUSION: Chronotherapeutics provides a neurobiological model and a series of promising, possibly effective non-pharmacological therapies, particularly for affective disorders. Light therapy deserves to be included in the multidisciplinary treatment guidelines relating to affective disorders. However, more, better and longer trials are needed in order to evaluate the various types of chronotherapies.

[Behavioural standard or coercive measure? Some considerations regarding the special issue on ROM]. / ROM: gedragsnorm of dwangmaatregel? Overwegingen bij het themanummer over routine outcome monitoring.

BACKGROUND: The cost of mental health care has possibly risen more than costs in other sectors of health care in the Netherlands. In an attempt to control the rising costs, new policies have been implemented that include the introduction of selective financial penalties for those in need of mental health care as well as the start of performance-based mental health care reimbursement. In order to achieve the latter goal, a nation-wide large-scale data collection was introduced based on clinical routine outcome monitoring (ROM) data, with a view to using these data for benchmarking. AIM: Closer inspection of the benchmarking efforts in terms of scientific validity. METHOD: Qualitative review and analysis. RESULTS: Analysis shows that the type of ROM data that is collected in the Netherlands is valid for tracking the outcomes of individual patients, but unsuitable for performance comparisons between institutions for reasons of case-mix, instrument-mix, bias and lack of sensitivity. CONCLUSION: Attempts to introduce benchmarking based on rom will probably have a negative impact on the practice of mental health care in the Netherlands. More input from mental health professionals and scientists is required in order to identify more rational and efficient ways of spending scarce resources.

Moving Beyond the Status Quo of Integrated Inpatient Medical and Psychiatric Care Units: The Path to Real-World Evaluation.

Integrated inpatient medical and psychiatric care units (IMPUs) are hospital wards that care for inpatients with both acute general medical and psychiatric disorders. IMPU development has stalled, and wide variation in IMPU designs may reflect the fact that IMPUs are still in an early evolutionary stage. High-quality evidence concerning the costs and effectiveness of IMPUs is sparse, because IMPUs do not lend themselves well to traditional evidence-based medicine methods. As a result, most studies of IMPUs have been only observational. Therefore, it is time for a different approach, in which goals for IMPUs are explicitly formulated and IMPU research is incorporated into evidence-based practice (EBP) instead of evidence-based medicine. EBP can be viewed as integrating best available evidence into organizational practices by using four pillars of evidence: organizational, experiential, stakeholder, and scientific. Such types of evidence require an investment in describing the field more precisely. When pragmatic reasoning, where clinical expertise and organizational needs determine IMPU designs, is replaced with EBP, researchers can more effectively perform studies that may convince health care policy makers that IMPUs represent a cost-effective way to improve patients' health and that they increase the well-being of both patients and hospital staff.

DEcrease STress through RESilience training for Students (DESTRESS) Study: Protocol for a randomized controlled trial nested in a longitudinal observational cohort study.

INTRODUCTION: Chronic stress and burnout are highly prevalent among academically trained healthcare professionals, negatively affecting their well-being and capacity to engage in their work. Resilience to stress develops early in one's career path, hence offering resilience training to university students in these professions is one approach to fostering well-being and mental health. The aim of this study is to assess whether offering mindfulness-based resilience training to university students in healthcare professions reduces their perceived chronic stress. METHODS AND ANALYSIS: The study has a hybrid design combining a longitudinal observational cohort with a nested randomized controlled trial (RCT) with sequential multiple assignment and multistage adaptive interventions while taking participants' preferences into account. All students in healthcare related programmes at the Erasmus University Rotterdam are invited to participate. Within the observational cohort, students with a score of 14 or higher on the Perceived Stress Scale (PSS) are invited to take part in the RCT (n = 706). Eligible participants are randomized to control or active intervention in a ratio of 1:6. Those randomized to the control group and non-randomized participants in the cohort receive passive web-based psychoeducation about chronic stress and burnout through referral to specific websites. Participants randomized to the intervention group receive one of 8 active mindfulness-based interventions. They select a rank order of 4 preferred interventions and are randomized across these with equal probability. Non-response to the intervention is followed by sequential randomized assignment to another intervention, for a total maximum of 3 sequential interventions. All participants receive questionnaires at baseline, before and after each 8-week intervention period, and at 1- and 2-year follow-up. The primary outcome is perceived chronic stress measured with the PSS. Secondary outcomes include mental well-being, burnout, quality of life, healthcare utilization, drug use, bodyweight, mental and physical stress-related symptoms, resilience, and study progress. ETHICS AND REGISTRATION: Approval from the Medical Ethics Review Committee was obtained under protocol number MEC-2018-1645. The trial is registered in the Netherlands National Trial Register by registration number NL7623, 22/03/2019, https://www.trialregister.nl/.

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment.

Major depressive disorder is a chronic disabling disease, often triggered and exacerbated by stressors of a social nature. Hippocampal volume reductions have been reported in depressed patients. In support of the neurogenesis theory of depression, in several stress-based animal models of depression, adult hippocampal neurogenesis was reduced and subsequently rescued by parallel antidepressant treatment. Here, we investigated whether repeated social defeat and subsequent individual housing for 3 months induces long-lasting changes in adult hippocampal neurogenesis in rats, and whether these can be normalized by late antidepressant treatment, as would match human depression. Neurogenesis was analysed by stereological quantification of the number of immature doublecortin (DCX)-immunopositive cells, in particular young (class I) and more mature (class II) DCX(+) cells, to distinguish differential effects of stress or drug treatment on these subpopulations. Using this social defeat paradigm, the total DCX(+) cell number was significantly reduced. This was most profound for older (class II) DCX(+) cells with long apical dendrites, whereas younger, class I cells remained unaffected. Treatment with the broad-acting tricyclic antidepressant imipramine, only during the last 3 weeks of the 3-month period after social defeat, completely restored the reduction in neurogenesis by increasing both class I and II DCX(+) cell populations. We conclude that despite the lack of elevated corticosterone plasma levels, neurogenesis is affected in a lasting manner by a decline in a distinct neuronal population of more mature newborn cells. Thus, the neurogenic deficit induced by this social defeat paradigm is long-lasting, but can still be normalized by late imipramine treatment.

Policy and Practice Review: A First Guideline on the Use of Pharmacogenetics in Clinical Psychiatric Practice.

Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

Differential frontal-striatal and paralimbic activity during reversal learning in major depressive disorder and obsessive-compulsive disorder.

BACKGROUND: Several lines of research suggest a disturbance of reversal learning (reward and punishment processing, and affective switching) in patients with major depressive disorder (MDD). Obsessive-compulsive disorder (OCD) is also characterized by abnormal reversal learning, and is often co-morbid with MDD. However, neurobiological distinctions between the disorders are unclear. Functional neuroimaging (activation) studies comparing MDD and OCD directly are lacking. METHOD: Twenty non-medicated OCD-free patients with MDD, 20 non-medicated MDD-free patients with OCD, and 27 healthy controls performed a self-paced reversal learning task in an event-related design during functional magnetic resonance imaging (fMRI). RESULTS: Compared with healthy controls, both MDD and OCD patients displayed prolonged mean reaction times (RTs) but normal accuracy. In MDD subjects, mean RTs were correlated with disease severity. Imaging results showed MDD-specific hyperactivity in the anterior insula during punishment processing and in the putamen during reward processing. Moreover, blood oxygen level-dependent (BOLD) responses in the dorsolateral prefrontal cortex (DLPFC) and the anterior PFC during affective switching showed a linear decrease across controls, MDD and OCD. Finally, the OCD group showed blunted responsiveness of the orbitofrontal (OFC)-striatal loop during reward, and in the OFC and anterior insula during affective switching. CONCLUSIONS: This study shows frontal-striatal and (para)limbic functional abnormalities during reversal learning in MDD, in the context of generic psychomotor slowing. These data converge with currently influential models on the neuropathophysiology of MDD. Moreover, this study reports differential neural patterns in frontal-striatal and paralimbic structures on this task between MDD and OCD, confirming previous findings regarding the neural correlates of deficient reversal learning in OCD.

Prenatal maternal psychopathology and stress and offspring HPA axis function at 6 years.

OBJECTIVE: Intrauterine exposures such as maternal psychopathology and stress are known to influence the physical and mental health of the offspring. One of the proposed pathways underlying these associations is dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity in the offspring. This study examined the relation of perinatal maternal symptoms of psychopathology and stress with offspring HPA axis activity at 6 years as measured by hair cortisol and cortisone concentrations. METHODS: The study was part of the population-based Generation R Study, a prospective population-based cohort from fetal life onwards. 2546 children and their mothers formed the study population. Perinatal maternal psychopathology and stress were assessed by questionnaires in the second and third trimester. Principal components for both psychopathology and stress were created to reduce the number of explanatory variables. Child hair samples for cortisol and cortisone measurements were collected at the age of 6. Linear regression analysis, adjusted for covariates, was used to examine associations between maternal psychopathology and stress and child hair cortisol and cortisone levels. RESULTS: The maternal psychopathology principal component was associated with higher child hair cortisone (adjusted B = 0.24, 95%CI 0.08;0.40, p-value < 0.01). Effect estimates of the individual dimensions ranged from 0.97 (95%CI 0.21;1.73, p-value = 0.01) for interpersonal sensitivity to 1.67 (95%CI 0.86;2.47, p-value < 0.01) for paranoid ideation. In addition, children exposed to intrauterine stress, as measured by the principal component, had higher hair cortisone levels (adjusted B = 0.54, 95%CI 0.21;0.88, p-value < 0.01). Exposure to maternal psychopathology and stress was not associated with offspring hair cortisol. Stratification by child sex resulted in associations between maternal symptoms of psychopathology during pregnancy and child hair cortisone levels in boys and associations between maternal symptoms of stress during pregnancy and child hair cortisone levels in girls. CONCLUSION: Our results suggest that maternal psychopathology and stress during pregnancy are associated with long-term HPA axis activity of the offspring. The association of maternal psychopathology and stress during pregnancy with offspring hair cortisone levels is a novel finding. Future studies should examine whether these psychophysiological differences between exposed and non-exposed children underlie offspring morbidity associated with maternal psychopathology and stress during pregnancy.