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Background: Psychopathology has been long recognized as a fluctuating process with various expressions over time, which can only be properly understood if we follow individuals and their social context from childhood up until adulthood. Longitudinal population-based studies have yielded powerful data to analyze this process. However, the resulting publications have not been reflected upon with regard to (a) the homotypic and heterotypic stability of internalizing and externalizing problems and (b) how transactions between psychopathology and environmental factors shape its development. Methods: In this narrative review, we primarily focused on population-based studies that followed cohorts repeatedly from an early age (

The social defeat hypothesis of schizophrenia, which proposes that the chronic experience of outsider status or subordinate position leads to increased striatal dopamine activity and thereby to increased risk, has been criticized. The aims of this paper are to improve the definition of defeat and to integrate the social defeat hypothesis with the neurodevelopmental hypothesis. Marmot advanced the idea that low status is pathogenic in that it is associated with a lack of social participation and a lack of autonomy. Given the similarity with outsider status and subordinate position, we re-define social defeat as low status. From this new perspective it is also likely that pre-schizophrenic impairments (of neurodevelopmental origin or not) are pathogenic in that they contribute to low status. The effect of low status may be enhanced by repeated exposure to humiliation, but few studies have measured this variable. Since most individuals exposed to low status do not develop schizophrenia, we propose that this risk factor increases the risk of disorder in the presence of a poor homeostatic control of dopamine neurons in midbrain and dorsal striatum. This is consistent with studies of healthy subjects which report a negative association between low socio-economic status and dopamine D2/D3 receptor availability in the dorsal striatum. In this new version of the social defeat hypothesis we propose that the combination of low status, repeated humiliation and poor homeostatic control of dopamine neurons in midbrain and dorsal striatum leads to increased striatal dopamine activity and thereby to an increased risk of schizophrenia.

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level'' dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity'' by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach. (C) 2020 Published by Elsevier Masson SAS.

Author(s): Hopwood, Christopher J; Krueger, Robert F; Watson, David; Widiger, Thomas A; Althoff, Robert R; Ansell, Emily B; Bach, Bo; Bagby, R Michael; Blais, Mark A; Bornovalova, Marina A; Chmielewski, Michael; Cicero, David C; Conway, Christopher; De Clerq, Barbara; De Fruyt, Filip; Docherty, Anna R; Eaton, Nicholas R; Edens, John F; Forbes, Miriam K; Forbush, Kelsie T; Hengartner, Michael P; Ivanova, Masha Y; Leising, Daniel; Lukowitsky, Mark R; Lynam, Donald R; Markon, Kristian E; Miller, Joshua D; Morey, Leslie C; Mullins-Sweatt, Stephanie N; Ormel, Johan; Patrick, Christopher J; Pincus, Aaron L; Ruggero, Camilo; Samuel, Douglas B; Sellbom, Martin; Tackett, Jennifer L; Thomas, Katherine M; Trull, Timothy J; Vachon, David D; Waldman, Irwin D; Waszczuk, Monika A; Waugh, Mark H; Wright, Aidan GC; Yalch, Mathew M; Zald, David H; Zimmermann, Johannes

Few investigations have directly compared personality and internalizing symptoms stability within the same sample and have not included personality facets. This study examined rank-order stability and mean-level change of Big Five domains, facets of neuroticism and extraversion, and internalizing symptoms in a sample of 550 adolescent females. Personality and symptoms were assessed every nine months for three years. Three year rankorder stability was higher for personality domains and facets compared to symptoms. Notable exceptions included lower stability of depressivity and positive emotionality facets. Facets and symptoms showed similar mean level change. Overall, we observed modest and variable temporal differences between symptoms and traits; symptoms exhibited high rank-order stability and low mean-level change, but domains and facets were generally more stable.

This study tested two opposing hypotheses on the continuity of psychopathology throughout adolescence and young adulthood; differentiation versus dynamic mutualism. Differentiation predicts that co-occurrence decreases, while dynamic mutualism predicts that co-occurrence increases due to causal interactions amongst mental health problems.Using data from the Dutch TRacking Adolescents' Individual Lives Survey (n = 2228, 51% female), we studied the development of self-reported internalizing, externalizing, and attention problems at ages 11 to 26 across six waves. Random-intercept cross-lagged panel modeling was employed to distinguish within-person development from stable between-person processes.Large stable between-person associations indicated that adolescents with internalizing problems tended to have both externalizing and attention problems as well. On a within-person level, mental health problems showed partial stability and strong cross-sectional co-occurrence. Within-wave associations of internalizing with externalizing or attention problems decreased between age 11 and 16 years, after which they increased again. Little heterotypic continuity was found: age 11 externalizing predicted age 13 attention, which in turn predicted age 16 externalizing problems, and internalizing predicted externalizing problems across ages 22 to 26. Findings were similar for males and females.Our findings suggest co-occurrence decreases during early and middle adolescence, supporting differentiation. While co-occurrence increased again into young adulthood, this could not be labeled as dynamic mutualism because little evidence for heterotypic continuity was found in this phase of life. The strong stable links between internalizing, externalizing, and attention problems stress the importance of targeting these mental health problems and their shared risk factors together.

Treatments for depression have improved, and their availability has markedly increased since the 1980s. Mysteriously the general population prevalence of depression has not decreased. This “treatment-prevalence paradox” (TPP) raises fundamental questions about the diagnosis and treatment of depression. We propose and evaluate seven explanations for the TPP. First, two explanations assume that improved and more widely available treatments have reduced prevalence, but that the reduction has been offset by an increase in: 1) misdiagnosing distress as depression, yielding more “false positive” diagnoses; or 2) an actual increase in depression incidence. Second, the remaining five explanations assume prevalence has not decreased, but suggest that: 3) treatments are less efficacious and 4) less enduring than the literature suggests; 5) trial efficacy doesn't generalize to real-world settings; 6) population-level treatment impact differs for chronic-recurrent versus non-recurrent cases; and 7) treatments have some iatrogenic consequences. Any of these seven explanations could undermine treatment impact on prevalence, thereby helping to explain the TPP. Our analysis reveals that there is little evidence that incidence or prevalence have increased as a result of error or fact (Explanations 1 and 2), and strong evidence that (a) the published literature overestimates short- and long-term treatment efficacy, (b) treatments are considerably less effective as deployed in “real world” settings, and (c) treatment impact differs substantially for chronic-recurrent cases relative to non-recurrent cases. Collectively, these a-c explanations likely account for most of the TPP. Lastly, little research exists on iatrogenic effects of current treatments (Explanation 7), but further exploration is critical.

BackgroundPerinatal depression and anxiety are associated with unfavourable child outcomes.AimsTo assess among women with antenatal depression or anxiety the effectiveness of prenatally initiated cognitive–behavioural therapy (CBT) on mother and child compared with care as usual (CAU). Trial registration: Netherlands Trial Register number NTR2242.MethodPregnant women (n= 282) who screened positive for symptoms of depression and/or anxiety were randomised to either CBT (n= 140) or CAU (n= 142). The primary outcome was child behavioural and emotional problems at age 18 months, assessed using the Child Behavior Checklist (CBCL). Secondary outcomes were maternal symptoms during and up to 18 months after pregnancy, neonatal outcomes, mother–infant bonding and child cognitive and motor development at age 18 months.ResultsIn total, 94 (67%) women in the CBT group and 98 (69%) in the CAU group completed the study. The mean CBCL Total Problems score was non-significantly higher in the CBT group than in the CAU group (mean difference: 1.38 (95% CI −1.82 to 4.57);t= 0.85,P= 0.399). No effects on secondary outcomes were observed except for depression and anxiety, which were higher in the CBT group than in the CAU group at mid-pregnancy. Apost hocanalysis of the 98 women with anxiety disorders showed lower infant gestational age at delivery in the CBT than in the CAU group.ConclusionsPrenatally initiated CBT did not improve maternal symptoms or child outcomes among non-help-seeking women with antenatal depression or anxiety. Our findings are not in line with present recommendations for universal screening and treatment for antenatal depression or anxiety, and future work may include the relevance of baseline help-seeking.

Large increases in treatment of Common Mental Disorders (CMD) have failed to reduce population prevalence and global burden. Preventive strategies are needed to lower CMD prevalence and burden. Giving prevention a real chance to prove its promise will require: (a) full embedment in social institutions; (b) long-term structural funding; (c) targeting major CMD determinants early in life combining population-level and individual-level strategies; and, (d) integrated evaluation of short-term and long-term effects to guide implementation. Targeting life skills and resilience of children and parenting skills of their parents has the potential for long-term benefits for multiple outcomes including well-being, social, economic, and financial domains as well as mental health outcomes. However, the large investments may not occur without compelling proof of effectiveness, but evaluation of effectiveness cannot occur without long-term, structural investments. Overcoming this impasse requires a paradigm shift. Randomized controlled trials of initial efficacy need to be supplemented by evaluation strategies for long-term surveillance of community-based programs that guide implementation while assessing long-term effectiveness.

BACKGROUND: Mental health problems during adolescence may create a problematic start into adulthood for affected individuals. Usually, categorical indicators of adolescent mental health issues (yes/no psychiatric disorder) are used in studies into long-term functional outcomes. This however does not take into account the full spectrum of mental health, nor does it consider the trajectory of mental health problem development over time. The aim of this study was twofold: (1) to identify distinct developmental trajectories of (co-occurring) internalizing and externalizing mental health symptoms over the course of adolescence (ages 11-19), and (2) to document the associations between these adolescent trajectories and economic, social, and health outcomes in young adulthood (age 22), unadjusted and adjusted for childhood functioning, putative confounders and current mental health.METHODS: Data were used from the Dutch TRAILS cohort study (subsample n = 1524, 47.3% males). Self-reported INT and EXT symptoms using the Youth/Adult Self Report were assessed four times (ages 11y, 13y, 16y, 19y). Adolescent mental health trajectories were estimated using Parallel-Processes Latent Class Growth Analyses. Self-reported economic, social, and health outcomes and parent-reported current mental health (using Adult Behaviour Checklist) were assessed at age 22. Multiple logistic regression analyses were performed to test associations between trajectories and outcomes.RESULTS: Four distinct trajectory classes were identified: (1) a normative class with decreasing-low INT+EXT symptoms (n = 460), (2) continuous moderately-high INT+EXT (n = 298), (3) continuous moderate, INT>EXT (n = 414), and (4) decreasing moderate, EXT>INT (n = 352). Compared to the normative class, the other three trajectories generally predicted less optimal early-adult outcomes, with the strongest effects observed for individuals with continuous moderate-high levels of both INT and EXT symptoms throughout adolescence. The associations largely remained after adjustment for pre-adolescent functioning, selected confounders and current mental health.CONCLUSIONS: Both adolescent trajectories and current mental health had substantial independent effects on early-adult functioning.

Despite substantial investments in the treatment of major depressive disorder (hereafter ‘depression’), especially antidepressant medications and cognitive behavioral therapy, epidemiological data do not indicate that depression burden, as measured by the period prevalence, has decreased in recent decades. Although improving the delivery and quality of treatment will undoubtedly reduce episode duration and recurrence risk, and thereby reduce depression burden, the effect is probably limited because treatment does not always improve long-term outcomes. To further reduce the burden, prevention of depression episodes is crucial. Unfortunately, so far preventive efforts have not succeeded in reducing depression burden either. This, we argue, arises from a lack of socially-embedded structural prevention efforts and the difficulty of reducing the impact of major determinants. First we summarize the evidence on period prevalence and treatment trends and the limitations of current prevention strategies that have hampered both their effectiveness and large-scale implementation. Then we analyze the modifiability of major determinants of depression and identify the prerequisites for effective prevention to reduce depression burden and explain their importance. Prerequisites include embedment in major social institutions, structural funding, legal consolidation, starting early in life, simultaneous targeting of major personal and environmental determinants and their interactions. This includes addressing both poor parenting and children's maladaptive personality traits and insufficient life skills, and combining universal, selective, and indicated prevention strategies with an emphasis on universal prevention. Although it is necessary to determine the feasibility and cost-effectiveness of the proposed prevention strategy, we think that without it, the depression epidemic will not subside.

Despite major expansions of evidence-based treatments of common mental disorders in recent decades, especially antidepressant medication, the point prevalence of depression has not decreased; instead it probably increased in young adults. We question whether antidepressants (AD)-monotherapy and low-fidelity-to-guideline psychological treatment (PT) might have no effect or even adverse effects in some patients and contexts that dilute the benefits of treatment at the population level, making it harder for population-based studies to detect treatment-driven prevalence reductions. Randomized Clinical Trial (RCT)s have not identified these effects because AD-monotherapy and low-fidelity PT are uncommon in RCTs where treatment protocols are specified and carefully monitored, unlike treatment in real-world settings. Second, RCTs may have missed the bigger picture of ultimate outcomes due to too short follow-ups. We elaborate two mechanisms through which AD-monotherapy and low-fidelity PT could produce adverse effects on long-term illness course. Both mechanisms are speculative and we outline how to test.

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level'' dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity'' by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach. (C) 2020 Published by Elsevier Masson SAS.

BackgroundResearch in depression has progressed rapidly over the past four decades. Yet depression rates are not subsiding and treatment success is not improving. We examine the extent to which the gap between science and practice is associated with the level of integration in how depression is considered in research and stakeholder-relevant documents.MethodsWe used a network-science perspective to analyze similar uses of depression relevant terms in the Google News corpus (approximately 1 billion words) and the Web of Science database (120 000 documents).ResultsThese analyses yielded consistent pictures of insular modules associated with: (1) patient/providers, (2) academics, and (3) industry. Within academia insular modules associated with psychology, general medical, and psychiatry/neuroscience/biology were also detected.ConclusionsThese analyses suggest that the domain of depression is fragmented, and that advancements of relevance to one stakeholder group (academics, industry, or patients) may not translate to the others. We consider potential causes and associated responses to this fragmentation that could help to unify and advance translation from research on depression to the clinic, largely involving harmonizing employed language, bridging conceptual domains, and increasing communication across stakeholder groups.

BackgroundAntidepressant medications (ADMs) are widely used and long-term use is increasing. Given this extensive use and recommendation of ADMs in guidelines, one would expect ADMs to be universally considered effective. Surprisingly, that is not the case; fierce debate on their benefits and harms continues. This editorial seeks to understand why the controversy continues and how consensus can be achieved.Methods‘Position’ paper. Critical analysis and synthesis of relevant literature.ResultsAdvocates point at ADMs impressive effect size (number needed to treat, NNT = 6–8) in acute phase treatment and continuation/maintenance ADM treatment prevention relapse/recurrence in acute phase ADM responders (NNT = 3–4). Critics point at the limited clinically significant surplus value of ADMs relative to placebo and argue that effectiveness is overstated. We identified multiple factors that fuel the controversy: certainty of evidence is low to moderate; modest efficacy on top of strong placebo effects allows critics to focus on small net efficacy and advocates on large gross efficacy; ADM withdrawal symptoms masquerade as relapse/recurrence; lack of association between ADM treatment and long-term outcome in observational databases. Similar problems affect psychological treatments as well, but less so. We recommend four approaches to resolve the controversy: (1) placebo-controlled trials with relevant long-term outcome assessments, (2) inventive analyses of observational databases, (3) patient cohort studies including effect moderators to improve personalized treatment, and (4) psychological treatments as universal first-line treatment step.ConclusionsGiven the public health significance of depression and increased long-term ADM usage, new approaches are needed to resolve the controversy.

Psychische stoornissen beginnen vaak in de kindertijd of de adolescentie. Dit kan leiden tot een slechte start van het volwassen leven. Deze studie onderzocht de voorspellende waarde van de huidige en vroegere geestelijke gezondheid voor het functioneren van jongvolwassenen op economisch, sociaal en psychologisch gebied en voor het gezondheidsgedrag, verder aangegeven als functionele uitkomsten. Bij 1.584 jongeren die vanaf de preadolescentie (11 jaar) tot in de volwassenheid worden gevolgd (deelnemers aan het TRAILS-onderzoek), werd op 19-jarige leeftijd de Composite International Diagnostic Interview (CIDI) afgenomen om de aanwezigheid van huidige en vroegere psychische stoornissen volgens CIDI-DSM-IV te meten. Tevens werden 19 functionele uitkomsten in vier domeinen (economisch, sociaal, psychologisch en gezondheidsgedrag) gemeten. Veertien uitkomsten werden voorspeld door zowel huidige als vroegere stoornissen, drie alleen door vroegere stoornissen en twee alleen door huidige stoornissen. Welk type stoornis de belangrijkste voorspeller was, hing af van de uitkomst; vroegere internaliserende stoornissen voorspelden vooral psychologische uitkomsten, maar vroegere externaliserende stoornissen vooral gezondheidsgedrag. Een geschiedenis van comorbiditeit voorspelde economische en sociale uitkomsten. Om het functioneren van 19-jarigen te begrijpen, is het nodig om zowel de huidige als vroegere geestelijke gezondheid te onderzoeken.

From the literature it is not clear whether low resting heart rate (HR) reflects low or high sensitivity to the detrimental effects of adverse environments on externalizing problems. We studied parental psychiatric history (PH), reflecting general vulnerability, as possible moderator explaining these inconsistencies. Using Linear Mixed Models, we analyzed data from 1914 subjects, obtained in three measurement waves (mean age 11, 13.5, and 16 years) from the TRacking Adolescents’ Individual Lives Survey population-based cohort and the parallel clinic-referred cohort. As hypothesized, more chronic stressors predicted more externalizing problems in vulnerable individuals with high resting HR but not in those with low resting HR, suggesting high vs. low sensitivity, respectively, to adverse environmental influences. Low sensitivity to adverse environmental influences in vulnerable individuals exposed to high stressor levels was additionally confirmed by high heart rate variability (Root Mean Squared Successive Difference; RMSSD). In adolescents with low vulnerability, in contrast, the association between chronic stressors and externalizing problems did not substantially differ by resting HR and RMSSD. Future research may demonstrate whether our findings extend to other adverse, or beneficial, influences. Notwithstanding their theoretical interest, the effects were small, only pertained to parent-reported externalizing problems, refer to a small subset of respondents in our sample, and are in need of replication. We conclude that HR and RMSSD are unlikely to be strong moderators of the association between stressors and externalizing problems.

The hypothalamic-pituitary-adrenal (HPA) axis has been proposed to be a key mechanism underlying the link between adversity and mental health, but longitudinal studies on adversity and HPA-axis functioning are scarce. Here, we studied adversity-driven changes in HPA-axis functioning during adolescence (N = 141). HPA-axis functioning (basal cortisol, cortisol awakening response, anticipation of, reaction to and recovery after a stress task) was measured twice, at age 16 and 19. Adversity (i.e., social defeat and loss/illness) since age 16 was measured extensively with the Life Stress Interview at age 19. Adolescents who reported being exposed to social defeat showed increases in basal cortisol (eta(2) = 0.029) and decreases in reaction to the stress task (eta(2) = 0.030) from age 16-19, compared to their peers in the loss/illness and no stress group. The current study provides unique longitudinal data on the role of adversity in HPA-axis functioning. Evidence is provided that adversity can affect the body's neuroendocrine response to stress, dependent on the nature of both the HPA-measures and adverse events under study.

The reliability and validity of traditional taxonomies are limited by arbitrary boundaries between psychopathology and normality, often unclear boundaries between disorders, frequent disorder co-occurrence, heterogeneity within disorders, and diagnostic instability. These taxonomies went beyond evidence available on the structure of psychopathology and were shaped by a variety of other considerations, which may explain the aforementioned shortcomings. The Hierarchical Taxonomy Of Psychopathology (HiTOP) model has emerged as a research effort to address these problems. It constructs psychopathological syndromes and their components/subtypes based on the observed covariation of symptoms, grouping related symptoms together and thus reducing heterogeneity. It also combines co-occurring syndromes into spectra, thereby mapping out comorbidity. Moreover, it characterizes these phenomena dimensionally, which addresses boundary problems and diagnostic instability. Here, we review the development of the HiTOP and the relevant evidence. The new classification already covers most forms of psychopathology. Dimensional measures have been developed to assess many of the identified components, syndromes, and spectra. Several domains of this model are ready for clinical and research applications. The HiTOP promises to improve research and clinical practice by addressing the aforementioned shortcomings of traditional nosologies. It also provides an effective way to summarize and convey information on risk factors, etiology, pathophysiology, phenomenology, illness course, and treatment response. This can greatly improve the utility of the diagnosis of mental disorders. The new classification remains a work in progress. However, it is developing rapidly and is poised to advance mental health research and care significantly as the relevant science matures. (PsycINFO Database Record

Adolescents’ temperamental frustration is a developmental precursor of adult neuroticism and psychopathology. Because the mechanisms that underlie the prospective association between adolescents’ high frustration and psychopathology (internalizing/externalizing) have not been studied extensively, we quantified three pathways: stress generation [mediation via selection/evocation of stressful life events (SLEs)], cross–sectional frustration–psychopathology overlap (‘carry–over’/common causes), and a direct (non–mediated) vulnerability effect of frustration, including moderation of SLE impact. Frustration and psychopathology were assessed at age 16 with the Early Adolescent Temperament Questionnaire and the Youth Self–Report. No gender differences in frustration were observed. At age 19, psychopathology was reassessed by using the Adult Self–Report, while occurrence of endogenous (self–generated) and exogenous (not self–generated) SLEs during the interval (ages 16–19) were ascertained with the Life Stress Interview, an investigator–based contextual–stressfulness rating procedure (N = 957). Half of the prospective effect of frustration on psychopathology was explained by baseline overlap, including effects of ‘carry–over’ and common causes, about 5% reflected stress generation (a ‘vicious’ cycle with the environment adolescents navigate and shape), and 45% reflected unmediated association: a direct vulnerability effect including stress sensitivity or moderation of SLE impact. After adjustment for their overlap, frustration predicted the development of externalizing but not internalizing symptoms. Copyright © 2016 European Association of Personality Psychology

PURPOSE OF REVIEW: Since the 70s, treatment of depression, especially pharmacologically, has expanded enormously. However, epidemiological studies show that 12-month population prevalence rates have not dropped. This observation raises multiple questions. How good are treatments of depression actually? Do they improve long-term outcomes? Have the treatment gaps narrowed? And how can we make mental healthcare more effective at the population level?RECENT FINDINGS: Recent publications suggest some answers. Controlled treatment trials show that effectiveness of specific treatments (pharmacological, psychological) is modest and probably overestimated owing to substantial spontaneous recovery and nonspecific therapeutic effects. Treatment gaps are still substantial and prevention has unclear long-term effects and is not structurally embedded. Future relevance of genetic information for better personalized treatment is potentially high but uncertain. Increasingly, the potential of treatment to improve long-term outcome is being questioned.SUMMARY: To reduce prevalence, it is essential to narrow the treatment gaps, provide timely interventions and high-quality treatment, eradicate waiting lists, prescribe antidepressants more cautiously and better managed, consider psychological alternatives, and provide more psychosocial treatment in primary care with physician-assistants. In addition, research is needed on long-term outcome of different treatment modalities, and least but not last the value of structurally socially embedded preventive interventions.

The recent successful genome-wide association studies (GWASs) for depression have yielded more than 80 replicated loci and brought back the excitement that had evaporated during the years of negative GWAS findings. The identified loci provide anchors to explore their relevance for depression, but this comes with new challenges. Using the watershed model of genotype–phenotype relationships as a conceptual aid and recent genetic findings on other complex phenotypes, we discuss why it took so long and identify seven future challenges. The biggest challenge involves the identification of causal mechanisms since GWAS associations merely flag genomic regions without a direct link to underlying biological function. Furthermore, the genetic association with the index phenotype may also be part of a more extensive causal pathway (e.g., from variant to comorbid condition) or be due to indirect influences via intermediate traits located in the causal pathways to the final outcome. This challenge is highly relevant for depression because even its narrow definition of major depressive disorder captures a heterogeneous set of phenotypes which are often measured by even more broadly defined operational definitions consisting of a few questions (minimal phenotyping). Here, Mendelian randomization and future discovery of additional genetic variants for depression and related phenotypes will be of great help. In addition, reduction of phenotypic heterogeneity may also be worthwhile. Other challenges include detecting rare variants, determining the genetic architecture of depression, closing the “heritability gap”, and realizing the potential for personalized treatment. Along the way, we identify pertinent open questions that, when addressed, will advance the field.

BackgroundAs depression has a recurrent course, relapse and recurrence prevention is essential.AimsIn our randomised controlled trial (registered with the Nederlands trial register, identifier: NTR1907), we found that adding preventive cognitive therapy (PCT) to maintenance antidepressants (PCT+AD) yielded substantial protective effects versus antidepressants only in individuals with recurrent depression. Antidepressants were not superior to PCT while tapering antidepressants (PCT/−AD). To inform decision-makers on treatment allocation, we present the corresponding cost-effectiveness, cost-utility and budget impact.MethodData were analysed (n = 289) using a societal perspective with 24-months of follow-up, with depression-free days and quality-adjusted life years (QALYs) as health outcomes. Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were derived to provide information about cost-effectiveness. The budget impact was examined with a health economic simulation model.ResultsMean total costs over 24 months were €6814, €10 264 and €13 282 for AD+PCT, antidepressants only and PCT/−AD, respectively. Compared with antidepressants only, PCT+AD resulted in significant improvements in depression-free days but not QALYs. Health gains did not significantly favour antidepressants only versus PCT/−AD. High probabilities were found that PCT+AD versus antidepressants only and antidepressants only versus PCT/−AD were dominant with low willingness-to-pay thresholds. The budget impact analysis showed decreased societal costs for PCT+AD versus antidepressants only and for antidepressants only versus PCT/−AD.ConclusionsAdding PCT to antidepressants is cost-effective over 24 months and PCT with guided tapering of antidepressants in long-term users might result in extra costs. Future studies examining costs and effects of antidepressants versus psychological interventions over a longer period may identify a break-even point where PCT/−AD will become cost-effective.Declaration of interestC.L.H.B. is co-editor ofPLOS Oneand receives no honorarium for this role. She is also co-developer of the Dutch multidisciplinary clinical guideline for anxiety and depression, for which she receives no remuneration. She is a member of the scientific advisory board of the National Insure Institute, for which she receives an honorarium, although this role has no direct relation to this study. C.L.H.B. has presented keynote addresses at conferences, such as the European Psychiatry Association and the European Conference Association, for which she sometimes receives an honorarium. She has presented clinical training workshops, some including a fee. She receives royalties from her books and co-edited books and she developed preventive cognitive therapy on the basis of the cognitive model of A. T. Beck. W.A.N. has received grants from the Netherlands Organisation for Health Research and Development and the European Union and honoraria and speakers' fees from Lundbeck and Aristo Pharma, and has served as a consultant for Daleco Pharma.

Neuroticism and genetic variation in the serotonin-transporter (SLC6A4) and catechol-O-methyltransferase (COMT) gene are risk factors for psychopathology. Alterations in the functional integration and segregation of neural circuits have recently been found in individuals scoring higher on neuroticism. The aim of the current study was to investigate how genetic risk factors impact functional network organization and whether genetic risk factors moderate the association between neuroticism and functional network organization. We applied graph theory analysis on resting-state fMRI data in a sample of 120 women selected based on their neuroticism score, and genotyped two polymorphisms: 5-HTTLPR (S-carriers and L-homozygotes) and COMT (rs4680-rs165599; COMT risk group and COMT non-risk group). For the 5-HTTLPR polymorphism, we found that subnetworks related to cognitive control show less connections with other subnetworks in S-carriers compared to L-homozygotes. The COMT polymorphism moderated the association between neuroticism and functional network organization. We found that neuroticism was associated with lower efficiency coefficients in visual and somatosensory-motor subnetworks in the COMT risk group compared to the COMT non-risk group. The findings of altered topology of specific subnetworks point to different cognitive-emotional processes that may be affected in relation to the genetic risk factors, concerning emotion regulation in S-carriers (5-HTTLPR) and emotional salience processing in COMT risk carriers. Electronic supplementary material The online version of this article (doi:10.1007/s11682-016-9626-2) contains supplementary material, which is available to authorized users.

Subject-specific and marginal models have been developed for the analysis of longitudinal ordinal data. Subject-specific models often lack a population-average interpretation of the model parameters due to the conditional formulation of random intercepts and slopes. Marginal models frequently lack an underlying distribution for ordinal data, in particular when generalized estimating equations are applied. To overcome these issues, latent variable models underneath the ordinal outcomes with a multivariate logistic distribution can be applied. In this article, we extend the work of O'Brien and Dunson (2004), who studied the multivariate t-distribution with marginal logistic distributions. We use maximum likelihood, instead of a Bayesian approach, and incorporated covariates in the correlation structure, in addition to the mean model. We compared our method with GEE and demonstrated that it performs better than GEE with respect to the fixed effect parameter estimation when the latent variables have an approximately elliptical distribution, and at least as good as GEE for other types of latent variable distributions.

Contains fulltext : 158700.pdf (Publisher’s version ) (Open Access) Although loss of pleasure (i.e., anhedonia) is one of the two core symptoms of depression, very little research has examined the relation between depressive symptoms and the experience of pleasure in daily life. This exploratory study in two population-based adolescent samples aimed to examine how depressive symptoms and anhedonia specifically were related to (1) the proportion and intensity of positive events, (2) mean and variability of positive affect (PA), (3) reactivity to positive events, and (4) reactivity to PA (i.e., whether PA elicits positive events). We used Experience Sampling to measure positive events and PA several times a day during 6 to 14 days in early (N = 284) and late (N = 74) adolescents. Results showed that depressive symptoms were related to a lower proportion and intensity of positive events, lower mean PA, and higher variability in PA regardless of sex and stage of adolescence. No clear evidence was found for differential reactivity to positive events or to PA. Anhedonia was not associated with most daily life experiences of pleasure. Our findings, though preliminary, suggest that although adolescents with many depressive symptoms experience less positive events and lower PA, they are able to enjoy pleasurable events to the same extent as individuals with fewer depressive symptoms. 11 p.

Behavioral-genetic studies show substantial non-genetic influences on variance of neuroticism within a population. Longitudinal studies show a small but steady drop in test-retest correlations with increasing time intervals. This suggest environmental effects on neuroticism, but a systematic overview of which environmental determinants account for change in neuroticism is lacking. We review (specific or unique) environmental influences that modify the neuroticism setpoint in adulthood and therewith individual life trajectories. Results are interpreted in light of the so-called ‘mixed model’ in which within-person changes in neuroticism are subdivided over short term perturbations around the setpoint of neuroticism versus more persistent changes in the setpoint itself. To account for genetic confounding and shared environmental influences studies of monozygotic (MZ) twin pairs discordant for neuroticism and longitudinal studies that report on environmental factors that predict within-individual change in neuroticism are reviewed. Our results indicate that the neuroticism setpoint is consistently touched by experiences that affect central aspects of one’s identity and status, mainly role transitions as partner (marriage/divorce) and employee (job loss/promotion). Especially interpersonal stress, conflict, and major events that were unpredictable, uncontrollable, unexpected, undesirable, and ‘off time’ from a life history perspective were followed by changes in neuroticism that persisted more than six months, which suggest setpoint change. Most change after severe SLEs persisted over a decade. Long-term and detailed studies are required to elucidate the details of the ‘mixed model’ of change in neuroticism. An understanding of the specifics of the events that lead to persistent changes in neuroticism may enable us to craft prevention strategies to tackle the vulnerability for mental disorders inherent in high neuroticism, rather than to wait for their manifestation.