Low status, humiliation, dopamine and risk of schizophrenia.

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.

Annual Research Review: Stability of psychopathology: lessons learned from longitudinal population surveys.

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 (<18 years) onwards, across multiple stages of development, using statistical methods that permit inferences about within-person bidirectional associations between internalizing and externalizing problems or psychopathology-environment transactions. RESULTS: There is robust evidence that mental health problems in childhood or adolescence predict psychiatric problems later in development. In terms of the broadband domains internalizing and externalizing problems, homotypic stability greatly exceeds heterotypic stability and transitions from purely internalizing to purely externalizing problems or vice versa are rare. Homotypic rank-order stabilities seem to increase over time. Findings regarding transactions with environmental factors are less robust, due to widely varying research topics and designs, and a scarcity of studies that separated between-person differences from within-person changes. In general, however, the literature shows little consistent evidence for substantial mutual prospective influences between psychopathology and environmental factors. CONCLUSIONS: Longitudinal surveys have strongly augmented insight into homotypic and heterotypic stability and change. Attempts to unravel the myriad of risk and protective factors that place individuals on particular pathways or deflect them from these pathways are still in a pioneering phase and have not yet generated robust findings. As a way forward, we propose to join forces and develop a common risk factor taxonomy.

Is personality stable and symptoms fleeting? A longitudinal comparison in adolescence.

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 rank-order 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.

Continuity of Psychopathology Throughout Adolescence and Young Adulthood.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

More treatment but no less depression: The treatment-prevalence paradox.

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.

Les progrès dans la réalisation de la classification quantitative de la psychopathologie.

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.

On Imbalance of Impulse Control and Sensation Seeking and Adolescent Risk: An Intra-individual Developmental Test of the Dual Systems and Maturational Imbalance Models.

Heterogeneity in development of imbalance between impulse control and sensation seeking has not been studied until now. The present study scrutinized this heterogeneity and the link between imbalance and adolescent risk. Seven-wave data of 7,558 youth (50.71% males; age range from 12/13 until 24/25) were used. Three developmental trajectories were identified. The first trajectory, "sensation seeking to balanced sensation seeking", included participants with a higher level of sensation seeking than impulse control across all ages. The second trajectory, "moderate dominant control", included participants showing moderate and increasing impulse control relative to sensation seeking across all ages. The third trajectory, "strong late dominant control", included participants showing the highest level of impulse control which was about as strong as sensation seeking from early to middle adolescence and became substantially stronger from late adolescence to early adulthood. Although the systematic increase of impulse control in all subgroups is in line with both models, neither of these combined trajectories of control and sensation seeking was predicted by the Dual Systems Model or the Maturational Imbalance Model. Consistent with both models the "sensation seeking to balanced sensation seeking" trajectory showed the highest level of substance use. It can be concluded that, even though both theories adequately predict the link between imbalance and risk, neither the Dual Systems Model nor the Maturational Imbalance Model correctly predict the heterogeneity in development of imbalance between impulse control and sensation seeking.

Debate: Giving prevention a chance to prove its worth in lowering common mental disorder prevalence: how long will it take?

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.

Can loss of agency and oppositional perturbation associated with antidepressant monotherapy and low-fidelity psychological treatment dilute the benefits of guideline-consistent depression treatment at the population level?

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.

The association of developmental trajectories of adolescent mental health with early-adult functioning.

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.

The wide-ranging life outcome correlates of a general psychopathology factor in adolescent psychopathology.

BACKGROUND: The structure of psychopathology has been much debated within the research literature. This study extends previous work by providing comparisons of the links between psychopathology and several life outcomes (temperamental, economic, social, psychological and health) using a three-correlated-factors model, a bifactor model, a revised-bifactor model and a higher-order model. METHODS: Data from a sample of Dutch adolescents were used (n = 2 230), and psychopathology factors were modelled using self-reported and parent-reported longitudinal data from youth across four assessments during adolescence, from ages 11 to 19. Outcome variables were assessed at age 22 using adolescent-reports and parent-reports and more objective measures (e.g. body mass index). RESULTS: While no measurement model was clearly superior, we found modest associations between the psychopathology factors and life outcomes. Importantly, after taking into account a general factor, the associations with life outcomes decreased for the residual parts of thought problems (across all domains) and internalizing problems (for temperamental and psychological outcomes), but not for externalizing problems, compared with the traditional three-correlated-factors model. Patterns were similar for adolescent-reported and parent-reported data. CONCLUSIONS: Findings suggest that a general factor is related to psychopathology and life outcomes in a meaningful way. Results are discussed in terms of individual differences in propensity to psychopathology and more broadly in light of recent developments concerning the structure of psychopathology. © 2019 The Authors Personality and Mental Health Published by John Wiley & Sons Ltd.

Effects of psychological treatment of mental health problems in pregnant women to protect their offspring: randomised controlled trial.

BACKGROUND: Perinatal depression and anxiety are associated with unfavourable child outcomes. AIMS: To 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. METHOD: Pregnant 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. RESULTS: In 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. A post hoc analysis of the 98 women with anxiety disorders showed lower infant gestational age at delivery in the CBT than in the CAU group. CONCLUSIONS: Prenatally 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.

Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology.

Genetic discovery in psychiatry and clinical psychology is hindered by suboptimal phenotypic definitions. We argue that the hierarchical, dimensional, and data-driven classification system proposed by the Hierarchical Taxonomy of Psychopathology (HiTOP) consortium provides a more effective approach to identifying genes that underlie mental disorders, and to studying psychiatric etiology, than current diagnostic categories. Specifically, genes are expected to operate at different levels of the HiTOP hierarchy, with some highly pleiotropic genes influencing higher order psychopathology (e.g., the general factor), whereas other genes conferring more specific risk for individual spectra (e.g., internalizing), subfactors (e.g., fear disorders), or narrow symptoms (e.g., mood instability). We propose that the HiTOP model aligns well with the current understanding of the higher order genetic structure of psychopathology that has emerged from a large body of family and twin studies. We also discuss the convergence between the HiTOP model and findings from recent molecular studies of psychopathology indicating broad genetic pleiotropy, such as cross-disorder SNP-based shared genetic covariance and polygenic risk scores, and we highlight molecular genetic studies that have successfully redefined phenotypes to enhance precision and statistical power. Finally, we suggest how to integrate a HiTOP approach into future molecular genetic research, including quantitative and hierarchical assessment tools for future data-collection and recommendations concerning phenotypic analyses. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

The antidepressant standoff: why it continues and how to resolve it.

BACKGROUND: Antidepressant 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. RESULTS: Advocates 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. CONCLUSIONS: Given the public health significance of depression and increased long-term ADM usage, new approaches are needed to resolve the controversy.

Depression: more treatment but no drop in prevalence: how effective is treatment? And can we do better?

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 genetics of depression: successful genome-wide association studies introduce new challenges.

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.

Cost-effectiveness, cost-utility and the budget impact of antidepressants versus preventive cognitive therapy with or without tapering of antidepressants.

BACKGROUND: As 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. METHOD: Data 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. RESULTS: Mean 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. CONCLUSIONS: Adding 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 of PLOS One and 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.