The Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic and mechanistic aspects of psychopathology. We used a multi-omics approach to examine how HiTOP’s psychopathology spectra (externalizing [EXT], internalizing [INT], and shared EXT + INT) map onto RDoC’s units of analysis.

We conducted analyses across five RDoC units of analysis: genes, molecules, cells, circuits, and physiology. Using genome-wide association studies from the companion Part I article, we identified genes and tissue-specific expression patterns. We used drug repurposing analyses that integrate gene annotations to identify potential therapeutic targets and single-cell RNA sequencing data to implicate brain cell types. We then used magnetic resonance imaging data to examine brain regions and circuits associated with psychopathology. Finally, we tested causal relationships between each spectrum and physical health conditions.

Using five gene identification methods, EXT was associated with 1,759 genes, INT with 454 genes, and EXT + INT with 1,138 genes. Drug repurposing analyses identified potential therapeutic targets, including those that affect dopamine and serotonin pathways. Expression of EXT genes was enriched in GABAergic, cortical, and hippocampal neurons, while INT genes were more narrowly linked to GABAergic neurons. EXT + INT liability was associated with reduced gray matter volume in the amygdala and subcallosal cortex. INT genetic liability showed stronger causal effects on physical health – including chronic pain and cardiovascular diseases – than EXT.

Our findings revealed shared and distinct pathways underlying psychopathology. Integrating genomic insights with the RDoC and HiTOP frameworks advanced our understanding of mechanisms that underlie EXT and INT psychopathology.

There is considerable comorbidity between externalizing (EXT) and internalizing (INT) psychopathology. Understanding the shared genetic underpinnings of these spectra is crucial for advancing knowledge of their biological bases and informing empirical models like the Research Domain Criteria (RDoC) and Hierarchical Taxonomy of Psychopathology (HiTOP).

We applied genomic structural equation modeling to summary statistics from 16 EXT and INT traits in individuals genetically similar to European reference panels (EUR-like; n = 16,400 to 1,074,629). Traits included clinical (e.g. major depressive disorder, alcohol use disorder) and subclinical measures (e.g. risk tolerance, irritability). We tested five confirmatory factor models to identify the best fitting and most parsimonious genetic architecture and then conducted multivariate genome-wide association studies (GWAS) of the resulting latent factors.

A two-factor correlated model, representing EXT and INT spectra, provided the best fit to the data. There was a moderate genetic correlation between EXT and INT (r = 0.37, SE = 0.02), with bivariate causal mixture models showing extensive overlap in causal variants across the two spectra (94.64%, SE = 3.27). Multivariate GWAS identified 409 lead genetic variants for EXT, 85 for INT, and 256 for the shared traits.

The shared genetic liabilities for EXT and INT identified here help to characterize the genetic architecture underlying these frequently comorbid forms of psychopathology. The findings provide a framework for future research aimed at understanding the shared and distinct biological mechanisms underlying psychopathology, which will help to refine psychiatric classification systems and potentially inform treatment approaches.

Progress towards understanding the aetiology of major depression is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity.

To compare risk factor profiles for three subgroups of major depression according to episode context.

Using self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of major depression: postpartum depression (3581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) major depression phenotype excluding the two other contexts (34 699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with the polygenic risk scores (PRS) for major depression and with other risk factors previously associated with major depression (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education).

Major depression PRS was associated with all subgroups, but postpartum depression cases had higher PRS than heterogeneous major depression cases (OR = 1.06, 95% CI 1.02–1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Depression following diagnosis of a chronic disease had weaker association with neuroticism and reported trauma in adulthood and childhood relative to heterogeneous depression.

The observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined aetiological insights.

No significant relationships.

Symptoms related to chronic stress are prevalent and entail high societal costs, yet there is a lack of international consensus regarding diagnostics and treatment. A new stress-related diagnosis, exhaustion disorder, was introduced into the Swedish version of ICD-10 in 2005. Since then, use of the diagnosis has increased rapidly.

To create the first comprehensive synthesis of research on exhaustion disorder to report on the current state of knowledge. Preregistration: Open Science Framework (osf.io), doi 10.17605/OSF.IO/VFDKW.

A PRISMA-guided scoping review of all empirical studies of exhaustion disorder was conducted. Searches were run in the MEDLINE, PsycInfo and Web of Science databases. Data were systematically charted and thematically categorised based on primary area of investigation.

Eighty-nine included studies were sorted into six themes relating to lived experience of exhaustion disorder (n = 9), symptom presentation and course (n = 13), cognitive functioning (n = 10), biological measures (n = 24), symptom measurement scales (n = 4) and treatment (n = 29). Several studies indicated that individuals with exhaustion disorder experience a range of psychiatric and somatic symptoms beyond fatigue, but robust findings within most thematic categories were scarce. The limited number of studies, lack of replication of findings and methodological limitations (e.g. small samples and scarcity of specified primary outcomes) preclude firm conclusions about the diagnostic construct.

More research is needed to build a solid knowledge base for exhaustion disorder. International collaboration regarding the conceptualisation of chronic stress and fatigue is warranted to accelerate the growth of evidence.

The relationship between irritability as a subjective experience and the behavioural indicators typically used to measure the construct are not known. Its links to mood, and contextual relationships, vary with age and are yet to be thoroughly examined.

First, to interrogate the relationship between the subjective experience of irritability and mood, and that with its behavioural indicators. Second, to determine how these relationships vary with age and over time.

This study examined data from a previous clinical trial of adolescents and young adults (N = 82) with bipolar disorder, who received a psychological intervention over 18 months. Participants completed a battery of questionnaires, which included assessments of irritability. Analyses of covariance were conducted to examine the interaction between mood symptoms, subjective measures of irritability, behavioural measures of irritability and age over time.

Subjective irritability scores differed significantly over time when controlling for manic, but not depressive, symptom scores. Further, subjective irritability significantly differed when controlling for behavioural measures of irritability (temper outbursts and argumentativeness). There were significant interactions between scores of depressive symptoms, temper outbursts and subjective irritability with age, wherein younger participants showed no correlation between depressive symptoms and temper outbursts. In addition, younger participants showed lower correlations between subjective irritability and both depressive and temper outburst scores, than older participants.

Subjective irritability is linked to mood morbidity and behavioural outbursts, and these relationships are contingent on age. Our novel findings suggest that subjective irritability should be assessed in greater detail in patients with mood disorders.

Pronoia is a neologism originally coined in 1982 to describe a state of mind that is, in essence, the positive counterpart of paranoia. It is characterized by feeling that the world is conspiring on behalf of the person experiencing pronoia.

Brief literature review.

The authors review the available literature on pronoia and present a broad overview of its description and defining characteristics. An initial search utilizing key health journal databases revealed a scarcity in available documents, therefore a generalized search utilizing the search engine Google Scholar was performed with the term “pronoia”. Relevant articles obtained from the respective bibliographic references were also consulted.

The primary outcome of this work is a summary of the available literature in order to build a more comprehensive understanding on pronoia. All relevant information was collated to form a cohesive description of the condition and its characteristics. We address a gap in the literature by offering a description of the lesser prevalent concept of pronoia.

Our results demonstrate a scarcity in the available literature describing the pronoia phenomenon when compared to its well-documented counterpart, paranoia. Further exploration into this topic is merited so as to close the gap on paranoia’s lesser-known positive counterpart. By signalling the existence of this concept, we strive to contribute to an increased identification of a concept that is many times underdiagnosed due to a lack of attention to its existence.

No significant relationships.