Anka Bernhard

Conduct disorder (CD) is a common psychiatric disorder in youth, characterized by severe and recurrent aggressive and antisocial behaviors and associated with substantial healthcare and societal costs. Rates of CD increase during adolescence in both sexes, with the male‐to‐female ratio narrowing to approximately 1:1. Although earlier work suggested potentially distinct pathways to CD in girls versus boys, few studies were adequately designed to investigate sex differences, limiting generalizability of existing findings from predominantly male samples to girls. Recent large‐scale projects, such as the European multisite FemNAT‐CD study, have addressed these limitations by oversampling girls and explicitly examining sex‐specific characteristics. However, a systematic integration of these findings is lacking. This review therefore aims to synthesize current evidence on sex differences in CD across four core domains: clinical phenotype, risk factors, neurobiology, and treatment. It integrates key findings from FemNAT‐CD alongside other relevant literature, with particular emphasis on implications for theories of (female) CD. Overall, girls and boys with CD appear far more similar than different. Youth with CD of both sexes differ markedly from their typically developing peers in comparable ways, particularly in neurobiological characteristics (e.g. emotion functioning, brain structural changes, neuroendocrine stress responses). Differences between girls and boys with CD are most evident in the clinical phenotype, including age‐of‐onset, callous‐unemotional traits/limited prosocial emotions, aggression subtypes, and cooccurring psychiatric disorders. Overall, sex differences in CD are subtle and difficult to detect. Remaining limitations of the current evidence base and ways to enhance the clinical relevance of research in this field are discussed.

Altered Autonomic Nervous System (ANS) function has been described in youth with Major Depressive Disorder (MDD), but studies are scarce and rarely consider sex, nor both parasympathetic and sympathetic ANS measures. Stress regulation plays a key role in the emergence and maintenance of MDD. Here, we aimed to investigate ANS stress reactivity within a clinical sample of female and male youth with MDD compared to healthy controls (HCs). Parasympathetic and sympathetic ANS stress reactivity (Heart Rate, HR; Respiratory Heart Rate Variability, RespHRV; Pre-ejection Period, PEP) was studied in response to a standardized psychosocial stress task (Trier Social Stress Test) in n = 100 youth with MDD (60% female; 12–18 years), and n = 70 HCs, while controlling for relevant confounders (e.g., age, puberty). Besides higher levels of self-reported psychological stress, youth with MDD showed lower HR increase, lower parasympathetic (less increase of RespHRV), and lower sympathetic (less reduction of PEP) ANS stress response compared to HCs. No effects of sex were found. Findings indicate blunted parasympathetic and sympathetic ANS stress responses contrasting stronger psychological stress experience in both female and male youth with MDD compared to HCs. This altered psychophysiological stress response may provide valuable insights for the development and optimization of future diagnostic and therapeutic approaches for youth with MDD. Further studies are needed to investigate the underlying biological backgrounds and longitudinal trajectories to understand the influence on stress regulation on onset and remission of MDD.

Conduct disorder (CD) is the leading global cause of mental health burden in children and adolescents and has recently been hypothesized to be a neurodevelopmental disorder. Although prior research has identified neuroanatomical differences associated with CD, it remains unclear whether these differences reflect atypical brain development. Here, we investigated the difference between an individual’s brain age and chronological age as a proxy for variations in brain maturation. Using a pretrained model, we estimated brain age from structural neuroimaging data obtained from 1,119 youth with CD and 1,183 typically developing controls across 14 international cohorts participating in the ENIGMA-Antisocial Behavior Working Group. Youth with CD exhibited a statistically robust but small acceleration in brain age compared to typically developing youth (around 0.50 years), which was restricted to the adolescence-onset subtype of the disorder. Our large-scale, coordinated analysis provides the first evidence of accelerated neurodevelopment as a potential mechanism underlying CD.

Background: Neurocognitive models suggest that callous‐unemotional (CU) traits in youths with conduct disorder (CD) are linked to emotion recognition impairments, particularly in identifying distress emotions like fear and sadness. However, CD may be accompanied by grandiose‐manipulative (GM) and/or impulsive‐irresponsible (II) traits in addition to CU traits, consistent with the notion that psychopathy is a multifaceted construct. It remains unclear whether subgroups of CD youths with GM or II traits, as well as a combination of multiple psychopathic traits, show distinct patterns of emotion recognition impairment. Methods: We therefore assessed emotion recognition accuracy, focusing on the six basic emotions, in 538 youths with CD (315 girls, 9–18 years) who were assigned to one of eight mutually exclusive subgroups based on high or low scores (above/below the 75th percentile cut‐offs) on CU, GM, and II traits as assessed by the Youth Psychopathy Inventory (YPI) self‐report. Results: Support vector machine analyses supported the validity of the subgroup assignment based on YPI cut‐off scores (sensitivities/specificities ≥75%–100%). Multinomial logistic regression models revealed that the CD subgroup with high levels across all three psychopathy traits had the most pervasive impairment in terms of higher error rates for recognizing sadness, disgust, and surprise. Notably, high CU traits were not consistently associated with impairments in fear and sadness recognition. Instead, CD youths with both high GM and II traits, but normal CU traits, showed impaired fear recognition. Conclusion: These findings challenge existing models that prioritize CU traits as the main driver of emotion recognition impairments in CD. Instead, different psychopathy traits appear to contribute distinctively to such impairments, including the recognition of distress emotions. This suggests that CU traits alone may not sufficiently explain the neurocognitive heterogeneity in emotion recognition seen in youths with CD.

Facial emotion recognition (FER) biases refer to systematic tendencies to recognize specific emotions when processing facial expressions. In youths with conduct disorder (CD), who are characterized by highly impairing antisocial behavior, research on FER biases has focused on hostile attribution biases. This work has shown that youths with CD perceive ambiguous social cues as angry. However, youths with CD may not only show biases towards anger, which is why we investigated FER biases in youths with CD towards the six basic emotions. Within the European FemNAT-CD study, we analyzed data from 610 youths with CD (60% female) and 818 typically developing controls (TDCs; 68% female), aged 9 to 18 years ( M = 14.1, SD = 2.41 years). FER biases were assessed using the Emotion Hexagon Task by showing morphed emotional expressions and asking participants to choose the predominant emotion. Biases were calculated as tendency towards an emotion shown at 0%, 10%, 30%, or 50% intensity. Our findings from hierarchical linear modelling indicate that youths with CD exhibited stronger FER biases than TDCs across all emotions, meaning that they misclassified each emotion more often. However, this difference varied by intensity, with youths with CD displaying weaker biases at higher intensity levels and a smaller increase in bias with increasing intensity level. Our findings indicate that youths with CD not only show a hostile attribution bias but rather misclassify emotions as predominant when they are present at low intensity, regardless of type of emotion.

Background: Exposure to psychosocial stress is one of the strongest risk factors for major depressive disorder (MDD) in youth, but underlying neurobiological mechanisms are poorly understood. Previous studies on the neuroendocrine stress response in youth with MDD are scarce, limited to cortisol, and rarely considered sex differences. Due to puberty‐associated neuroendocrine transitions increasing the risk for MDD onset in adolescence, this study aimed to investigate sex‐specific stress responses of stress and sex hormones as well as of neuropeptides.Methods: In 103 pubertal youths with MDD and 72 healthy controls (HCs; 62% females, 12–18 years), psychological stress as well as salivary cortisol, testosterone, and oxytocin reactivity to a standardized psychosocial stress test (Trier Social Stress Test, TSST) were assessed. Effects of group and sex, and their interactions were analyzed using hierarchical linear models, while controlling for potentially confounding factors (such as age and pubertal status).Results: Females and males with MDD showed a stronger psychological stress response than HCs. In contrast, both female and male youth with MDD showed blunted cortisol, testosterone, and oxytocin stress responses compared to HCs. In addition, baseline testosterone was elevated in MDD compared to HCs.Conclusions: Results indicate a discrepant stress reactivity in youth with MDD, with increased psychological, but decreased neuroendocrine responses to psychosocial stress. Blunted neuroendocrine stress responses in youth with MDD were found across different neuroendocrine systems and in both females and males with MDD. These novel findings point to a fundamentally changed stress response in youth with MDD irrespective of sex, which may influence successful stress regulation in the affected adolescents.

Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5’ of the neurite modulator SLITRK5 (FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely mediated by epigenetic mechanisms impairing specific brain developmental networks and therefore exerting a long-term effect on neural functions in CD. Our results are exploratory and thus, further replication is needed.