Multigenerational adversity impacts on human gut microbiome composition and socioemotional functioning in early childhood.

Adversity exposures in the prenatal and postnatal period are associated with an increased risk for psychopathology, which can be perpetuated across generations. Nonhuman animal research highlights the gut microbiome as a putative biological mechanism underlying such generational risks. In a sample of 450 mother-child dyads living in Singapore, we examined associations between three distinct adversity exposures experienced across two generations-maternal childhood maltreatment, maternal prenatal anxiety, and second-generation children's exposure to stressful life events-and the gut microbiome composition of second-generation children at 2 y of age. We found distinct differences in gut microbiome profiles linked to each adversity exposure, as well as some nonaffected microbiome features (e.g., beta diversity). Remarkably, some of the microbial taxa associated with concurrent and prospective child socioemotional functioning shared overlapping putative functions with those affected by adversity, suggesting that the intergenerational transmission of adversity may have a lasting impact on children's mental health via alterations to gut microbiome functions. Our findings open up a new avenue of research into the underlying mechanisms of intergenerational transmission of mental health risks and the potential of the gut microbiome as a target for intervention.

Psychosis superspectrum I: Nosology, etiology, and lifespan development.

This review describes the Hierarchical Taxonomy of Psychopathology (HiTOP) model of psychosis-related psychopathology, the psychosis superspectrum. The HiTOP psychosis superspectrum was developed to address shortcomings of traditional diagnoses for psychotic disorders and related conditions including low reliability, arbitrary boundaries between psychopathology and normality, high symptom co-occurrence, and heterogeneity within diagnostic categories. The psychosis superspectrum is a transdiagnostic dimensional model comprising two spectra-psychoticism and detachment-which are in turn broken down into fourteen narrow components, and two auxiliary domains-cognition and functional impairment. The structure of the spectra and their components are shown to parallel the genetic structure of psychosis and related traits. Psychoticism and detachment have distinct patterns of association with urbanicity, migrant and ethnic minority status, childhood adversity, and cannabis use. The superspectrum also provides a useful model for describing the emergence and course of psychosis, as components of the superspectrum are relatively stable over time. Changes in psychoticism predict the onset of psychosis-related psychopathology, whereas changes in detachment and cognition define later course. Implications of the superspectrum for genetic, socio-environmental, and longitudinal research are discussed. A companion review focuses on neurobiology, treatment response, and clinical utility of the superspectrum, and future research directions.

Exploring the genetic etiology across the continuum of the general psychopathology factor: a Swedish population-based family and twin study.

Psychiatric comorbidity can be accounted for by a latent general psychopathology factor (p factor), which quantifies the variance that is shared to varying degrees by every dimension of psychopathology. It is unclear whether the entire continuum of the p factor shares the same genetic origin. We investigated whether mild, moderate, and extreme elevations on the p factor shared the same genetic etiology by, first, examining the linearity of the association between p factors across siblings (N = 580,891 pairs). Second, we estimated the group heritability in a twin sample (N = 17,170 pairs), which involves testing whether the same genetic variants influence both extreme and normal variations in the p factor. In both samples, the p factor was based on 10 register-based psychiatric diagnoses. Results showed that the association between siblings' p factors appeared linear, even into the extreme range. Likewise, the twin group heritabilities ranged from 0.42 to 0.45 (95% CI: 0.33-0.57) depending on the thresholds defining the probands (2-3.33 SD beyond the mean; >2 SD beyond the mean; >4.33 SD beyond the mean; and >5.33 SD beyond the mean), and these estimates were highly similar to the estimated individual differences heritability (0.41, 95% CI: 0.39-0.43), indicating that scores above and below these thresholds shared a common genetic origin. Together, these results suggest that the entire continuum of the p factor shares the same genetic origin, with common genetic variants likely playing an important role. This implies, first, genetic risk factors for the aspect that is shared between all forms of psychopathology (i.e., genetic risk factors for the p factor) might be generalizable between population-based cohorts with a higher prevalence of milder cases, and clinical samples with a preponderance of more severe cases. Second, prioritizing low-cost genome-wide association studies capable of identifying common genetic variants, rather than expensive whole genome sequencing that can identify rare variants, may increase the efficiency when studying the genetic architecture of the p factor.

Psychosis superspectrum II: neurobiology, treatment, and implications.

Alternatives to traditional categorical diagnoses have been proposed to improve the validity and utility of psychiatric nosology. This paper continues the companion review of an alternative model, the psychosis superspectrum of the Hierarchical Taxonomy of Psychopathology (HiTOP). The superspectrum model aims to describe psychosis-related psychopathology according to data on distributions and associations among signs and symptoms. The superspectrum includes psychoticism and detachment spectra as well as narrow subdimensions within them. Auxiliary domains of cognitive deficit and functional impairment complete the psychopathology profile. The current paper reviews evidence on this model from neurobiology, treatment response, clinical utility, and measure development. Neurobiology research suggests that psychopathology included in the superspectrum shows similar patterns of neural alterations. Treatment response often mirrors the hierarchy of the superspectrum with some treatments being efficacious for psychoticism, others for detachment, and others for a specific subdimension. Compared to traditional diagnostic systems, the quantitative nosology shows an approximately 2-fold increase in reliability, explanatory power, and prognostic accuracy. Clinicians consistently report that the quantitative nosology has more utility than traditional diagnoses, but studies of patients with frank psychosis are currently lacking. Validated measures are available to implement the superspectrum model in practice. The dimensional conceptualization of psychosis-related psychopathology has implications for research, clinical practice, and public health programs. For example, it encourages use of the cohort study design (rather than case-control), transdiagnostic treatment strategies, and selective prevention based on subclinical symptoms. These approaches are already used in the field, and the superspectrum provides further impetus and guidance for their implementation. Existing knowledge on this model is substantial, but significant gaps remain. We identify outstanding questions and propose testable hypotheses to guide further research. Overall, we predict that the more informative, reliable, and valid characterization of psychopathology offered by the superspectrum model will facilitate progress in research and clinical care.

Memory editing from science fiction to clinical practice.

Science fiction notions of altering problematic memories are starting to become reality as techniques emerge through which unique memories can be edited. Here we review memory-editing research with a focus on improving the treatment of psychopathology. Studies highlight two windows of memory vulnerability: initial storage, or consolidation; and re-storage after retrieval, or reconsolidation. Techniques have been identified that can modify memories at each stage, but translating these methods from animal models to humans has been challenging and implementation into clinical therapies has produced inconsistent benefits. The science of memory editing is more complicated and nuanced than fiction, but its rapid development holds promise for future applications.

Multivariate Assessment of Inhibitory Control in Youth: Links With Psychopathology and Brain Function.

Inhibitory control is central to many theories of cognitive and brain development, and impairments in inhibitory control are posited to underlie developmental psychopathology. In this study, we tested the possibility of shared versus unique associations between inhibitory control and three common symptom dimensions in youth psychopathology: attention-deficit/hyperactivity disorder (ADHD), anxiety, and irritability. We quantified inhibitory control using four different experimental tasks to estimate a latent variable in 246 youth (8-18 years old) with varying symptom types and levels. Participants were recruited from the Washington, D.C., metro region. Results of structural equation modeling integrating a bifactor model of psychopathology revealed that inhibitory control predicted a shared or general psychopathology dimension, but not ADHD-specific, anxiety-specific, or irritability-specific dimensions. Inhibitory control also showed a significant, selective association with global efficiency in a frontoparietal control network delineated during resting-state functional magnetic resonance imaging. These results support performance-based inhibitory control linked to resting-state brain function as an important predictor of comorbidity in youth psychopathology.

Elemental psychopathology: distilling constituent symptoms and patterns of repetition in the diagnostic criteria of the DSM-5.

BACKGROUND: The DSM-5 features hundreds of diagnoses comprising a multitude of symptoms, and there is considerable repetition in the symptoms among diagnoses. This repetition undermines what we can learn from studying individual diagnostic constructs because it can obscure both disorder- and symptom-specific signals. However, these lost opportunities are currently veiled because symptom repetition in the DSM-5 has not been quantified. METHOD: This descriptive study mapped the repetition among the 1419 symptoms described in 202 diagnoses of adult psychopathology in section II of the DSM-5. Over a million possible symptom comparisons needed to be conducted, for which we used both qualitative content coding and natural language processing. RESULTS: In total, we identified 628 distinct symptoms: 397 symptoms (63.2%) were unique to a single diagnosis, whereas 231 symptoms (36.8%) repeated across multiple diagnoses a total of 1022 times (median 3 times per symptom; range 2-22). Some chapters had more repetition than others: For example, every symptom of every diagnosis in the bipolar and related disorders chapter was repeated in other chapters, but there was no repetition for any symptoms of any diagnoses in the elimination disorders, gender dysphoria or paraphilic disorders. The most frequently repeated symptoms included insomnia, difficulty concentrating, and irritability - listed in 22, 17 and 16 diagnoses, respectively. Notably, the top 15 most frequently repeating diagnostic criteria were dominated by symptoms of major depressive disorder. CONCLUSION: Overall, our findings lay the foundation for a better understanding of the extent and potential consequences of symptom overlap.

Neural response to monetary and social rewards and familial risk for psychopathology in adolescent females.

BACKGROUND: Adolescence is a key developmental period for the emergence of psychopathology. Reward-related brain activity increases across adolescence and has been identified as a potential neurobiological mechanism of risk for different forms of psychopathology. The reward positivity (RewP) is an event-related potential component that indexes reward system activation and has been associated with both concurrent and family history of psychopathology. However, it is unclear whether the RewP is also associated with higher-order psychopathology subfactors and whether this relationship is present across different types of reward. METHODS: In a sample of 193 adolescent females and a biological parent, the present study examined the association between adolescent and parental psychopathology subfactors and adolescent RewP to monetary and social reward. RESULTS: Results indicated that the adolescent and parental distress subfactors were negatively associated with the adolescent domain-general RewP. The adolescent and parental positive mood subfactors were negatively associated with the adolescent domain-general and domain-specific monetary RewP, respectively. Conversely, the adolescent and parental fear/obsessions subfactors were positively associated with the adolescent domain-general RewP. The associations between parental and adolescent psychopathology subfactors and the adolescent RewP were independent of each other. CONCLUSIONS: The RewP in adolescent females is associated with both concurrent and parental psychopathology symptoms, suggesting that it indexes both severity and risk for higher-order subfactors.

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Are Genetic and Environmental Risk Factors for Psychopathology Amplified in Children with Below-Average Intelligence? A Population-Based Twin Study.

There is a negative association between intelligence and psychopathology. We analyzed data on intelligence and psychopathology to assess this association in seven-year-old Dutch twin pairs (ranging from 616 to 14,150 depending on the phenotype) and estimated the degree to which genetic and environmental factors common to intelligence and psychopathology explain the association. Secondly, we examined whether genetic and environmental effects on psychopathology are moderated by intelligence. We found that intelligence, as assessed by psychometric IQ tests, correlated negatively with childhood psychopathology, as assessed by the DSM-oriented scales of the Child Behavior Check List (CBCL). The correlations ranged between - .09 and - .15 and were mainly explained by common genetic factors. Intelligence moderated genetic and environmental effects on anxiety and negative affect, but not those on ADHD, ODD, and autism. The heritability of anxiety and negative affect was greatest in individuals with below-average intelligence. We discuss mechanisms through which this effect could arise, and we end with some recommendations for future research.

The Heritability of Psychopathology Symptoms in Early Adolescence: Moderation by Family Cultural Values in the ABCD Study.

Family cultural values that emphasize support, loyalty, and obligation to the family are associated with lower psychopathology in Hispanic/Latino/a youth, but there is a need to understand the implications of family cultural values for youth development in racially/ethnically heterogeneous samples. This study examined phenotypic associations between parent- and youth-reported family cultural values in late childhood on youth internalizing and externalizing symptoms in early adolescence, and whether family cultural values moderated genetic and environmental influences on psychopathology symptoms. The sample comprised 10,335 children (Mage=12.89 years; 47.9% female; 20.3% Hispanic/Latino/a, 15.0% Black, 2.1% Asian, 10.5% other) and their parents from the Adolescent Brain Cognitive Development (ABCD) Study, and biometric models were conducted in the twin subsample (n = 1,042 twin pairs; 43.3% monozygotic). Parents and youth reported on their family cultural values using the Mexican American Cultural Values Scale at youth age 11-12, and parents reported on youth internalizing and externalizing symptoms using the Child Behavior Checklist at youth ages 11-12 and 12-13. Greater parent- and youth-reported family cultural values predicted fewer youth internalizing and externalizing symptoms. Biometric models indicated that higher parent-reported family cultural values increased the nonshared environmental influences on externalizing symptoms whereas youth-reported family cultural values decreased the nonshared environmental influences on internalizing symptoms. This study highlights the need for behavior genetic research to consider a diverse range of cultural contexts to better understand the etiology of youth psychopathology.

Overcoming the translational crisis of contemporary psychiatry - converging phenomenological and spatiotemporal psychopathology.

Despite all neurobiological/neurocomputational progress in psychiatric research, recent authors speak about a 'crisis of contemporary psychiatry'. Some argue that we do not yet know the computational mechanisms underlying the psychopathological symptoms ('crisis of mechanism') while others diagnose a neglect of subjectivity, namely first-person experience ('crisis of subjectivity'). In this perspective, we propose that Phenomenological Psychopathology, due to its focus on first-person experience of space and time, is in an ideal position to address the crisis of subjectivity and, if extended to the brain's spatiotemporal topographic-dynamic structure as key focus of Spatiotemporal Psychopathology, the crisis of mechanism. We demonstrate how the first-person experiences of space and time differ between schizophrenia, mood disorders and anxiety disorders allowing for their differential-diagnosis - this addresses the crisis of subjectivity. Presupposing space and time as shared features of brain, experience, and symptoms as their "common currency", the structure of abnormal space and time experience may also serve as template for the structure of the brain's spatiotemporal neuro-computational mechanisms - this may address the crisis of mechanism. Preliminary scientific evidence in our examples of schizophrenia, bipolar disorder, anxiety disorder, and depression support such clinically relevant spatiotemporal determination of both first-person experience (crisis of subjectivity) and the brain's neuro-computational structure (crisis of mechanism). In conclusion, converging Phenomenological Psychopathology with Spatiotemporal Psychopathology might help to overcome the translational crisis in psychiatry by delineating more fine-grained neuro computational and -phenomenal mechanisms; this offers novel candidate biomarkers for diagnosis and therapy including both pharmacological and non-pharmacological treatment.

Investigating genetically stratified subgroups to better understand the etiology of alcohol misuse.

Alcohol misuse (AM) is highly prevalent and harmful, with theorized subgroups differing on internalizing and externalizing dimensions. Despite known heterogeneity, genome-wide association studies (GWAS) are usually conducted on unidimensional phenotypes. These approaches have identified important genes related to AM but fail to capture a large part of the heritability, even with recent increases in sample sizes. This study aimed to address phenotypic heterogeneity in GWAS to aid gene finding and to uncover the etiology of different types of AM. Genetic and phenotypic data from 410,414 unrelated individuals of multiple ancestry groups (primarily European) in the UK Biobank were obtained. Mixture modeling was applied to measures of alcohol misuse and internalizing/externalizing psychopathology to uncover phenotypically homogenous subclasses, which were carried forward to GWAS and functional annotation. A four-class model emerged with "low risk", "internalizing-light/non-drinkers", "heavy alcohol use-low impairment", and "broad high risk" classes. SNP heritability ranged from 3 to 18% and both known AM signals and novel signals were captured by genomic risk loci. Class comparisons showed distinct patterns of regional brain tissue enrichment and genetic correlations with internalizing and externalizing phenotypes. Despite some limitations, this study demonstrated the utility of genetic research on homogenous subclasses. Not only were novel genetic signals identified that might be used for follow-up studies, but addressing phenotypic heterogeneity allows for the discovery and investigation of differential genetic vulnerabilities in the development of AM, which is an important step towards the goal of personalized medicine.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Neuroimaging profiling identifies distinct brain maturational subtypes of youth with mood and anxiety disorders.

Mood and anxiety disorders typically begin in adolescence and have overlapping clinical features but marked inter-individual variation in clinical presentation. The use of multimodal neuroimaging data may offer novel insights into the underlying brain mechanisms. We applied Heterogeneity Through Discriminative Analysis (HYDRA) to measures of regional brain morphometry, neurite density, and intracortical myelination to identify subtypes of youth, aged 9-10 years, with mood and anxiety disorders (N = 1931) compared to typically developing youth (N = 2823). We identified three subtypes that were robust to permutation testing and sample composition. Subtype 1 evidenced a pattern of imbalanced cortical-subcortical maturation compared to the typically developing group, with subcortical regions lagging behind prefrontal cortical thinning and myelination and greater cortical surface expansion globally. Subtype 2 displayed a pattern of delayed cortical maturation indicated by higher cortical thickness and lower cortical surface area expansion and myelination compared to the typically developing group. Subtype 3 showed evidence of atypical brain maturation involving globally lower cortical thickness and surface coupled with higher myelination and neural density. Subtype 1 had superior cognitive function in contrast to the other two subtypes that underperformed compared to the typically developing group. Higher levels of parental psychopathology, family conflict, and social adversity were common to all subtypes, with subtype 3 having the highest burden of adverse exposures. These analyses comprehensively characterize pre-adolescent mood and anxiety disorders, the biopsychosocial context in which they arise, and lay the foundation for the examination of the longitudinal evolution of the subtypes identified as the study sample transitions through adolescence.

Traumatic stress load and stressor reactivity score associated with accelerated gray matter maturation in youths indexed by normative models.

Understanding how traumatic stress affects typical brain development during adolescence is critical to elucidate underlying mechanisms related to both maladaptive functioning and resilience after traumatic exposures. The current study aimed to map deviations from normative ranges of brain gray matter for youths with traumatic exposures. For each cortical and subcortical gray matter region, normative percentiles of variations were established using structural MRI from typically developing youths without any traumatic exposure (n = 245; age range = 8-23) from the Philadelphia Neurodevelopmental Cohort (PNC). The remaining PNC participants with neuroimaging data (n = 1129) were classified as either within the normative range (5-95%), delayed (>95%) or accelerated (<5%) maturational ranges for each region using the normative model. An averaged quantile regression index was calculated across all regions. Mediation models revealed that high traumatic stress load was positively associated with poorer cognitive functioning and greater psychopathology, and these associations were mediated by accelerated gray matter maturation. Furthermore, higher stressor reactivity scores, which represent a less resilient response under traumatic stress, were positively correlated with greater acceleration of gray matter maturation (r = 0.224, 95% CI = [0.17, 0.28], p < 0.001), suggesting that more accelerated maturation was linked to greater stressor response regardless of traumatic stress load. We conclude that traumatic stress is a source of deviation from normative brain development associated with poorer cognitive functioning and more psychopathology in the long run.

Sleep patterns among preschool offspring of parents with and without psychopathology: Association with the development of psychopathology in childhood.

BACKGROUND: Disturbed sleep during early childhood predicts social-emotional problems. However, it is not known how various early childhood sleep phenotypes are associated with the development of childhood psychopathology, nor whether these relationships vary as a function of parental psychopathology. We identified sleep phenotypes among preschool youth; examined whether these phenotypes were associated with child and parent factors; and determined if early sleep phenotypes predicted later childhood psychopathology. METHODS: Using data from the Pittsburgh Bipolar Offspring study, parents with bipolar disorder (BD), non-BD psychopathology, and healthy controls reported about themselves and their offspring (n = 218) when their children were ages 2-5. Offspring and parents were interviewed directly approximately every 2 years from ages 6-18. Latent class analysis (LCA) identified latent sleep classes; we compared these classes on offspring demographics, parental sleep variables, and parental diagnoses. Kaplan-Meier survival models estimated hazard of developing any new-onset Axis-I disorders, as well as BD specifically, for each class. RESULTS: The optimal LCA solution featured four sleep classes, which we characterized as (1) good sleep, (2) wake after sleep onset problems, (3) bedtime problems (e.g., trouble falling asleep, resists going to bed), and (4) poor sleep generally. Good sleepers tended to have significantly less parental psychopathology than the other three classes. Risk of developing new-onset Axis-I disorders was highest among the poor sleep class and lowest among the good sleep class. CONCLUSIONS: Preschool sleep phenotypes are an important predictor of the development of psychopathology. Future work is needed to understand the biopsychosocial processes underlying these trajectories.

Editorial: Thinking outside the box - enhancing causal models of neurodevelopmental disorders.

Neurodevelopmental disorders are best conceptualised as the result of multiple risk factors, which accumulate and determine the likelihood of reaching the threshold for fulfilling agreed diagnostic criteria. This multiple-risk framework allows the inclusion of research findings focusing on single disorders, while highlighting the need for extending and specifying existing causal models. Such specifications need to address at least three challenges: First, causal models need to account for the heterogeneity of symptoms within neurodevelopmental disorders, the dissociations between disorders, and also the high comorbidity rates observed between them. Second, causal models need to take into account the fact that associations between risk factors and psychopathology may be developmentally conditioned and are likely to change over time. Third, causal models need to incorporate a better understanding of the causal pathways between neurobiological risk factors and their interaction with environmental risk factors. Several articles in the present issue address these challenges, by assessing the interplay between neurobiological and environmental risk factors, and their impact on psychopathology, and by investigating how this relationship changes over time.

Emotion regulation as central to psychopathology across childhood and adolescence: a commentary on Nobakht et al. (2023).

An important goal of clinical/developmental research is to identify factors contributing to the onset and maintenance of psychopathology - particularly factors that could be modified through intervention. Large-scale, multi-informant, longitudinal studies provide valuable opportunities for testing such etiological hypotheses, as illustrated by Nobakht et al.'s recent six-wave cohort study spanning ages 4-14. At a within-person level, emotion regulation (ER) deficits consistently predicted oppositional defiant disorder (ODD) symptoms (including both irritability and defiance), whereas victimization did not. These results comport with growing evidence highlighting ER's centrality to ODD and psychopathology more broadly. While the ER findings carry promising implications, caution is warranted in interpreting the results for victimization given that its association with psychopathology is well-documented. More research is needed to test precise questions about within- and between-person processes involving ER, victimization, and psychopathology across development. Pressing research questions include whether, how, and when youths' ER can be modified, and with what effects on clinical outcomes.

Annual Research Review: Sex, gender, and internalizing conditions among adolescents in the 21st century - trends, causes, consequences.

Internalizing conditions of psychopathology include depressive and anxiety disorders; they most often onset in adolescence, are relatively common, and contribute to significant population morbidity and mortality. In this research review, we present the evidence that internalizing conditions, including depression and anxiety, as well as psychological distress, suicidal thoughts and self-harm, and fatal suicide, are considerably increasing in adolescent populations across many countries. Evidence indicates that increases are currently greatest in female adolescents. We present an epidemiological framework for evaluating the causes of these increases, and synthesize research on whether several established risk factors (e.g., age of pubertal transition and stressful life events) and novel risk factors (e.g., digital technology and social media) meet conditions necessary to be plausible causes of increases in adolescent internalizing conditions. We conclude that there are a multitude of potential causes of increases in adolescent internalizing conditions, outline evidence gaps including the lack of research on nonbinary and gender nonconforming populations, and recommend necessary prevention and intervention foci from a clinical and public health perspective.