Irritability Trajectories, Cortical Thickness, and Clinical Outcomes in a Sample Enriched for Preschool Depression

doi:10.1016/j.jaac.2018.02.010

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 57, Issue 5, May 2018, Pages 336-342.e6

https://doi.org/10.1016/j.jaac.2018.02.010 Get rights and content

Objective

Cross-sectional, longitudinal, and genetic associations exist between irritability and depression. Prior studies have examined developmental trajectories of irritability, clinical outcomes, and associations with child and familial depression. However, studies have not integrated neurobiological measures. The present study examined developmental trajectories of irritability, clinical outcomes, and cortical structure among preschoolers oversampled for depressive symptoms.

Method

Beginning at 3 to 5 years old, a sample of 271 children enriched for early depressive symptoms were assessed longitudinally by clinical interview. Latent class mixture models identified trajectories of irritability severity. Risk factors, clinical outcomes, and cortical thickness were compared across trajectory classes. Cortical thickness measures were extracted from 3 waves of magnetic resonance imaging at 7 to 12 years of age.

Results

Three trajectory classes were identified among these youth: 53.50% of children exhibited elevated irritability during preschool that decreased longitudinally, 30.26% exhibited consistently low irritability, and 16.24% exhibited consistently elevated irritability. Compared with other classes, the elevated irritability class exhibited higher rates of maternal depression, early life adversity, later psychiatric diagnoses, and functional impairment. Further, elevated baseline irritability predicted later depression beyond adversity and personal and maternal depression history. The elevated irritability class exhibited a thicker cortex in the left superior frontal and temporal gyri and the right inferior parietal lobule.

Conclusion

Irritability manifested with specific developmental trajectories in this sample enriched for early depression. Persistently elevated irritability predicted poor psychiatric outcomes, higher risk for later depression, and decreased overall function later in development. Greater frontal, temporal, and parietal cortical thickness also was found, providing neural correlates of this risk trajectory.

Section snippets

Participants

Participants were drawn from the prospective longitudinal Preschool Depression Study (PDS; N = 306; present analyses examined 271 with ≥3 annual clinical assessments available as is necessary for growth curve modeling; Table S1, available online, presents demographics by subsample). The PDS has the broad goal of exploring clinical and neural outcomes relating to preschool-onset depression. Details of the study have been published previously.²⁰ Briefly, 3- to 5-year-old children and their

Irritability Trajectory Characteristics

Of the 5 models tested (Table S3, available online), the model of 3 latent classes (Figure 1) showed the lowest Bayesian information criterion, the lowest Akaike information criterion, and the highest entropy, suggesting the best and most parsimonious fit and best classification of individuals. Some children (14.24%) showed high irritability during the preschool period, which remained high across development (“high irritability” class). Many children (53.14%) showed preschool-age irritability

Discussion

This is the first study to relate latent trajectories of irritability symptoms across early development to cortical thickness in a sample of youth enriched for depressive symptoms during the preschool period. We identified 3 latent trajectories classes based on repeated semistructured clinical interviews from preschool age through adolescence. The class with chronically elevated irritability showed poor clinical outcomes, specifically increased rates of depression and other psychopathology and

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(2010)

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Irritability is a transdiagnostic indicator of child and adolescent internalizing and externalizing problems that is measurable from early life. The objective of this systematic review was to determine the strength of the association between irritability measured from 0 to 5 years and later internalizing and externalizing problems, to identify mediators and moderators of these relationships, and to explore whether the strength of the association varied according to irritability operationalization.
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Early irritability is a consistent transdiagnostic predictor of internalizing and externalizing symptoms in childhood and adolescence. More work is required to understand how to accurately characterize irritability across this developmental period, and to understand mechanisms underlying the relationship between early irritability and later mental health problems.
One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as living with a disability. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.
Early irritability as a transdiagnostic neurodevelopmental vulnerability to early onset mental health problems: A systematic review; https://www.crd.york.ac.uk/prospero/; CRD42020214658.
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Cross-sectionally, higher levels of irritability were associated with greater amygdala connectivity with the posterior cingulate, controlling for child age. No age-dependent effects were observed in the cross-sectional analyses. Longitudinal analyses in the younger cohort revealed that early higher vs. lower levels of irritability, controlling for later irritability, were associated with decreases in amygdala and ventral striatum connectivity with multiple frontal and parietal regions over time. There were no significant findings in the older cohort.
Findings suggest that irritability is related to altered neural connectivity during rest regardless of age in early to middle childhood and that early childhood irritability may be linked to altered changes in neural connectivity over time. Understanding how childhood irritability interacts with neural processes can inform pathophysiological models of pediatric irritability and the development of targeted mechanistic interventions.
Roads Diverged: Developmental Trajectories of Irritability From Toddlerhood Through Adolescence
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Irritability is a dimensional trait that manifests from early life and is a robust transdiagnostic risk factor for psychopathology and impairment. A large, national dataset was leveraged to identify and broadly characterize trajectories from toddlerhood through adolescence, which is crucial for timely, targeted interventions.
Data on irritability and a broad array of potential factors affecting irritability development from 4,462 children assessed longitudinally at ages 3, 5, 9, and 15 were included. Latent class growth models identified groups of children based on their nonlinear irritability trajectories from toddlerhood to adolescence. LASSO regression then identified key characteristics differentiating trajectory groups.
Five distinct irritability trajectories were identified, two of which were stable, maintaining medium or high irritability from age 3 to 15. Three trajectories showed undulating change over development, with an inflection point at the transition to adolescence (age 9): Most children had consistently low irritability. Two smaller groups started with high irritability at age 3 but diverged, sharply decreasing or increasing until a turning point at age 9. Developmental patterning of harsh/neglectful parenting and child internalizing symptoms most strongly differentiated trajectory groups. Sociodemographic characteristics, attachment style, neighborhood support, cognitive functioning, and genetic variation also differentiated trajectories.
The results demonstrated the importance of the transition to adolescence as a critical inflection point for youths with fluctuating irritability trajectories. Identifying these patterns and multiple malleable factors associated with stably high or rising trajectories is an important step toward targeted interventions for the most vulnerable subgroups.
We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.
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Psychiatric symptoms are commonly comorbid in childhood. The ability to disentangle unique and shared correlates of comorbid symptoms facilitates personalized medicine. Cognitive control is implicated broadly in psychopathology, including in pediatric disorders characterized by anxiety and irritability. To disentangle cognitive control correlates of anxiety versus irritability, the current study leveraged both cross-sectional and longitudinal data from early childhood into adolescence.
For this study, 89 participants were recruited from a large longitudinal research study on early-life temperament to investigate associations of developmental trajectories of anxiety and irritability symptoms (from ages 2 to 15) as well as associations of anxiety and irritability symptoms measured cross-sectionally at age 15 with neural substrates of conflict and error processing assessed at age 15 using the flanker task.
Results of whole-brain multivariate linear models revealed that anxiety at age 15 was uniquely associated with decreased neural response to conflict across multiple regions implicated in attentional control and conflict adaptation. Conversely, irritability at age 15 was uniquely associated with increased neural response to conflict in regions implicated in response inhibition. Developmental trajectories of anxiety and irritability interacted in relation to neural responses to both error and conflict.
Our findings suggest that neural correlates of conflict processing may relate uniquely to anxiety and irritability. Continued cross-symptom research on the neural correlates of cognitive control could stimulate advances in individualized treatment for anxiety and irritability during child and adolescent development.
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Citation Excerpt :
Future studies should include more diverse samples, report sociodemographic composition of the study samples, and evaluate and discuss how the sociodemographic sample characteristics affect their findings. Importantly, more research is needed to examine the impact of early life adversity and trauma on the etiology and development of childhood irritability, as youths from marginalized and adverse backgrounds represent one of the most vulnerable groups to develop irritability symptoms and deserve timely intervention.32,61,62 Studies differ in irritability measures.
Childhood irritability, operationalized as disproportionate and frequent temper tantrums and low frustration tolerance relative to peers, is a transdiagnostic symptom across many pediatric disorders. Studies using task-dependent functional magnetic resonance imaging (fMRI) to probe neural dysfunction in irritability have increased. However, an integrated review summarizing the published methods and synthesized fMRI results remains lacking.
We conducted a systematic search using irritability terms and task functional neuroimaging in key databases in March 2021, and identified 30 studies for our systematic review. Sample characteristics and fMRI methods were summarized. A subset of 28 studies met the criteria for extracting coordinate-based data for quantitative meta-analysis. Ten activation-likelihood estimations were performed to examine neural convergence across irritability measures and fMRI task domains.
Systematic review revealed small sample sizes (median = 58, mean age range = 8-16 years) with heterogeneous sample characteristics, irritability measures, tasks, and analytical procedures. Meta-analyses found no evidence for neural activation convergence of irritability across neurocognitive functions related to emotional reactivity, cognitive control, and reward processing, or within each domain. Sensitivity analyses partialing out variances driven by heterogeneous tasks, irritability measures, stimulus types, and developmental ages all yielded null findings. Results were compared with a review on irritability-related structural anomalies from 11 studies.
The lack of neural convergence suggests a need for common, standardized irritability assessments and more homogeneous fMRI tasks. Thoughtfully designed fMRI studies probing commonly defined neurocognitive functions may be more fruitful to elucidate the neural mechanisms of irritability. Open science practices, data mining in large neuroscience databases, and standardized analytical methods promote meaningful collaboration in irritability research.

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: This work was supported by NIMH grants R01MH66031, R01MH084840, R01MH090786, R01MH098454-S, and R01MH064769-06A1. Work by Drs. Pagliaccio, Pine, and Leibenluft was supported by the Intramural Research Program at the NIMH.

: Disclosure: Drs. Pagliaccio, Pine, Barch, Luby, and Leibenluft report no biomedical financial interests or potential conflicts of interest.

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New researchIrritability Trajectories, Cortical Thickness, and Clinical Outcomes in a Sample Enriched for Preschool Depression

Objective

Method

Results

Conclusion

Section snippets

Participants

Irritability Trajectory Characteristics

Discussion

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Pediatr

Dev Cogn Neurosci

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Neuroimage

Neuroimage

J Am Acad Child Adolesc Psychiatry

J Anxiety Disord

J Anxiety Disord

J Psychiatr Res

Biol Psychiatry

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

Intelligence

Developmental trajectories of irritability and bidirectional associations with maternal depression

J Am Acad Child Adolesc Psychiatry

Pathways from maternal depressive symptoms to adolescent depressive symptoms: the unique contribution of irritability symptoms

J Child Psychol Psychiatry

Chronic anger as a precursor to adult antisocial personality features: the moderating influence of cognitive control

J Abnorm Psychol

More than the terrible twos: the nature and severity of behavior problems in clinic-referred preschool children

J Abnorm Child Psychol

Individual differences conducive to aggression and violence: trajectories and correlates of irritability and hostile rumination through adolescence

Aggress Behav

Antecedents of new-onset major depressive disorder in children and adolescents at high familial risk

JAMA Psychiatry

Longitudinal stability of genetic and environmental influences on irritability: from childhood to young adulthood

Am J Psychiatry

Adolescent irritability: phenotypic associations and genetic links with depressed mood

Am J Psychiatry

Neural mechanisms of frustration in chronically irritable children

Am J Psychiatry

Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder

Am J Psychiatry

New research
Irritability Trajectories, Cortical Thickness, and Clinical Outcomes in a Sample Enriched for Preschool Depression