Data-Driven ADHD Subtypes Highlight Need to Look Beyond Symptoms Alone

Zhang, S. H., Yang, T. X., Wu, Z. M., Wang, Y. F., Lui, S. S., Yang, B. R., & Chan, R. C. (2023). Identifying subgroups of attention‐deficit/hyperactivity disorder from the psychopathological and neuropsychological profiles. Journal of Neuropsychology. https://doi.org/10.1111/jnp.12334 

Key Points

1. The study identified four subgroups of ADHD based on psychopathological and neuropsychological profiles: (1) severe impairment in psychopathology and executive functions (EF), (2) mild executive dysfunctions and normal-level psychopathology, (3) severe externalizing problems, and (4) severe executive dysfunctions.
2. The subgroups showed differences in clinical characteristics and functional impairments.
3. The subgroup with severe EF deficits displayed more learning problems and worse life skills compared to the subgroup with severe externalizing problems.
4. Subtypes characterized by externalizing problems showed higher rates of the ADHD combined subtype and comorbid oppositional defiant disorder (ODD).
5. Different ADHD subtypes exhibited distinct profiles of internalizing and externalizing problems as well as varying levels of executive dysfunctions.
6. Executive functions are a critical intervention target for addressing heterogeneity in ADHD.

Rationale

ADHD is a highly heterogeneous neurodevelopmental disorder. Previous research has demonstrated variability in ADHD symptom profiles, clinical course, comorbidities, and cognitive deficits (Martin et al., 2008; Willoughby, 2003).

For example, 30-70% of individuals with ADHD have comorbid learning difficulties, while 44% have autism spectrum disorder (Joshi et al., 2017; Pastor & Reuben, 2008).

Executive functions (EF), the cognitive processes that regulate behavior and thought, are one factor that may account for ADHD heterogeneity.

Studies show between 30-84% of children with ADHD have working memory deficits, 21-27% have inhibitory control deficits, and 35-38% have set-shifting impairments or generalized EF deficits (Coghill et al., 2014; Gomez et al., 2014; Kofler et al., 2019; Sonuga-Barke et al., 2010).

However, most previous research on ADHD subtypes focused only on “cool” EF related to non-emotional control (e.g., working memory, inhibitory control), neglecting “hot” EF involved in emotional control (Bergwerff et al., 2019).

The present study aimed to identify and validate ADHD subtypes based on both cool and hot EF deficits, as well as psychopathology profiles.

This dimensional, Research Domain Criteria (RDoC)-based approach can clarify ADHD heterogeneity and inform targeted interventions.

Method

• 362 drug-naive children with ADHD (mean age 9.1 years) and 103 typically developing controls were recruited in China.
• Participants were assessed using:
  • Child Behavior Checklist (CBCL)
  • Behavior Rating Inventory of Executive Function (BRIEF) to measure cool and hot EF
  • Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P)
  • Conners Parent Symptom Questionnaire (PSQ)
• A hierarchical cluster analysis identified subgroups based on CBCL and BRIEF scores.
• Differences between subgroups were analyzed using ANOVA and chi-square tests.

Sample

• 362 children (mean age 9.1 years, 83% male) diagnosed with ADHD but not medicated
• 103 typically developing controls (mean age 9.2 years, 72% male)
• Groups matched on age, sex, and IQ
• ADHD samples recruited from ADHD clinics at three hospitals in China
• Control sample recruited from local primary schools
• Exclusion criteria: neurological disorder, head injury, ASD

Statistical analysis

• Hierarchical cluster analysis with Ward’s method based on CBCL and BRIEF scores
• ANOVA and post-hoc Tukey tests to analyze differences between clusters
• Chi-square tests to analyze differences in categorical variables
• p < .05 defined significance

Results

• Four clusters were identified:
  1. Severe impairment in psychopathology and EF (n=163)
  2. Mild EF deficits, normal psychopathology (n=46)
  3. Severe externalizing problems (n=113)
  4. Severe EF deficits (n=40)
• The severe impairment and externalizing subgroups showed:
  • More inattention, hyperactivity, and oppositional behaviors
  • Higher rates of ADHD-combined type and ODD
  • More functional impairment in school, family, life skills, self-concept
• The EF deficits subgroup showed:
  • More learning problems, lower academic competence
  • Worse life skills than externalizing subgroup
• The mild EF deficits subgroup showed least impairments

Insight

This study provides valuable insights into the heterogeneity of ADHD by identifying subtypes based on multidimensional assessments of psychopathology and neuropsychology.

The findings align with the Research Domain Criteria approach of characterizing mental disorders dimensionally rather than categorically.

Notably, the subgroup with primarily EF deficits showed distinct impairments in learning and life skills compared to the subtype with predominantly externalizing problems.

This highlights the critical role of EF in real-world impairments for a subset of children with ADHD.

It suggests interventions targeting EF, rather than just behavior management, may be key for improved functioning.

Overall, the study demonstrates the utility of data-driven subtyping to parse the complexity of ADHD. The subgroups showed meaningful differences in clinical presentation, functional impacts, and implied treatment needs.

Moving forward, connecting dimensional profiles to genetics, brain imaging, and treatment outcomes can further precision medicine for ADHD.

Strengths

• Large sample size with over 360 children with ADHD
• Inclusion of both parent-reported psychopathology and neuropsychological assessments
• Focus on multidimensional profile using both emotional and non-emotional EF measures
• Use of data-driven statistical approach to empirically derive subgroups
• Examination of clinical characteristics and functional impairments by subtype
• Drug-naive sample avoids medication confounds

Limitations

• Recruited from ADHD clinics, so findings may not generalize to community samples
• Relied on parent-report measures, lacks objective assessments
• Cross-sectional design provides no information about the stability of subgroups
• Sample was 83% male, so results may not extend to females with ADHD
• Limited to Chinese sample, need replication in other countries/cultures

Implications

• Demonstrates utility of RDoC dimensional approach to parsing ADHD heterogeneity
• Identifying neuropsychological and psychopathological profiles can inform individualized treatment
• Results highlight critical role of EF deficits in real-world impairments for a subtype of ADHD
• Suggests interventions targeting EF specifically could improve functioning
• Data-driven subtyping provides framework to connect biology and behavior in ADHD

Conclusion

This study identified four subgroups of ADHD based on psychopathology and executive functioning profiles using a novel, dimensional research approach.

The data-driven subtypes showed meaningful differences in clinical presentation, functional impairment, and treatment needs. The findings underscore the importance of characterizing the neuropsychological heterogeneity of ADHD to advance precision medicine.

While limited by reliance on parent-report measures and a Chinese sample, the results highlight executive functions as a key intervention target for a subset of children with ADHD struggling with learning and life skills.

Overall, the dimensional subtyping provides a model to connect biological mechanisms to behavioral profiles in this multifaceted, impairing neurodevelopmental disorder.

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