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De Francesco et al. J Transl Genet Genom 2024;8:102-18 https://dx.doi.org/10.20517/jtgg.2023.51 Page 112

The comorbidity between CDS, Internalizing and Externalizing Disorders
To date, a growing body of research associates CDS with a variety of psychopathologies and functional
[50]
impairments . Particularly, the hypothesis that CDS defines a transdiagnostic symptomatology more
closely associated with the INT Disorders dimension, rather than the EXT dimension and the diagnosis of
ADHD, is widely endorsed [50,51] . The typical CDS symptoms indeed appear to be more strongly correlated
with anxiety and depression compared to oppositional and aggressive behaviors [3,55-57] . Moreover, they
demonstrate a greater association with suicidal risk, social withdrawal, and peer exclusion compared to
ADHD [50,57-59] as well as sleep problems [58,60] . These findings offer a potential interpretation of the results
obtained by Harrington & Waldman , which demonstrate a limited capacity of CDS symptoms in
[60]
differentiating clinical presentations of ADHD. Skirbekk et al. also conducted a study that investigated the
[61]
relationship between CDS, ADHD, and Anxiety Disorders in a sample of 141 subjects aged between 7 and
13 years. Participants were divided into four groups based on the presence of ADHD alone, comorbidity
between ADHD and Anxiety Disorders, the presence of Anxiety Disorders without comorbidity of ADHD,
[61]
and the absence of pathology (control group) . The results show higher CDS scores in the group with
comorbidity between ADHD and Anxiety Disorders. However, the presence of a significant difference
between the group with only Anxiety Disorders and the neurotypical controls suggests the hypothesis of an
[61]
actual correlation between CDS and Anxiety Disorders, while controlling for comorbidity with ADHD .
These hypotheses are supported by the study of Fredrick et al. on the relationship between ADHD, CDS,
mind-wandering, and rumination, highlighting that, when controlling for CDS, the association between
mind-wandering and ADHD appears to decrease, while the association between CDS and mind-wandering
remains constant even when controlling for ADHD . A possible interpretation of these data seems to be
[52]
that the strong correlation observed between ADHD and mind-wandering [62,63] may be mediated by
symptoms associated with CDS . Moreover, a significant relationship between ADHD and the tendency
[52]
for rumination did not appear to emerge. Instead, this tendency seems to manifest prominently and hold
particular significance within the symptomatology associated with CDS. According to the authors, this
[52]
association may provide a foundation for further examination of the comorbidity between CDS and INT .
Furthermore, elevated levels of CDS appear to lead to emotional and social difficulties regardless of
potential comorbidity with ADHD . In this context, the disorder seems to be linked to an increase in
[54]
anxious and depressive symptoms, as well as difficulties in the social domain [54,62] . Considering the
[59]
possibility of defining CDS as a disorder characterized by INT symptoms, Sáez et al. evaluated the
hypothesis that information provided by parents and teachers might be only partial. Therefore, a more
reliable assessment of the disorder may result from the analysis of symptoms reported by both parents and
teachers, as well as by the individuals themselves. However, the most interesting finding of this study
concerns the significant association between CDS, a tendency towards group isolation, and a preference for
[59]
loneliness .
These factors seem to provide an explanation for the observed correlation between CDS and suicidal risk,
which seems to persist even when controlling for ADHD and depressive symptoms [51,59] . The mechanisms
underlying the social isolation associated with CDS remain unknown. On one hand, this could arise from
the social difficulties related to attentional and emotional regulation deficits; on the other hand, it is equally
possible that a preference for solitude makes it more difficult for individuals with CDS to engage in positive
social interactions . Although the hypothesis of a potential comorbidity between CDS and INT symptom
[59]
classes is widely discussed in the literature [54,62,64] , further studies are needed to delve into the relationship
between these two categories of symptoms.

In contrast to INT symptoms, the relationship between EXT symptoms (such as inattention, hyperactivity,
oppositionality, provocativeness, conduct problems, antisocial behavior, and substance use) and CDS is
more contradictory. Indeed, several studies highlight that CDS is either positively/ negatively associated or