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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 108

phobia, agoraphobia, specific phobia, generalized anxiety disorder, substance abuse disorder, alcohol abuse
disorder, and antisocial personality disorder) were examined. These disorders were identified through
structured interviews based on the diagnostic criteria of the DSM-III-R, administered for the first time to a
[27]
probabilistic sample, rather than exclusively to clinical cases . Krueger’s results highlighted that the
structural model that was most able to explain the comorbidities between disorders was composed of three
[27]
factors labeled as Anxious-Misery, Fear, and Externalizing . Given the high correlation between the first
two domains (r = 0.73), they were combined into a single variable called Internalizing . Kendler et al.
[27]
[28]
provided evidence for the replicability of the structural model from a genetic perspective . In particular,
they carried out a twin study on 5600 subjects considering the most common INT and EXT symptoms as
phenotypes (e.g., Major Depression, Generalized Anxiety Disorder, Alcohol Dependence, Conduct
[28]
Disorders, etc) . Firstly, the inclusion of all of these symptoms in the model-fitting analysis at the same
time has pointed out that the best-fitting model was an independent pathway with two strongly correlated
[28]
common additive genetic factors, namely Ac1 and Ac2 . More specifically, Ac1 showed greater loadings on
INT symptoms, while Ac2 on the EXT ones. In addition, they replicated the analyses focusing only on INT
symptoms, finding that the best fit to the data was provided again by an Independent Pathway model with
two common correlated genetic factors . In this case, Ac1 had greater loadings on symptoms belonging to
[28]
the “Anxious-Misery” domain (e.g., Depression and Generalized Anxiety Disorder), while Ac2 loaded on
[28]
symptoms related to the “Fear” cluster (e.g., Animal and situational Phobia) . Finally, in 2006, Krueger and
Markon reviewed all the existing literature on susceptibility models for common mental disorders identified
[29]
through the diagnostic criteria of the DSM, using population-based samples as their study subjects . The
results of this study, obtained through model-fitting analyses that compared the models reported in each
study, once again provided evidence for the superior fit of the three-factor model to the data. This
reaffirmed the division of INT into the categories of distress, commonly associated with a predisposition to
major depression, dysthymia, and generalized anxiety disorder, and fear, which primarily encompasses
more specific anxiety disorders .
[29]

Epidemiology of Internalizing and Externalizing Disorders
As far as epidemiology is concerned, during childhood and adolescence, the prevalence of the disorders
attributed to these two categories is stated to be approximately 20%, with a tendency to endure in early
adulthood, despite some substantial modifications . In particular, lifetime estimates of major depressive
[30]
disorder range from 23.2% to 43.3%, with an average onset between 11 and 14 years, whereas anxiety
disorders, which are the most prevalent adult psychopathologies, show a prevalence range from 2% to 24%
with a median rate of 8% in childhood and adolescence .
[31]
Specifically, when considering the epidemiology of anxiety disorder in youths, it has to be specified that
Generalized Anxiety Disorder and Social Anxiety have the highest prevalence rates, whereas Panic Disorder
and Obsessive Compulsive Disorders tend to be more prevalent in preadolescents and adolescents . The
[32]
worldwide prevalence of ADHD varies from 1.7% to 17.8%, with a median prevalence rate of 4%, while
conduct disorder and oppositional defiant disorder prevalence fluctuates between 5% and 14% . The
[32]
prevalence of children exhibiting both INT-EXT symptoms shows a range of variation depending on the
study population and geographic location. This variation extends from 2.4% in a British sample tracked
from childhood into adolescence to 13.7% within the age group of 6 to 12 years in a Canadian cohort, and
from 17.8% to 34.4% in a cross-sectional community sample of students spanning kindergarten through
12th grade in four U.S. states . Prevalence rates appear to be strongly influenced by the gender assigned at
[33]
birth: individuals assigned as male at birth (AMAB) show three times higher risk of developing conduct
disorder than those assigned as female at birth (AFAB), whereas the difference is less clear when analyzing
[32]
oppositional defiant disorder prevalence . Studies indicate no significant variation in depression rates
between genders during preadolescence; conversely, in adolescence and early adulthood, the prevalence of