N EW R E S E A R C H

Phasic Versus Tonic Irritability: Differential Associations

With Attention-Deficit/Hyperactivity Disorder
Symptoms
Elise M. Cardinale, PhD , Gabrielle F. Freitag, BA, Melissa A. Brotman, PhD ,
Daniel S. Pine, MD , Ellen Leibenluft, MD, Katharina Kircanski, PhD

Objective: Irritability is a multifaceted construct in pediatric psychopathology. It has been conceptualized as having a phasic dimension and a tonic
dimension. Disruptive mood dysregulation disorder is defined by the presence of both dimensions. Severe irritability, or disruptive mood dysregulation
disorder, is highly comorbid with attention-deficit/hyperactivity disorder (ADHD). However, it is unknown whether the presence of ADHD modulates
the expression of phasic and tonic irritability.
Method: A data-driven, latent variable approach was used to examine irritability and ADHD symptoms in a transdiagnostic pediatric sample (N ¼
489) with primary disruptive mood dysregulation disorder, ADHD, subclinical irritability symptoms, or no diagnosis. Using latent profile analyses, we
identified 4 classes: high levels of both irritability and ADHD symptoms, high levels of irritability and moderate levels of ADHD symptoms, moderate
levels of irritability and high levels of ADHD symptoms, and low levels of both irritability and ADHD symptoms. Confirmatory factor analysis
operationalized phasic irritability and tonic irritability.
Results: As expected, the 2 latent classes characterized by high overall irritability exhibited the highest levels of both phasic and tonic irritability.
However, between these 2 high irritability classes, highly comorbid ADHD symptoms were associated with significantly greater phasic irritability than
were moderately comorbid ADHD symptoms. In contrast, the 2 high irritability groups did not differ on levels of tonic irritability.
Conclusion: These findings suggest that phasic, but not tonic, irritability has a significant association with ADHD symptoms and that phasic and
tonic might be distinct, though highly related, irritability dimensions. Future research should investigate potential mechanisms underlying this dif-
ferential association.
Key words: ADHD, aggression, DMDD, irritability, latent variable analysis
J Am Acad Child Adolesc Psychiatry 2021;60(12):1513–1523.

rritability, defined as an increased proneness to current study adopted a data-driven, latent variable approach to
I anger relative to peers, is a common symptom in
pediatric psychopathology.1 While irritability cuts
across many diagnoses in youths, disruptive mood dysregula-
examine patterns of phasic and tonic irritability and ADHD
symptoms in a transdiagnostic sample of youths.
Children with ADHD often present with significant
tion disorder (DMDD)2 classifies youths with the most severe, emotional lability,9,10 including chronic irritability.1,5 Pre-
chronic, and impairing irritability.3 Specifically, DMDD con- vious research in community samples indicates that 4.3%–
ceptualizes irritability as including both a phasic dimension, ie, 23.5% of youths with ADHD meet diagnostic criteria for
severe and developmentally inappropriate outbursts, and a DMDD,3,11 with estimates as high as 35.8% in children
tonic dimension, ie, persistent irritable mood between out- with a diagnosis with ADHD combined type.8 Indeed, in
bursts. Clinical samples of youths with DMDD exhibit high patients with ADHD, increased anger and irritability are
rates of co-occurring attention-deficit/hyperactivity disorder associated with greater severity of core ADHD symptoms12
(ADHD).4,5 Conversely, irritability is a common symptom in and increased risk for negative outcomes, including peer
youths with ADHD.6–8 However, it is unknown whether or rejection, substance abuse, and depression.8,13,14 In fact,
how the presence of ADHD modulates the expression of ir- based on physiological data, ADHD with severe co-
ritability, particularly phasic vs tonic irritability, which has occurring irritability, as seen in DMDD, has been pro-
implications for treatment. To address this question, the posed to represent a distinct subtype of ADHD.7

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CARDINALE et al.

The conceptualization of irritability as a construct in examined whether the LPA-derived classes differed in their
general as well as its presentation in DMDD specifically in- patterns of phasic and tonic irritability.
cludes both phasic and tonic dimensions. Phasic irritability Given indirect evidence for the reduction of phasic irri-
involves a rapid onset of angry affect and associated behav- tability symptoms following stimulant medication adminis-
iors, such as verbal and sometimes physical aggression (eg, tration,24–26 we predicted that, in the context of high
physically pushing, shoving, slapping, or kicking another irritability, high vs low levels of ADHD symptoms would be
person), typically in response to identifiable environmental related to greater phasic, but not tonic, irritability. Finally,
triggers, such as frustration. Tonic irritability captures longer- given the common co-occurrence of anxiety and opposition-
lasting but less intense grouchiness, crankiness, and annoy- ality28 with irritability, we performed additional analyses
ance in between outbursts.1,15 Phasic and tonic symptoms of controlling for anxiety and oppositionality to test for any
irritability are the 2 core dimensions of observable behavior confounding effects of these common comorbidities.
underlying the clinical definition of DMDD and thus Together, these analyses provide the first direct examination of
represent the clearest target for translational research and ADHD symptoms in relation to phasic and tonic irritability.
development of precision-based treatments of DMDD.16
Although the conceptualization of irritability and
DMDD include both phasic and tonic dimensions, few METHOD
studies have parsed these dimensions, and it is unclear Participants
whether they have differential clinical, behavioral, or bio- The sample consisted of 489 youths ages 7–18 years (mean
logical correlates.17–22 Despite the high comorbidity of [SD] age ¼ 12.03 [2.41] years) who were recruited from the
ADHD and irritability, no study has examined how ADHD community to participate in research at the National
symptoms may relate differentially to phasic and tonic ir- Institute of Mental Health (NIMH). The sample was pre-
ritability. In treatment studies of ADHD, following dominantly White (63.60%) and upper-middle class (in-
administration of stimulant medication, a reduction in ir- come >90,000; 70.69%). Full demographic characteristics
ritability symptoms broadly has been observed.20,23–25 are presented in Table 1.
However, this literature did not assess changes in phasic The sample was recruited to represent full ranges of
and tonic symptoms specifically. Indirect evidence for dif- irritability and ADHD symptoms, including youths with a
ferential associations comes from a recent treatment study, primary diagnosis of DMDD (n ¼ 191) or ADHD (n ¼
in which the optimization of stimulant medication before 102), youths with clinically significant irritability that did
the initiation of selective serotonin reuptake inhibitor vs not meet thresholds required for DMDD (subthreshold
placebo in the treatment of DMDD significantly reduced DMDD [sub-DMDD], n ¼ 19), and youths with no
ADHD symptoms and temper outbursts, but not irritable psychiatric diagnosis (Table 1). Youths with sub-DMDD
mood.26 Thus, ADHD symptoms may be differentially exhibited temper outbursts at least once per month, irrita-
associated with phasic vs tonic irritability, perhaps reflecting ble mood at least 1 day per week for most of the day, and
greater shared mechanisms (ie, impaired top-down pre- irritability-related impairment in at least one setting (home,
frontal control of subcortical regions).27 school, peers); all other criteria for sub-DMDD were the
The current study used latent variable methods to same as those for DMDD. Before participation, diagnoses
investigate ADHD symptoms as a potential modulator of were confirmed by a doctoral- or master’s-level clinician
phasic vs tonic irritability in a large, well-characterized using the Schedule for Affective Disorders and Schizo-
transdiagnostic sample of youths. First, we used latent phrenia for School-Age Children–Present and Lifetime
profile analysis (LPA) to derive classes of youths character- version (K-SADS-PL)29 including a DMDD module.30 All
ized by distinct patterns of irritability and ADHD symp- diagnoses were reviewed by a board-certified psychiatrist or
toms. This approach involved a data-driven evaluation of psychologist (D.S.P., M.A.B., or E.L.). Additional clinical
patterns of irritability and ADHD symptoms. In contrast to characteristics are presented in Table 1. Exclusionary criteria
median-split approaches, LPA statistically evaluates whether were IQ <70; diagnosis of autism spectrum disorder, past
and what distinct patterns of irritability and ADHD and/or current posttraumatic stress disorder, schizophrenia,
symptoms emerge in the sample. Next, we used confirma- or depression; use of any substance with psychoactive effects
tory factor analysis (CFA) to quantify separate indices of within 3 months; and neurological disorder. Parents pro-
phasic irritability and tonic irritability. With respect to vided written informed consent and youths provided writ-
phasic irritability, we included indices of both temper ten assent before participation. All study procedures were
outbursts and aggression, given that both represent behav- approved by the NIMH Institutional Review Board. Par-
ioral manifestations of underlying trait anger.28 We then ticipants received monetary compensation.
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 PHASIC VERSUS TONIC IRRITABILITY AND ADHD

TABLE 1 Sample Characteristics TABLE 1 Continued

Variable Value Variable Value
Mean (SD) Sub-DMDD 19 (3.89)
Age, years 12.03 (2.41) Healthy volunteer 177 (36.20)
IQ 110.46 (12.66) Diagnosisc
n (%) ADHD 251 (51.33)
Sex, malea 268 (54.81) Anxiety disorderd 108 (22.09)
Race CD 3 (0.61)
White 311 (63.60) DMDD 191 (39.06)
American Indian or Alaskan 3 (0.61) MDD 21 (4.29)
Native ODDe 24 (4.91)
Asian 23 (4.70) None 177 (36.20)
Black or African American 84 (17.18) Medicationf
Multiple races 45 (9.20) AED 25 (5.11)
Other 1 (0.20) ADHD medicationsg 136 (27.81)
Unknown 22 (4.50) SGA 52 (10.63)
Ethnicity SSRI 70 (14.31)
Latino or Hispanic 52 (10.63) None 314 (64.21)
Not Latino or Hispanic 423 (86.50)
Unknown 14 (2.86) Note: ADHD ¼ attention-deficit/hyperactivity disorder; AED ¼ antiepi-
leptic drug; ARI ¼ Affective Reactivity Index; CBRS Hyperactive/
Socioeconomic status
Impulsive ¼ DSM Hyperactive/Impulsive Subscale scores of the Conners
Highest education level Comprehensive Behavior Ratings Scale; CBRS Inattentive ¼ DSM Inat-
Graduate professional 195 (39.88) tentive Subscale scores of the Conners Comprehensive Behavior Ratings
degree (master’s or above) Scale; CD ¼ conduct disorder; DMDD ¼ disruptive mood dysregulation
4-year college graduate 65 (13.29) disorder; MDD ¼ major depressive disorder; ODD ¼ oppositional
defiant disorder; SGA ¼ second-generation antipsychotic; SSRI ¼ se-
Partial college (1 year) 41 (8.38)
lective serotonin reuptake inhibitor; Sub-DMDD ¼ subthreshold
High school graduate 10 (2.04) disruptive mood dysregulation disorder.
a
Partial high school (grade 10 7 (1.43) One participant declined to indicate sex. This participant was coded as
or 11) sex unspecified for analyses including sex in the model.
b
Junior high school (grades 4 (0.82) Percentage of total sample in each research group. Research group
refers to the primary group or diagnosis for which participants were
7e9)
recruited for research purposes. Participants could have comorbid
<7 years of school 8 (1.64) diagnoses.
Unknown 159 (32.52) c
Percentage of total sample with a diagnosis of each disorder. Partici-
Income pants could have multiple diagnoses.
d
>$180,000 95 (28.70) Anxiety disorder includes generalized anxiety disorder, separation
anxiety disorder, social anxiety disorder, and specific phobias.
$90,000e$179,999 139 (41.99) e
Following DSM-5 exclusion rules, ODD cannot be diagnosed
$60,000e$89,999 35 (10.57) with DMDD.
f
$40,000e$59,999 21 (6.34) Percentage of total sample taking each medication type. Participants
$25,000e$39,999 13 (3.93) could be taking more than one type of medication.
g
$15,000e$24,999 8 (2.42) Includes stimulants, anti-ADHD medication, and nonstimulant anti-
ADHD medication.
$10,000e$14,999 2 (0.60)
$5,000e$9,999 0 (0)
<$5,000 1 (0.30)
Measures
Unknown 175 (35.79)
Mean (SD) Latent Profiles of Irritability and ADHD Symptoms. O-
Symptom measure scores verall levels of irritability were assessed using the parent-
ARI 4.38 (4.15) report Affective Reactivity Index (ARI).31 The ARI is one
CBRS Inattentive 10.55 (8.53) of the most widely used measures of irritability and has been
CBRS Hyperactive/Impulsive 7.88 (7.42) used in samples comparable to the current one.32 Scores
n (%) ranged across all possible scores from a minimum of 0 to a
Research groupb maximum of 12 (mean [SD] ¼ 4.38 [4.15]). Internal
ADHD 102 (20.86) consistency of the ARI was high in the current study (a ¼
DMDD 191 (39.06) .94). Total scores on the ARI were z-transformed before
(continued) analysis.
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CARDINALE et al.

ADHD symptoms were assessed using the parent-report others”). For RMOAS, subscale scores were calculated using a
Conners Comprehensive Behavior Ratings Scale (CBRS) summed score. Scores ranged from 0 to 20 on the RMOAS
DSM Inattentive and Hyperactive/Impulsive subscales.33 Verbal Aggression subscale (mean [SD] ¼ 3.15 [4.23]), 0 to
Scores ranged across all possible scores from a minimum 44 on the Aggression Against Property subscale (mean [SD] ¼
of 0 to a maximum of 27 on the Inattentive subscale (mean 5.07 [7.09]), and 0 to 52 on the Aggression Towards Others
[SD] ¼ 10.55 [8.53]) and the Hyperactive/Impulsive sub- (mean [SD] ¼7.22 [11.20]). SCAR-H Aggression subscale
scale (mean [SD] ¼ 7.88 [7.42]). Internal consistency of scores were computed using the mean response on a 3-point
both the Inattentive (a ¼ .96) and the Hyperactive- Likert scale across all items. Scores ranged from 1 to 3 (mean
Impulsive (a ¼ .93) subscale was high in the current [SD] ¼ 1.49 [0.49]).
study. Again, all scores were z-transformed before analysis. Critically, the SCAR-H and RMOAS Aggression sub-
scales include items that broadly capture aggressive behav-
Phasic and Tonic Irritability and Aggression. For assess- iors and do not differentiate between reactive and proactive
ment of phasic irritability, the observed variables used to aggression. For example, the RMOAS Verbal Aggression
index temper outbursts included parent-, child-, and subscale includes both “How many times did your child
clinician-rated measures. Specifically, we used the clinician- threaten to hurt someone?” and “How many times did your
rated Temper Outbursts item (ie, “Do you get angry a lot? child shout angrily, curse, or insult people in a repetitive,
Do you have blow-ups or lose your temper? Do little things out-of-control way?”; these items could capture more pro-
get you mad? When you get really angry do you yell and active and more reactive forms of verbal aggression,
scream, stomp around, throw or break things?”) from either respectively. Given that these measures capture a more
the DMDD module or severe mood dysregulation module global assessment of aggression than typically characteristic
of the K-SADS-PL,30 the Explosiveness subscale of the of phasic irritability, we modeled aggression separately from
parent-report Screen for Children’s Affective Reactivity– temper outbursts as 2 independent latent factors.
Home (SCAR-H) (eg, “Being ‘hot-blooded’ and quick Similar to phasic irritability, the observed variables used
tempered”),34 and the Anger Expression-Out subscale to index irritable mood between outbursts included parent-,
(expression of angry feelings toward other persons or objects child-, and clinician-rated measures. Specifically, we used
in the environment) of the child-report State-Trait Anger the clinician-rated Mood Between Outbursts item (ie, “Do
Expression Inventory–Child/Adolescent (STAXI-CA) (eg, you often feel irritable, cranky, or angry? Do you feel this
“I do things like slam doors”).35 Responses to the K-SADS- way most of the day nearly every day?”) from the DMDD
PL Temper Outburst item ranged from 1 to 3 (mean and severe mood dysregulation modules of the K-SADS-PL,
[SD] ¼ 2.54 [0.75]), with 1 indicating not present, 2 item 12 (ie, “Being kinda grouchy”) from the parent-report
indicating subthreshold level, and 3 indicating threshold SCAR-H, and item 16 (ie, “I feel grouchy”) from the child-
level (temper outbursts occur at least 3 times a week and are report STAXI-CA. Responses to the DMDD module
grossly disproportionate to the stressor and inconsistent ranged from 1 to 3 (mean [SD] ¼ 2.51 [0.75]) where 1
with developmental level). SCAR-H Explosiveness subscale indicates not present, 2 indicates subthreshold levels of ir-
scores were computed as participants’ mean response across ritable mood between outbursts, and 3 indicates irritable
all items, which were scored on 3-point Likert scales. Scores mood between meets/exceeds threshold (present most of the
ranged from 1 to 3 (mean [SD] ¼ 1.69 [0.65]). STAXI-CA day and nearly every day). Responses to SCAR-H item 12
Anger Expression-Out subscale sum scores ranged from 5 to were given on a 3-point Likert scale and ranged from 1 to 3
15 (mean [SD] ¼ 9.30 [2.55]). (mean [SD] ¼ 1.85 [0.78]). Responses to STAXI-CA item
To index aggression, we used 3 aggression subscales from 16 were given on a 3-point Likert scale and ranged from 1
the parent-report Retrospective Modified Overt Aggression to 3 (mean [SD] ¼ 1.54 [0.61]).
Scale (RMOAS)36: Verbal Aggression (ie, “How many times
did your child threaten to hurt someone?”), Aggression Global Impairment. Overall severity of impairment result-
Against Property (ie, “How many times did your child break ing from psychiatric symptoms was measured by the Chil-
things, smash windows, or damage or deface property on dren’s Global Assessment Scale (CGAS).37 The CGAS is a
purpose?”), and Aggression Towards Others (ie, “How many well-established clinician-rated measure scored on the basis
times did your child hit someone with hands or an object, of clinical interviews with both the parent and the child.
kick, push, scratch, or pull hair?”) as well as the Aggression Scores on the CGAS ranged from 1 to 100 (mean [SD] ¼
subscale from the parent-report SCAR-H (eg, “Making 59.71 [18.04]), with lower CGAS scores reflecting greater
threatening gestures, like swinging at people or grabbing at levels of impairment.

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 PHASIC VERSUS TONIC IRRITABILITY AND ADHD

Comorbid Symptoms. In a subset of participants (n ¼ outbursts models were estimated using only 3 observed
483), anxiety symptoms were measured using the parent- variables each, they were just-identified models with insuf-
report Screen for Child Anxiety Related Emotional Disor- ficient degrees of freedom to estimate fit. Importantly, path
ders (SCARED) total score.38 Scores ranged from 0 to 58 coefficients are still valid, allowing for assessment of the
(mean [SD] ¼ 13.45 [12.89]), indicating variability in degree to which observed variables contribute to the latent
levels of anxiety through the clinical range (scores >25). variable. Factor scores were extracted for each latent variable
Oppositionality was measured using 4 items from the for each participant. In contrast to summed scores, factor
Conners CBRS (ie, “Argues with adults,” “Actively defies or scores capture the shared variance among measured variables
refuses to comply with adults’ requests,” “Blames others for within each model. Therefore, factor scores are less sus-
his/her mistakes or misbehavior,” “Spiteful or vindictive”) ceptible to measure-specific variance or impurities.
that were not confounded with irritability. A summed
Conners CBRS Oppositionality score was calculated for Comparison Between Classes. To examine associations of
each participant. Scores ranged across all possible scores (0– classes with phasic and tonic irritability, we conducted an
12) (mean [SD] ¼ 4.18 [3.61]). analysis of covariance (ANCOVA) with class entered as a
between-subjects factor and age and sex entered as cova-
Data Analysis riates. Effect sizes are reported for all analyses. For omnibus
Latent Profile Analysis. LPA was conducted in R Version effects, we report partial eta-squared (hp2), and for pairwise
3.6.0 using the tidyLPA package to assess latent classes as a comparisons, we report d.
function of irritability and ADHD symptoms. Successive
solutions were fit to the data by increasing the number of
classes by 1 until the best-fitting solution was found. RESULTS
Models were evaluated using the Bayesian information cri- LPA of Irritability and ADHD Symptoms
terion, Akaike information criterion, entropy, and boot- Results of the LPA supported a 4-class solution (Figure 1;
strapped parametric likelihood ratio test. Indices of good Table 2; Table S1, available online). A 5-class solution failed
model fit include lower Bayesian information criterion and to converge and exhibited a very low probability (< .1%) of
Akaike information criterion values, entropy >0.80, and a some classes being assigned cases. The 4 classes all differed
significant bootstrapped parametric likelihood ratio test (< significantly from one another on ARI scores (F3,485 ¼
0.05). We also evaluated models based on the size of the 1075.94, p < .001, hp2 ¼ 0.87), Conners CBRS Inattentive
smallest derived class, using a cutoff of 5% for the smallest scores (F3,485 ¼ 577.89, p < .001, hp2 ¼ 0.78), and Conners
derived class. These model selection criteria were consistent CBRS Hyperactive-Impulsive scores (F3,485 ¼ 424.00, p <
with prior work done with similar populations.32,39 There .001, hp2 ¼ 0.72) (all pairwise comparisons p < 0.01).
were no missing data on the ARI or Conners CBRS. Par- For ease of interpretation, each class was characterized
ticipants were subsequently categorized according to their using ARI raw scores and Conners CBRS T scores
most likely class. (Table 3). For Conners CBRS T scores, published cutoffs
are33 70 ¼ very elevated, 65–69 ¼ elevated, 60–64 ¼
Confirmatory Factor Analysis. We conducted CFAs using high average, 40–59 ¼ average, and <40 ¼ low. For ARI
the lavaan package40 in R to extract estimates of temper scores, the current classes’ levels are <1 ¼ low, <3 ¼
outbursts, aggression, and irritable mood between out- moderate, and 8 ¼ high.32 Based on these criteria, we
bursts. Three independent models were fit using full in- characterized the 4 classes as high levels of both irritability
formation maximum likelihood to handle missing data. A and ADHD symptoms (n [%] ¼ 130 [26.58%]), high
single latent variable each for temper outbursts, aggression, levels of irritability and moderate levels of ADHD symp-
and irritable mood between outbursts was estimated using toms (n [%] ¼ 87 [17.79%]), moderate levels of irritability
the observed variables described above. For the aggression and high levels of ADHD symptoms (n [%] ¼ 62
latent variable, model fit was assessed using the comparative [12.68%]), and low levels of both irritability and ADHD
fit index, Tucker Lewis index, and root mean square error of symptoms (n [%] ¼ 210 [42.94%]).
approximation. For comparative fit index and Tucker Lewis
index, values >0.950 indicate strong model fit. For root Demographic Variables and Global Impairment
mean square error of approximation, values <0.05 indicate Examination of demographic variables by derived class
good model fit and values <0.08 indicate adequate model showed that the 4 classes differed significantly in age
fit. Because temper outbursts and irritable mood between (F3,484 ¼ 28.74, p < .001, hp2 ¼ 0.15), sex (c26 ¼ 37.61,

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CARDINALE et al.

FIGURE 1 Mean Scores on the Symptom Measures for Each Anger Expression-Out subscale and the K-SADS Temper
Class in the 4-Class Solution Outbursts item (0.52 and 0.72, respectively). Participants’
factor scores were extracted (N ¼ 456: high levels of both
irritability and ADHD symptoms, n ¼ 129; high levels of
irritability and moderate levels of ADHD symptoms, n ¼
85; moderate levels of irritability and high levels of ADHD
symptoms, n ¼ 61; low levels of both irritability and
ADHD symptoms, n ¼ 181).
An ANCOVA examined temper outbursts factor scores
by class, covarying age and sex. Classes differed significantly
in temper outbursts (F3,450 ¼ 211.91, p < .001, hp2 ¼
0.59. Post hoc pairwise comparisons using the estimated
marginal means indicated that temper outbursts differed
significantly between all classes (all ps < .002, ds ¼ 0.46–
2.81), with the highest temper outburst score in the high
Note: Irritability as measured by the parent report Affective Reactivity Index (ARI), levels of both irritability and ADHD symptoms class, fol-
CBRS Inattentive and CBRS Hyperactive/Impulsive as measured by the DSM Inat-
tentive and Hyperactive/Impulsive subscales of the Conners Comprehensive
lowed by the high levels of irritability and moderate levels of
Behavior Rating Scale. z-score of 1 ¼ ARI Parent score of 8.52, Conners CBRS Inat- ADHD symptoms class, then the moderate levels of irrita-
tentive score of 19.08, and Conners CBRS Hyperactive/Impulsive score of 15.29; z- bility and high levels ADHD symptoms class, and last the
score of 0 ¼ ARI Parent score of 4.38, Conners CBRS Inattentive score of 10.55,
low levels of irritability and ADHD symptoms class
Conners CBRS Hyperactive/Impulsive score of 7.88; z-score of 1 ¼ ARI Parent
score of 0.23, Conners CBRS Inattentive score of 2.02, and Conners CBRS Hyper- (Figure 3; Table S2, available online).
active/Impulsive score of 0.46. ADHD ¼ attention-deficit/hyperactivity disorder. For aggression, CFA estimated a single latent variable
Please note color figures are available online. using the 4 observed variables (Figure 2). Model fit indices
indicated good model fit (Tucker Lewis index ¼ 1.00;
p < .001, 4 ¼ 0.28), race (c218 ¼ 60.88, p < .001, comparative fit index ¼ 1.00; root mean square error of
4 ¼ 0.20), and overall severity of impairment (F3,294 ¼ approximation ¼ 0, 90% CI [0, 0.08]; c22 ¼ 1.38, p ¼
161.70, p < .001, hp2 ¼ 0.63) (for pairwise comparisons .50). All 4 observed variables loaded significantly on the
see Table 3). The classes did not differ in IQ (F3,392 ¼ 0.06, latent factor (all ps < .001). Participants’ factor scores were
p ¼ .98, hp2 ¼ 0.00) or ethnicity (c26 ¼ 5.72, p ¼ extracted (N ¼ 452: high levels of both irritability and
.46, 4 ¼ 0.08). ADHD symptoms, n ¼ 125; high levels of irritability and
moderate levels of ADHD symptoms, n ¼ 83; moderate
levels of irritability and high levels of ADHD symptoms,
Associations of Classes With Phasic and Tonic Irritability n ¼ 57; low levels of both irritability and ADHD symp-
Phasic Irritability. For temper outbursts, CFA estimated a toms, n ¼ 187).
single latent variable using the 3 observed variables An ANCOVA examined aggression factor scores by
(Figure 2). Because the model was just-identified, fit sta- class, covarying age and sex. Classes differed significantly in
tistics could not be computed. All 3 observed variables aggression (F3,446 ¼ 114.53, p < .001, hp2 ¼ 0.44). Post
loaded significantly on the temper outburst latent variable hoc pairwise comparisons using the estimated marginal
(all ps < .001). Of note, the loading of the SCAR-H means indicated that aggression differed significantly be-
Explosiveness subscale was very high (0.94), both in abso- tween all classes (all ps < .001, ds ¼ 0.63–2.13), with the
lute terms and relative to the loadings for the STAXI-CA highest aggression score in the high levels of both irritability

TABLE 2 Fit Information for Latent Profile Analysis Models With 2–5 Classes

Classes Log likelihood AIC BIC Entropy BLRT Smallest class proportion, %
2 L1659.09 3338.18 3380.10 0.91 < 0.01 49.08
3 L1567.36 3162.71 3221.40 0.88 < 0.01 24.72
4 L1490.02 3016.04 3091.50 0.89 < 0.01 12.68
5 L1490.01 3024.02 3116.26 0.73 0.36 < 0.01

Note: AIC ¼ Akaike information criterion; BIC ¼ Bayesian information criterion; BLRT ¼ bootstrapped parametric likelihood ratio test.

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 PHASIC VERSUS TONIC IRRITABILITY AND ADHD

TABLE 3 Demographics and Symptom Measures by Each Class in the 4-Class Solution

High Moderate Low

irritability þ High irritability þ irritability þ irritability þ
high ADHD moderate ADHD high ADHD low ADHD Omnibus p
Age 11.08 (1.90)a 10.91 (1.98)a 12.34 (2.20)b 13.00 (2.55)c < .001
IQ 110.31 (13.52) 110.81 (12.32) 110.94 (13.07) 110.27 (12.28) .98
Sex, n (% female) 43 (33.07)a 40 (45.98)a,c 14 (22.58)b 123 (58.85)c < .001
Race, (%) < .001
White 98 (75.38)a 65 (74.71)a 48 (77.42)a 100 (47.62)b
American Indian or Alaskan 1 (0.77)a 0 (0.00)a 1 (1.61)a 1 (0.48)a
Native
Asian 5 (3.85)a,b 6 (6.90)b 0 (0.00)a 12 (5.71)a,b
Black or African American 11 (8.46)a,b 3 (3.45)b 9 (14.52)a 61 (29.05)c
Multiple races 12 (9.23)a 8 (9.20)a 3 (4.84)a 22 (10.48)a
Other 0 (0.00)a 0 (0.00)a 0 (0.00)a 1 (0.48)a
Unknown 3 (2.31)a 5 (5.75)a 1 (1.61)a 13 (6.19)a
Ethnicity, n (%) .46
Latino or Hispanic 15 (11.54) 8 (9.20) 8 (12.90) 21 (10.00)
Not Latino or Hispanic 114 (87.69) 74 (85.06) 53 (85.48) 182 (86.67)
Unknown 1 (0.77) 5 (5.75) 1 (1.61) 7 (3.33)
Impairmente 47.06 (7.61)a 51.69 (11.89)b 61.58 (11.33)c 82.25 (13.74)d < .001
ARI Parent 8.99 (1.70)a 8.09 (1.93)b 2.52 (1.79)c 0.53 (1.00)d < .001
CBRS Inattentive T score 74.45 (8.96)a 58.95 (8.98)b 70.97 (8.75)c 46.54 (5.94)d < .001
CBRS Hyperactive/Impulsive 79.24 (9.04)a 62.54 (10.27)b 69.26 (13.18)c 46.99 (5.50)d < .001
T score

Note: Values are reported as mean (SD) unless otherwise noted. Cells marked with different superscript letters (a, b, c, d) are significantly different.
ADHD ¼ attention-deficit/hyperactivity disorder; ARI ¼ Affective Reactivity Index; CBRS Hyperactive/Impulsive ¼ DSM Hyperactive/Impulsive Sub-
scale scores of the Conners Comprehensive Behavior Ratings Scale; CBRS Inattentive ¼ DSM Inattentive Subscale scores of the Conners Compre-
hensive Behavior Ratings Scale.
e
Children’s Global Assessment Scale scores range from 1 to 100, with lower scores reflecting greater impairment.

and ADHD symptoms class followed by the high levels of An ANCOVA examined irritable mood factor scores by
irritability and moderate levels of ADHD symptoms class, class, covarying age and sex. Classes differed significantly in
then the moderate levels of irritability and high levels of irritable mood (F3,450 ¼ 120.16, p < .001, hp2 ¼ 0.45).
ADHD symptoms class, and last the low levels of both ir- Post hoc pairwise comparisons using the estimated marginal
ritability and ADHD symptoms class (Figure 3; Table S2 means indicated that irritable mood did not differ signifi-
available online). cantly between the high irritability and high ADHD
symptoms class vs the high irritability and moderate ADHD
Tonic Irritability. CFA estimated a single latent variable symptoms class (mean difference ¼ 0.13, 95% CI [0.01,
using the 3 observed variables (Figure 2). Because the model 0.27], p ¼ .06, d ¼ 0.25) (Figure 3). All other pairwise
was just-identified, fit statistics could not be computed. All comparisons were significant (all ps < .001, ds ¼ 0.52–
3 observed variables loaded significantly on the latent vari- 2.08) (Table S2, available online).
able (all ps < .001). Of note, the loading for STAXI-CA Given the high correlations between phasic and tonic
item 16 (0.30) was somewhat lower than the loadings for irritability (rs ¼ 0.58–0.79) (Table S3, available online), we
the K-SADS Mood Between item and SCAR-H item 12 repeated analyses for temper outbursts and aggression con-
(0.69 and 0.65, respectively). Participants’ factor scores trolling for irritable mood (F3,449 ¼ 59.20, p < .001, hp2 ¼
were extracted (N ¼ 456: high levels of both irritability and 0.28 and F3,436 ¼ 41.19, p < .001, hp2 ¼ 0.22, respectively)
ADHD symptoms, n ¼ 129; high levels of irritability and and for irritable mood between outbursts controlling for
moderate levels of ADHD symptoms, n ¼ 85; moderate temper outbursts (F3,449 ¼ 6.25, p < .001, hp2 ¼ 0.04) or
levels of irritability and high levels of ADHD symptoms, aggression (F3,436 ¼ 46.96, p < .001, hp2 ¼ 0.24). The
n ¼ 61; low levels of both irritability and ADHD symp- findings remained unchanged with one exception: irritable
toms, n ¼ 181). mood did not differ significantly between the low levels of
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CARDINALE et al.

FIGURE 2 Confirmatory Factor Analysis Models for Temper Outbursts, Aggression, and Irritable Mood Between Outbursts

Note: (A) temper outbursts, (B) aggression, and (C) irritable mood between outbursts. Path coefficients represent the loading of each item onto the latent factor. DMDD ¼
disruptive mood dysregulation disorder; RMOAS ¼ Retrospective Modified Overt Aggression Scale; SCAR-H ¼ Screen for Children’s Affective Reactivity–Home; STAXI ¼
State-Trait Anger Expression Inventory.
***p < .001.

both irritability and ADHD symptoms class vs the moderate Last, we repeated the analyses to address potential
levels of irritability and high levels of ADHD symptoms class confounding effects of co-occurring anxiety and opposi-
when controlling for temper outbursts (mean difference ¼ tionality.28 Overall, the pattern of findings did not change
0.03, 95% CI [0.11, 0.16], p ¼ .69, d ¼ 0.05). All pairwise when either anxiety or oppositionality was entered as a
comparisons are in Tables S4 and S5, available online. covariate in the models. Critically, when comparing the 2

FIGURE 3 Estimated Marginal Means for Temper Outbursts, Aggression, and Irritable Mood Between Outbursts Factor Scores
Across Each Class in the 4-Class Solution

Note: Error bars represent 95% CI. The only nonsignificant pairwise comparison was for irritable mood between outbursts scores between the high irritability þ high ADHD
and high irritability þ moderate ADHD groups. ADHD ¼ attention-deficit/hyperactivity disorder; ns ¼ nonsignificant. Please note color figures are available online.

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 PHASIC VERSUS TONIC IRRITABILITY AND ADHD

high-irritability classes, high relative to moderate co- Interestingly, factor scores for the resulting latent variables
occurring ADHD symptoms were associated with larger were highly correlated with one another, supporting that
effects for temper outbursts and aggression than irritable tonic and phasic irritability symptoms are strongly related.
mood. See Supplement 1 (Tables S6–S9), available online, Future factor analytic studies could compare models of phasic
for a full discussion of these analyses. and tonic irritability that vary in factor structure and asso-
ciations between latent variables. This would allow for a
direct test of the degree to which phasic and tonic irritability
DISCUSSION symptoms are correlated. Such an approach would require
additional measured variables, particularly for irritable mood
The present study is the first to use data-driven methods to
between outbursts, which in the current study relied on only
identify profiles of irritability and ADHD symptoms in a
3 item-level variables. Further rigorous work on disen-
large, transdiagnostic sample of youths. Using LPA, we
tangling these constructs relies on the development of addi-
identified 4 symptom classes: high levels of both irritability
tional measures of tonic irritability. Additionally, the current
and ADHD symptoms, low levels of both irritability and
study included temper outbursts and aggression as separate
ADHD symptoms, and 2 opposing, intermediate profiles
latent variables capturing behavioral manifestations of un-
characterized by high levels of irritability and moderate
derlying trait anger. These constructs were modeled sepa-
levels of ADHD symptoms vs moderate levels of irritability
rately owing to the broad measures of aggression included in
and high levels of ADHD symptoms. With respect to phasic the study. Future work might examine further whether
and tonic components of irritability, as expected across the measures of reactive aggression specifically and temper out-
2 classes characterized by high overall irritability, we bursts constitute a shared overarching construct of phasic
observed significant levels of temper outbursts, irritable irritability.
mood between outbursts, and aggression in both groups. Critically, despite high correlations between tonic and
However, when comparing these 2 high-irritability classes, phasic irritability symptoms, when comparing the 2 high-
high relative to moderate co-occurring ADHD symptoms irritability classes that differed in levels of co-occurring
were associated with significantly greater temper outbursts ADHD symptoms, ie, high vs moderate, we observed large
and aggression, but not irritable mood between outbursts. between-group effect sizes for temper outbursts and aggres-
This clinically important pattern of findings suggests that sion, but only a small effect size for irritable mood that was not
while phasic and tonic irritability are strongly related con- statistically significant. This differential association may arise
structs, they are potentially dissociable through their asso- from shared mechanisms between ADHD symptoms and
ciations with comorbid ADHD symptoms. phasic irritability. In particular, the differential association of
The best fit solution of our LPA indicated classes char- ADHD symptoms with temper outbursts and aggression may
acterized by differing levels of irritability and ADHD symp- implicate shared alterations in top-down, prefrontal modula-
toms. Of note, no classes emerged with high levels of one tion of subcortical brain processes, such as prepotent or
clinical dimension and low levels of the other. This suggests automatic behavioral responses to stimuli.27,43 Deficits in
that in a clinical sample, irritability and ADHD symptoms co- cognitive control have been viewed as central to the construct
occur to some extent in all classes where symptoms are pre- of ADHD.44 Prior research implicates aberrant frontostriatal
sent. The 2 classes characterized by high irritability demon- activity and associated cognitive control deficits45 as a po-
strated poorer overall functioning, converging with prior tential endophenotype for ADHD.46 Temper outbursts and
findings that irritability is associated with considerable aggression may reflect underlying impairments in cognitive
impairment.3,11,41 Moreover, the class with high levels of both control, consistent with evidence that normative levels of
irritability and ADHD symptoms demonstrated the poorest temper outbursts and reactive aggression decrease across
overall functioning. Thus, for treatment-seeking youths with development as prefrontal cortex maturation occurs.47,48 In
severe irritability, co-occurring ADHD symptoms appears to contrast, there may be less mechanistic overlap between irri-
be associated with increased impairment. table mood between outbursts and ADHD.
Prior research has focused on identifying an irritable The current study has several limitations. First, our
subtype of ADHD.7,8,42 Conversely, our analyses extend analyses adopted a classify-then-analyze approach. With this
previous work by probing the effect of co-occurring ADHD approach, LPA was used to first identify classes based on
symptoms on different dimensions of irritability. Using CFA, patterns of irritability and ADHD symptoms. We then
we were able to extract novel indices of phasic and tonic ir- compared phasic and tonic irritability across these classes.
ritability across parent-, child-, and clinician-informant re- This approach treats class assignment as precise and does
ports. These indices could be used in further research. not capture its uncertain or probabilistic nature. Second,
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CARDINALE et al.

most participants were treatment-seeking, contributing to and ADHD symptoms in a large, well-characterized, trans-
the relatively high rates of comorbidity, impairment, and diagnostic sample of youths. The novel findings suggest that
medication use. The sample was recruited to include clinical phasic and tonic irritability are differentially associated with
groups characterized by primary irritability and/or ADHD co-occurring ADHD symptoms. These findings suggest that
symptoms. Although this enabled a fine-grained approach highly comorbid irritability and ADHD symptoms represent
to clinical phenotyping of irritability and ADHD, it will be an increased risk for clinical impairment. Future work inves-
important to examine associations of phasic and tonic irri- tigating temper outbursts and irritable mood holds promise
tability with ADHD in community samples and across a for disentangling dimensions of irritability with potentially
wider range of psychiatric comorbidities.49 Thus, these distinct correlates and mechanisms. Identifying and targeting
findings may be relevant only for clinical samples charac- potential common mechanisms underlying irritability and
terized primarily by irritability and/or ADHD symptoms. ADHD, such as impaired cognitive control, may serve as a
Third, when possible, we included measured variables across promising intervention for DMDD with comorbid ADHD.
parent, child, and clinician informants to balance potential However, additional work is needed directly interrogating
informant effects. However, the measures of irritability and cognitive control deficits in irritable youths with varying levels
ADHD used in the LPA were limited to parent report. of ADHD symptoms.
Given known cross-informant variations in the assessment
of psychiatric symptoms in youths,50 future work might Accepted January 4, 2021.
fruitfully expand this latter approach to include additional Drs. Cardinale, Brotman, Pine, Leibenluft, Kircanski, and Ms. Freitag are with
informants. In addition, the development of measures spe- the Emotion and Development Branch, National Institute of Mental Health,
Bethesda, Maryland.
cifically aimed at differentiating phasic and tonic irritability
This work is supported by the National Institute of Mental Health (NIMH)
would greatly benefit from inclusion of multiple informants. Intramural Research Program (ZIAMH002781), conducted under National In-
Fourth, because the current study is cross-sectional, causal stitutes of Health Clinical Study Protocols 01-M-0192 (ClinicalTrials.gov iden-
tifier: NCT00018057) and a Bench-to-Bedside Award (479969).
pathways could not be assessed. Future longitudinal studies
Author Contributions
delineating developmental trajectories of irritability and Conceptualization: Cardinale, Freitag, Leibenluft, Kircanski
ADHD symptoms are needed to explicate the nature of the Data curation: Cardinale, Freitag, Brotman, Pine, Leibenluft, Kircanski
Formal analysis: Cardinale, Freitag
relationships among symptoms. Fifth, the current findings Funding acquisition: Brotman, Pine
suggest distinct mechanisms for phasic and tonic irritability Methodology: Cardinale, Kircanski
Supervision: Brotman, Pine, Leibenluft
as they relate to ADHD symptoms; however, analyses were Writing e original draft: Cardinale, Freitag, Kircanski
limited to the clinical data. Future work examining neural Writing e review and editing: Cardinale, Freitag, Brotman, Pine, Leibenluft,
Kircanski
and behavioral correlates of phasic and tonic irritability will
Disclosure: Drs. Cardinale, Brotman, Pine, Leibenluft, Kircanski, and Ms. Freitag
be essential to testing purported mechanisms. Finally, the have reported no biomedical financial interests or potential conflicts of inter-
sociodemographic composition of the sample was predom- est.

inantly White and of high socioeconomic status. In further Correspondence to Elise M. Cardinale, PhD, National Institute of Mental
Health, Bldg. 15K, MSC 2670, Bethesda, MD 20892-2670; e-mail: elise.
research in this area, more diverse samples should be [email protected]
recruited. 0890-8567/$36.00/Published by Elsevier Inc. on behalf of the American Acad-
emy of Child and Adolescent Psychiatry.
Despite these limitations, the current study is the first to
https://doi.org/10.1016/j.jaac.2020.11.022
leverage data-driven methods to identify patterns of irritability

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