1111246

research-article2022
CPJXXX10.1177/00099228221111246Clinical PediatricsLeón-Barriera et al

Article
Clinical Pediatrics

Treating ADHD and Comorbid 2023, Vol. 62(1) 39­–46

© The Author(s) 2022
Article reuse guidelines:
Anxiety in Children: A Guide for sagepub.com/journals-permissions
DOI: 10.1177/00099228221111246
https://doi.org/10.1177/00099228221111246

Clinical Practice journals.sagepub.com/home/cpj

Roberto León-Barriera, MD1 , Richard S. Ortegon, MD1,

Margaret M. Chaplin, MD1,2 , and Vania Modesto-Lowe, MD, MPH1,3

Abstract
Attention-deficit hyperactivity disorder (ADHD) is frequently comorbid with anxiety disorders with rates as high as
25% to 50% in children and adolescents. Despite various treatment options for ADHD symptoms, limited research
addresses treatment in the context of comorbidity. This article seeks to provide a review of the evidence regarding
treatment of this comorbid population. Distinct emotional, cognitive, and behavioral symptoms have been observed
in this population, suggesting a need for tailored treatment. Despite common concerns about anxiety exacerbation,
stimulant medications demonstrate good tolerability and good response in addressing symptoms. Atomoxetine has
also demonstrated some benefit and good tolerability for treating this comorbid population. Selective serotonin
reuptake inhibitors can be used as adjunctive treatment for anxiety but require careful monitoring of side effects.
Cognitive behavioral therapy (CBT) is an important treatment to improve anxiety symptoms in the absence of
significant ADHD symptoms. Psychosocial interventions are also essential to improve outcomes.

Keywords
ADHD, anxiety, comorbidity, treatment, pharmacology, psychosocial interventions

Introduction of Pediatrics guidelines underscores the importance of

routine assessment of comorbid disorders.7 Controversy
Attention-deficit hyperactivity disorder (ADHD) is char- has persisted however, regarding the proper treatment of
acterized by the Diagnostic and Statistical Manual of this population due to potential anxiogenic effects of
Mental Disorders, Fifth Edition (DSM-5) as inappropriate stimulants in children with anxiety disorders. In addition,
levels of inattention, impulsivity, and hyperactivity that selective serotonin reuptake inhibitors (SSRIs), which are
surface in childhood resulting in multiple impairments.1 the first-line pharmacological treatment for anxiety disor-
Anxiety disorders are characterized by a fear which is out ders, may cause activation and suicidal ideation in the
of proportion to a situation and that affects normal func- pediatric population.8 Furthermore, even when pharma-
tioning.1 These 2 disorders common to the pediatric popu- cotherapy does lead to symptom improvement, there may
lation are frequently comorbid in rates from 25% to not be a corresponding improvement in function at home
50%.2-4 In an Australian sample of 389 participants, 64% or at school. For all these reasons, it is important to look
of children with ADHD had at least one anxiety disorder, at the use of psychosocial and therapeutic interventions to
including social (48%), generalized (34%), and separa- enhance the effective treatment of these children.4
tion (32%) anxiety disorders.4 In addition to the epidemi-
ological significance, some data attest to the substantial
clinical burden posed by this comorbidity.4 Children with
1
ADHD often have difficulty with concentration, execu- Department of Psychiatry, University of Connecticut, Farmington,
tive function, and organization.4 Although the comorbid CT, USA
2
Department of Psychiatry, Farrel Treatment Center, New Britain,
population demonstrates decreased hyperactivity and CT, USA
impulsivity compared to ADHD-only, children with both 3
Connecticut Valley Hospital, Middletown, CT, USA
ADHD and anxiety may experience greater mood and
Corresponding Author:
executive dysfunction.4 Given the clinical relevance of Roberto León-Barriera, Department of Psychiatry, University of
this relationship, early recognition and treatment are Connecticut, Farmington, CT 06032-1941, USA.
important.5,6 A recent revision of the American Academy Email: [email protected]
40 Clinical Pediatrics 62(1)

Methods response inhibition.3,18,19,22 These tests typically consist

of concomitant tasks in which the person receives a sig-
An independent search of PubMed databases was carried nal to stop or to proceed with a specific task. Children
out. Keywords included: ADHD, anxiety, comorbidity, with ADHD and anxiety demonstrate improved perfor-
treatment, psychopharmacology, children, adolescents, mance on stop signal tests when compared to those in
and cognitive behavioral therapy (CBT). Date rage other ADHD subgroups.23,24 Studies have demonstrated
included in search was from inception through June less impulsivity in these comorbid patients compared to
2020. Filters for reviews, systematic reviews, clinical tri- other ADHD subgroups.22 Children with ADHD and
als, and randomized clinical trials were applied prior to comorbid oppositional defiant or conduct disorder were
screening. These 1458 articles were screened manually more impulsive when compared to comorbid anxiety
by their title for appropriateness. Three of the authors patients, suggesting that anxiety decreases impulsivity
screened these records manually. Initially, articles were in ADHD patients.23
reviewed independently and subsequently as a team. Studies have further attempted to quantify level of
Articles needed to focus specifically on comorbid ADHD impairment in this population. A 2014 study examined
and anxiety in the pediatric population. Articles were the impact on quality of life and function in comorbid
reviewed and included/excluded as outlined in Figure 1. ADHD/anxiety.4 Results indicated decreased academic
We would like to highlight that we did not include an functioning in children with ADHD and 2 or more anxi-
article that focused on desipramine, as it is rarely used in ety disorders.4 These findings imply that magnification
clinical practice due to reports of sudden death in chil- of functioning difficulties may be present only in those
dren.10 A limitation of our review is that only articles with severe anxiety. Regardless, treatment of this comor-
that were available in PubMed were included. It is pos- bidity has the potential to improve outcomes.
sible there are additional articles that discuss this comor-
bidity that do not appear on a PubMed search.
Pharmacological Treatment
Effect of Anxiety on Clinical Medications frequently used for ADHD fall into 2 cate-
gories: stimulants (e.g., methylphenidate [MPH]) and
Presentation of ADHD nonstimulants (e.g., atomoxetine [ATX]). The first-line
Studies have generally shown that elevated levels of anx- pharmacotherapy for childhood anxiety is SSRIs.25 Most
iety may exacerbate cognitive and emotional dysfunc- studies on the pharmacological treatment of ADHD and
tion.11 The presence of anxiety may make children with anxiety in the pediatric population focus on these agents.
ADHD present as more inattentive and less impul- A summary of treatment recommendations for this pop-
sive.12,13 In addition, children with this comorbidity ulation is presented in Table 1.
exhibit fewer conduct and aggressive symptoms.14,15
Such children displayed lower activity in the cerebellum,
Stimulant Medications
striatum, and thalamus during working memory tasks
relative to ADHD alone.16 This suggests a different sub- Stimulant medications are a first-line treatment for
type of ADHD with distinct pathogenesis.14,15,17,18 ADHD.26 While response rates can vary, concomitant
Conversely, some argue that anxiety is only a conse- intensive psychosocial intervention can improve out-
quence of ADHD-based impairments. Anxiety in chil- comes, especially in children with comorbid anxiety.27
dren with ADHD may be related to their inability to Still, controversy remains with using stimulants in this
function in other aspects of their daily life due to ADHD population. Package labels indicate anxiety as a relative
symptoms.19 It is possible that this anxiety worsens cog- contraindication to this treatment, raising concerns
nitive performance, but this is not entirely clear.13,15 about exacerbation of symptoms. Physician concerns
Supporters of this theory suggest the anxiety in ADHD may also arise from a lack of familiarity on safe imple-
patients originates from worrying about academic tasks.19 mentation of treatment.28 Moreover, parents may resist
In either case, heightened executive dysfunction and medications, citing the potential for addiction or adverse
inattention likely explain the impairments seen in these effects. Despite this, stimulants are a cornerstone in ade-
patients. quate management and other treatments, such as psy-
Neuropsychological functioning is also altered in this chosocial interventions, may not be effective prior to
population.20 Response inhibition allows a person to medication management.
engage in adaptive behaviors rather than act impul- Methylphenidate is the gold-standard treatment in
sively.21 Deficits in response inhibition are often seen in ADHD, with extensive research supporting its efficacy in
ADHD. Stop signal tests are the classic measurement of children and adolescents. However, efficacy in treating
León-Barriera et al 41

Figure 1. Study selection.

Source: Page et al.9
Abbreviation: ADHD, attention-deficit hyperactivity disorder.

comorbid anxiety has remained in question. Early studies anxiety had a significantly reduced response compared to
indicated a correlation between the presence of anxiety in nonanxious controls.29 Another double-blind, placebo-
ADHD and a decreased response to MPH. In a double- controlled, crossover study evaluated the effects of MPH
blind trial of MPH (N = 43), children with comorbid on working memory and activity level in anxious versus
42 Clinical Pediatrics 62(1)

Table 1. Summary of Treatment Recommendations for Pediatric ADHD and Anxiety.

Population Medication Comments

ADHD > Anxiety MPH CBT helpful for residual anxiety
ADHD < or = Anxiety Atomoxetine CBT, ±BPT
ADHD + severe and/or treatment Atomoxetine OR MPH + fluoxetine CBT may be of greater benefit than fluoxetine
resistant anxiety though head-to-head studies are lacking.

Abbreviations: ADHD, attention-deficit hyperactivity disorder; MPH, methylphenidate; CBT, cognitive behavioral therapy; BPT, behavioral
parent/teacher training.

nonanxious ADHD children.17 Forty ADHD children (22 participants responded regardless of severity of social
nonanxious, 18 anxious) received 3 doses (0.3, 0.6, and phobia.34 However, controlled studies are needed to rep-
0.9 mg/kg) of MPH.17 Measures included a serial addition licate these findings. Tolerability of MPH in this popula-
task to assess working memory and behavioral observa- tion has also received attention. One initial study
tions to assess activity level.17 Results suggested MPH suggested that comorbid ADHD/anxiety may make chil-
reduced hyperactivity equally in both groups, but a dif- dren more susceptible to side effects of MPH treat-
ferential response was found for working memory.17 ment.17 In this study, a greater heart rate increase with
Working memory improved to a larger degree in ADHD- low dose (0.3 mg/kg) MPH was seen after 1 hour of
only controls compared to the comorbid group.17 This is administration.17 However, fixed doses of MPH were
consistent with high levels of working memory impair- used without a titration schedule, which is not reflective
ments seen in this population.16 Similarly, other research- of clinical practice. Other studies using titration sched-
ers examined variables predicting response to MPH in ules did not show increased side effects.31,35,36 Available
ADHD children and found low levels of anxiety to be a evidence suggests that MPH has some efficacy and good
robust predictor of positive response to MPH. However, tolerability for treatment of this comorbid popula-
the finding that highly anxious children are less respon- tion.31,35,36 Pediatricians are advised to use their clinical
sive to MPH was not replicated in subsequent studies.30 judgment in making the decision whether to start MPH.
A 1999 study evaluated whether anxiety altered MPH It is reasonable to start MPH in children with a careful
efficacy for pediatric ADHD.31 Ninety-one children with titration schedule and monitoring for worsening of anxi-
ADHD were stratified by having ADHD versus ADHD/ ety and other side effects.10 In addition, the principle of
anxiety.31 Thirty-eight out of 91 children met criteria for “start low and go slow” may be useful to assess the
comorbid anxiety disorders.31 Participants were treated effects of MPH on anxiety symptoms. Methylphenidate
with MPH immediate release (IR) over a 4-month period appears to be a good first choice particularly if the anxi-
on a titration schedule to a standard dosage of 0.7 mg/ ety is mild and the ADHD symptoms are the primary
kg.31 Parental and teaching rating scales were used to impairment. In certain instances, anxiety may be pri-
measure changes in the children's aggression, hyperac- mary and ADHD less impairing. Additional efforts to
tivity, and inattention at baseline, after titration, and at clarify the best pharmacotherapy for this comorbid sub-
4-month follow-up.31 This study showed no difference in group have focused on ATX.
response to MPH between these groups initially and at 4
months in any of the measures.31 Moreover, a 2015 trial
Atomoxetine
showed a decrease in anxiety symptoms with MPH.32 Of
note, the sample only included children with subdiagnos- Atomoxetine is a selective presynaptic norepinephrine
tic anxiety and may not be generalizable to children with reuptake inhibitor and is approved by the United States
severe anxiety.32 Food and Drug Administration for the treatment of pedi-
An open-label Israeli study evaluated the response of atric ADHD/anxiety.37 Recent research has examined
subsyndromal separation anxiety to MPH in children efficacy for comorbid ADHD/anxiety in children and
with ADHD (N = 42) over 12 weeks.33 Methylphenidate adults.35,37-39 In 2005, researchers evaluated the effects of
was associated with a decrease in separation anxiety, as ATX alone or in combination with fluoxetine in the treat-
well as improvement in ADHD symptoms.33 The inves- ment of pediatric ADHD, anxiety, and depression.38
tigators also evaluated the effects of MPH on social pho- Atomoxetine was effective for ADHD, depressive, and
bia symptoms and ADHD.34 Twenty-one children with anxiety symptoms.38 A similar degree of improvement
ADHD and social phobia received MPH for 12 weeks, was seen with ATX alone and with fluoxetine.38 However,
resulting in substantial improvements in ADHD and generalization of these results is limited due to the focus
social phobia symptoms at its conclusion.34 Nearly all on depressive symptoms over anxiety and the absence of
León-Barriera et al 43

a placebo arm. The percentage of children who withdrew such as the Texas Children’s Medication Algorithm.
from the study due to side effects was minimal across all This guideline endorsed the use of ATX or MPH to
groups.38 However, the combination treatment group treat comorbid ADHD/anxiety as first line.10 If anxiety
experienced higher increase in heart rate, blood pressure, is unresponsive to these medications, SSRI initiation
and weight loss compared with ATX only.38 Subsequently, is recommended, especially if anxiety is severe and
in 2007, a double-blind placebo-controlled trial examined causing significant dysfunction.10 Considering the
the effects of ATX for children with ADHD/anxiety.37 potential for behavioral activation and suicidal ide-
Children with ADHD and generalized anxiety disorder, ation with SSRIs, close monitoring of these patients is
separation anxiety disorder, or social phobia were ran- essential.8 In addition to medication, it is essential to
domized to 12 weeks of ATX (n = 87) or placebo (n = address psychosocial factors to lower the symptom
89).37 Atomoxetine reduced ADHD/anxiety symptoms in burden associated with this comorbidity. In many
children who have ADHD with comorbid anxiety.37 cases of moderate to severe anxiety, medication alone
Atomoxetine was well tolerated and did not worsen anxi- may not be the best approach, and psychotherapeutic
ety.37 Sample size was not adequate to show which type options need to be considered.
of anxiety symptoms were more responsive to ATX. In
adults with ADHD, social phobia symptoms responded to
Psychotherapeutic and Behavioral
ATX, while generalized anxiety disorder (GAD) symp-
toms did not.39 This suggests a differential effect of ATX Interventions
across anxiety disorders and additional studies are needed The Multimodal Treatment Study of Children with
to clarify this issue in the pediatric population. Evidence Attention-Deficit Hyperactivity Disorder (MTA) is the
suggests that if anxiety symptoms are predominant or the largest study evaluating combined treatment relative
patient cannot tolerate MPH, it might be reasonable to to pharmacotherapy alone in children with ADHD and
prescribe ATX to treat both anxiety and ADHD symp- comorbid anxiety.12,15,36,41 Four groups were com-
toms.10 However, anxiety symptoms in some children pared: pharmacotherapy (MPH), psychosocial inter-
with this comorbidity may not respond to ATX or MPH, ventions (parent training/summer program and school
in which case SSRIs may be considered.10 adaptations), a combination of pharmacotherapy with
psychosocial interventions, and usual treatment.36 Of
note, ADHD was predominantly targeted, but improve-
Selective Serotonin Reuptake Inhibitors ment in anxiety was also seen.36 In fact, the MTA
Selective serotonin reuptake inhibitors are used for the showed that the comorbid ADHD/anxiety subgroup
management of depression and anxiety by increasing had the greatest response to psychosocial treatment
available serotonin in the postsynaptic receptors. While relative to other comorbidities.36 In clinical practice it
SSRIs are efficacious for the treatment of mood and is difficult to reproduce the intensive behavioral pack-
anxiety disorders, their benefit in the presence of age of the MTA. Nevertheless, it is widely recognized
ADHD with comorbid anxiety is less clear.28 A 2004 that psychosocial interventions are essential in treat-
study looked at the response of 32 children with anxi- ing these children.
ety to an SSRI after ADHD symptoms improved with In children with primary ADHD, evidence-based
MPH.40 Children with improved ADHD symptoms but interventions include behavioral parent and teacher
ongoing anxiety (n = 25) were randomized to either training (BPT), which teaches caregivers to use rewards
placebo + MPH or fluvoxamine + MPH for 8 weeks.40 and consequences to shape target behaviors.42 Token
Fluvoxamine doses ranged from 25 to 300 mg.40 While systems and positive reinforcement (positive attention,
the combination of fluvoxamine and MPH was well privileges) encourage desirable behaviors, while time-
tolerated, there was no group difference on measures of out or privilege removal discourages undesirable
anxiety.40 behaviors.15,42 For primarily anxious children, CBT is
Further efforts examined the effects of fluoxetine the standard treatment.43 Cognitive behavioral therapy
combined with ATX for children with this comorbid- helps the child to recognize anxiety and develop adap-
ity.38 Patients were randomized to ATX + fluoxetine (n tive thinking. One behavioral strategy is to develop a
= 127) or placebo + ATX (n = 46).38 Again, there was fear stepladder to gradually address fears and confront
no significant difference between the groups.40 Of previously avoided situations.43 Data indicate primary
note, the number of children studied with SSRIs was anxiety responds to CBT, even with comorbid ADHD.44
small, and this research merits further examination. Of interest, a treatment manual blending BPT and
As a result, guidelines regarding the use of SSRIs CBT was created in 2012.2 The program teaches parents
in these children derive largely from expert consensus, strategies to reward positive behaviors and implement
44 Clinical Pediatrics 62(1)

punishment for disruptive behaviors.2 It aims to improve benefit in managing this comorbidity, targeting residual
parental confidence in ADHD symptom management.2 symptoms, and improving functioning.
The anxiety component focuses on developing child In conclusion, current first-line agents for comorbid
and parent skills and approaches to cope with anxiety. ADHD and anxiety include either MPH or ATX. When
The modules include education about anxiety, reframing available, CBT can be used for residual anxiety and to
fearful thinking, and gradual exposure to feared stimuli.2 enhance functional improvement. While further research
This program was tailored to accommodate the short with larger sample sizes is needed to solidify these rec-
attention span of these children and included the use of ommendations, clinicians can feel confident that both
games, breaks, and incentives for on task behaviors.2 In MPH and ATX are safe and effective for this complex
a pilot study, investigators examined the effects of this population.
integrated program in 8 children with anxiety and
ADHD.2 The study suggests improvement in ADHD and Acknowledgments
anxiety symptoms, although only modest improvements The authors would like to thank Sophia Walker, MD (UConn
for ADHD were seen.2 Subsequently, 2 other small stud- Health) and Carolyn Malon, DDS (retired private practice) for
ies reported improvements in anxiety symptoms for youth their helpful comments and revision of the final manuscript.
with ADHD using CBT strategies.6,45 A randomized trial Drs. Malon and Walker have no conflicts of interest to declare.
in Australia evaluated CBT for children with ADHD and
anxiety.6 In this study, 12 children with ADHD and anxi- Author Contribution
ety were randomized to either CBT or treatment as
Drs. León-Barriera, Modesto-Lowe, and Ortegon contributed
usual.6 The other study examined the response of anxiety to the conception and design of the manuscript.
symptoms to CBT in 10 children.45 In both studies CBT Dr. León-Barriera and Dr. Ortegon wrote the first draft of the
resulted in significant improvements in anxiety and article.
ADHD symptoms, as well as in child and family quality Dr. León-Barriera and Dr. Modesto-Lowe revised and wrote
of life.6,45 the final draft.
Psychosocial research in this population shows prom- Dr. Ortegon revised the final draft.
ising results, and this modality remains an important Dr. Chaplin created the table and critically revised the final
part of the treatment plan in improving outcomes in this draft.
population. Parents are generally receptive to psychoso-
cial treatments, and these strategies offer the potential to Declaration of Conflicting Interests
improve functioning for these children and their fami- The author(s) declared no potential conflicts of interest with
lies. One caveat is that CBT strategies may be difficult respect to the research, authorship, and/or publication of this
to implement with highly impulsive and inattentive chil- article.
dren. It may also be difficult to find professionals trained
to provide CBT especially in rural areas.46 Cognitive Funding
behavioral therapy may be more effective for managing
The author(s) received no financial support for the research,
anxiety if ADHD symptoms are adequately controlled authorship, and/or publication of this article.
with medications.
ORCID iDs
Conclusion Roberto León-Barriera https://orcid.org/0000-0002-6518-
4758
Anxiety and ADHD have an elevated rate of comorbidity
Margaret M. Chaplin https://orcid.org/0000-0002-3603-
and a unique clinical presentation, requiring distinct diag- 8874
nostic and treatment strategies. Several studies affirm the
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