Pediatric Annals

Special Issue Article 

Identification and Treatment of Generalized Anxiety Disorder in Children in Primary Care

Erin Dillon-Naftolin, MD

Abstract

Youth with anxiety often present to their pediatricians with a chief complaint of physical symptoms without any mention of anxiety or worry. Even in the absence of reported symptoms of anxiety in such presentations, screening for an anxiety disorder as the potential source of the somatic complaints should be pursued. Generalized anxiety disorder (GAD) is a common disorder characterized by excessive anxiety and worry about a number of events coupled with at least one physical symptom. GAD is commonly underdiagnosed and treated. Consequently, many youth undergo extensive medical testing in search of a cause for their somatic symptoms before anxiety is considered. It is important to screen for anxiety early in the process of evaluating somatic complaints. This review highlights the evidence base for identifying and treating GAD in children and provides an update on its epidemiology and etiology. [Pediatr Ann. 2016;45(10):e349–e355.]

Abstract

Youth with anxiety often present to their pediatricians with a chief complaint of physical symptoms without any mention of anxiety or worry. Even in the absence of reported symptoms of anxiety in such presentations, screening for an anxiety disorder as the potential source of the somatic complaints should be pursued. Generalized anxiety disorder (GAD) is a common disorder characterized by excessive anxiety and worry about a number of events coupled with at least one physical symptom. GAD is commonly underdiagnosed and treated. Consequently, many youth undergo extensive medical testing in search of a cause for their somatic symptoms before anxiety is considered. It is important to screen for anxiety early in the process of evaluating somatic complaints. This review highlights the evidence base for identifying and treating GAD in children and provides an update on its epidemiology and etiology. [Pediatr Ann. 2016;45(10):e349–e355.]

Generalized anxiety disorder (GAD) in children, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5),1 is characterized by excessive anxiety and worry about a number of events and activities coupled with at least one physical symptom, which may include fatigue, poor concentration, restlessness, irritability, muscle tension, and sleep difficulties. Clinically, children with this diagnosis often initially present to the pediatrician's office with a primary complaint of physical symptoms such as pain, headaches, stomach problems, or heart palpitations. GAD is the second most common pediatric anxiety diagnosis, after social anxiety disorder (SAD), with an estimated prevalence as high as 15%.2 GAD commonly co-occurs with other anxiety disorders, particularly SAD and separation anxiety disorder, as well as depression and attention-deficit/hyperactivity disorder (ADHD).3 Despite their high prevalence, anxiety disorders often go undiagnosed and undertreated. A study by Chavira et al.4 looked at 714 families presenting to primary care and found that 20% of children scored above the clinical cutoff on a brief anxiety screen. In their study, among children with a current anxiety disorder, 31% had received counseling or medication treatment during their lifetime, compared to 40% of children with depression, and 79% with ADHD.4 Similarly, a study by Richardson et al.5 looked at youth with health insurance presenting to primary care and found that whereas 8.5% met criteria for an anxiety or depressive disorder, only 22% of those with a diagnosis had evidence of detection or treatment for their diagnosis in the prior year.

There is a complex interaction between physical symptoms, pain, and anxiety diagnoses. Medically unexplained physical symptoms, referred to as functional somatic symptoms (FSS), are common in pediatric medical settings and cause significant functional impairment and need for medical visits. In a study of adults, Means-Christensen et al.6 found that patients who endorse symptoms of muscle pain, headache, or stomach pain are approximately 2.5 to 10 times more likely to screen positively for panic disorder, GAD, or major depressive disorder. In particular, muscle pain and stomach pain predicted increased odds for GAD. The Great Smokey Mountains study7 found that stomachaches and headaches together were associated with anxiety disorders in girls, with nearly 70% of girls with both symptoms meeting criteria for an anxiety disorder. As the number of FSS symptoms and amount of functional impairment increases, there appears to be an increased likelihood of anxiety and depressive symptoms. Most importantly, successful treatment of anxiety and depressive disorders is associated with reduction in FSS.7 When patients present to primary care with FSS, it is important to have a high index of suspicion for undiagnosed anxiety and depression, even if patients are not complaining of emotional symptoms.

Etiology

Social and Familial Factors

Patients with high anxiety and chronic pain often share impaired coping skills that may increase and perpetuate symptoms. Specifically, passive coping responses such as avoidance, denial, and wishful thinking are associated with increased levels of somatic symptoms, anxiety, pain, and depression. Further, anxious thought patterns, such as catastrophizing, are well documented to predict higher pain intensity and pain-related disability.8 Parenting responses to anxiety and somatic symptoms are also important factors. In their efforts to prevent their children from experiencing anxiety, overprotective parents may model fear of the potential trigger and prevent their children from practicing coping skills, which serves to further facilitate avoidance.2 At the other extreme, some parents attempt to minimize their children's experience of pain or negative emotions by dismissing or criticizing their experience. Overprotection as well as minimization are considered maladaptive parent responses to pain and are associated with increased disability, greater health care use, and higher medical costs.8 Parental anxiety disorders have been associated with increased risk of anxiety disorder in their children as well as higher levels of functional impairment.9

Neurobiological Factors

Research into the neurobiology of GAD suggests that dysregulation of the central fear circuitry drives the disorder. Strawn et al.8 describe abnormal activity and connectivity among the anterior limbic network, amygdala, anterior cingulate cortex, and the ventrolateral prefrontal cortex, which may explain the physiology of the disorder and the effect of various pharmacologic treatments. These neurobiological factors are also suspected to be at the root of many disorders involving FSS and chronic pain. Neuroimaging studies suggest activation in the limbic system with emotional distress and in patients with functional abdominal pain. Further, increased cortisol release, which is controlled by the limbic system, is found in people with chronic anxiety and in youth with functional abdominal pain. Research also suggests reduced functioning of the parasympathetic nervous system in patients with functional abdominal pain and high anxiety as well as slower sympathetic nervous system recovery, which is also found in children with anxiety.10 This evidence suggests some common nervous system influences associated with anxiety, generalized sensitivity, and a lower pain threshold.10

Diagnosis

Clinical Assessment

Children with anxiety disorders often present to their primary care providers for behavioral concerns or physical complaints. Some may voice concern about anxiety, but others may just note associated symptoms of stomachaches, headaches, fatigue, muscle tension, general pain, palpitations, syncope, dizziness, paresthesia, numbness, trembling, poor concentration, urinary frequency, dry mouth, or memory loss.11 A pattern of distress about physical symptoms should trigger a clinical interview for psychosocial stressors and anxiety concerns as well as a review of past medical history, trauma history, family history of psychiatric illnesses, and history of substance use. Anxious teenagers are typically more aware of their symptoms than their parents, given the internalizing nature of the disorder, but collecting both the parent and youth report is helpful to gather a broader perspective of the symptoms. It is not uncommon for parent and child reports to differ widely. Younger children are more likely to focus on physical symptoms, whereas their parents may be able to give more perspective on avoidance behaviors.

Screening Measures

General screening measures for pediatric anxiety are also helpful to augment the clinical interview and to differentiate between different anxiety disorders. Although there are no pediatric measures focused exclusively on GAD, several measures screen broadly for anxiety disorders and are well studied and validated to map closely to DSM-IV12 anxiety diagnoses.

The Screen for Child Anxiety Related Emotional Disorders13 is widely used, well validated, and available for free. It is a 41-item measure for youth age 9 to 18 years that screens for somatization, panic, GAD, separation anxiety, and social phobia (SP). There is also a brief version that can be used for screening and tracking symptoms over time, and it is available in several languages.2,13

The Spence Children's Anxiety Scale14 is useful because it is available for free, can be used across a wide age range (preschool to adolescence), and it is translated into many different languages. It is a 44-item measure that screens for somatization, panic, GAD, separation anxiety, and SP.

The Multidimensional Anxiety Scale for Children15 is also widely used. It is a 39-item self-report measure for children age 8 to 19 years that measures four factors: social anxiety, separation anxiety/panic, physical symptoms, and harm avoidance. It does not, however, distinguish youth with GAD from youth with other anxiety disorders.15

Differential Diagnosis

There are many psychiatric conditions with significant symptom overlap with GAD. Most commonly, GAD overlaps with depression or other anxiety disorders. Poor focus and attention due to intrusive worries can mimic ADHD symptoms. Irritable, angry outbursts triggered by autonomic hyperarousal as part of the “fight or flight” response can be mistaken for oppositionality. Substance abuse, psychotic disorders, developmental disorders, learning disorders, and bipolar disorder can also present with anxiety symptoms as the chief complaint. In particular, screening for substance abuse and bipolar disorder is important because the presence of these diagnoses either alone, or as a comorbid disorder, is an important factor in medication choice.

Physical conditions that may masquerade as anxiety disorders include hyperthyroid, high caffeine intake, migraines, asthma, seizure disorders, lead intoxication, hypoglycemia, pheochromocytoma, central nervous system disorders, and cardiac arrhythmias. Medications that can cause anxiety symptoms include selective serotonin reuptake inhibitors (SSRIs), antipsychotics, steroids, sympathomimetics, antiasthmatics, diet pills, antihistamines, and cold medicines.9

Medical Testing

Evaluating common medical issues that can present similarly to anxiety disorders or that commonly present with the indicated somatic symptom is important. However, in generally healthy children, exhaustive diagnostic examinations are not warranted. Typically, physical examination and targeted laboratory testing are sufficient.4 Assessing baseline physical symptoms before medication trials are initiated helps to decrease risk of somatic complaints being interpreted as medication side effects.9

Treatment

There is a strong evidence base to support the use of both therapeutic and pharmacologic interventions for GAD. For mild symptoms with minimal functional impairment, The American Academy of Child and Adolescent Psychiatry (AACAP) recommends starting with psychoeducation or psychotherapy alone.9 However, when youth are suffering from moderate-to-severe symptoms, a multimodal approach with a combination of medication and cognitive-behavioral therapy (CBT) is recommended.9 Family preference/motivation, financial limitations, and availability of resources often shape initial treatment choice. In some communities, lack of access to therapists with expertise in CBT may lead providers and families to choose medication as the initial treatment option.

Psychoeducation

Psychoeducation is the first step to help increase child and family insight and motivation for treatment.16 Helping to differentiate between healthy anxiety and functionally impairing anxiety, educating about triggers that cause anxiety and ways it is maintained, discussion about the natural course of the disorder, and possible treatment options are important first steps a primary care provider can take. Parents and providers may find books such as Helping Your Anxious Child: A Step by Step Guide16 useful in educating themselves about childhood anxiety.

Behavioral Treatment

Milder symptoms of GAD may not warrant the inherent risks of medication intervention, and some families may not be willing to try medication even if the child has more severe symptoms. CBT is the therapy with the broadest evidence base for childhood anxiety disorders. Randomized controlled trials (RCTs) for treatment of GAD have shown significant improvement with CBT compared to waitlist control.17 Current evidence supports both short-term and long-term effectiveness of CBT. The CBT can be administered by any professional trained in this type of therapy, such as a psychologist or social worker The AACAP practice parameters9 identify CBT as the psychotherapy with the most empirical support for treatment of anxiety disorders in youth. CBT includes components of cognitive restructuring, problem-solving, relaxation training, modeling, contingency management, imaginal and in vivo exposure, and relapse prevention. For youth with GAD, a focus on relaxation training may help address the high physical arousal and awareness of physical sensation that is thought to cause the somatic symptoms. For parents, addressing the tendency to accommodate anxiety and provide reassurance is important. Helping them model acceptance of uncertainty may support exposure to anxiety and address chronic reassurance seeking.2 Psychodynamic therapy has been proposed as another means of therapeutic intervention, but few studies have demonstrated benefit in comparison with or in combination with alternative treatments.15

Psychopharmacological Treatment

Selective serotonin reuptake inhibitors

As discussed next, there is substantial evidence for the efficacy and safety of using SSRI medications for GAD in children and adolescents as young as age 6 years. However, there is currently no mediation approved for this use by the US Food and Drug Administration (FDA). The FDA has approved four SSRI medications for use in the treatment of obsessive-compulsive disorder (OCD), but because most RCTs of youth with non-OCD anxiety disorders include populations with mixed anxiety disorders, the FDA has not added specific approval for these diagnoses. Although using these medications remains “off-label,” the evidence base supports their use as part of evidence-based practice. Table 1 outlines SSRIs commonly used in children, the standard treatment approach, side-effect profile, and evidence base.


            SSRI Treatment Algorithma

Table 1.

SSRI Treatment Algorithm

Sertraline. The National Institute of Mental Health funded a large, randomized, multisite comparative treatment trial called the Child/Adolescent Anxiety Multimodal Study.18 It compared the acute efficacy (at 12 weeks) and durability (at 24 and 36 weeks postrandomization) of CBT, sertraline, and their combination with placebo in youth age 7 to 17 years with separation, generalized, and social anxiety disorders. GAD was present for 78% of the 488 patients. The results showed that each of the three active-treatment arms (CBT, sertraline, and combination) was more effective than placebo, and that combination was more effective than either CBT or sertraline alone. Response rates at 12 weeks of treatment were 80.7% for combination therapy (P < .001), 59.7% for CBT (P < .001), and 54.9% for sertraline (P < .001).18 At 6 months after active treatment, most (>80%) of the acute responders maintained a positive response. Similar to the acute outcomes, the combination-treatment group maintained better improvement than the CBT-alone and sertraline-alone groups, and the two monotherapies remained indistinguishable. However, there was some convergence between the scores for the combination and monotherapy groups, with less significant differences by 6 months.19

Fluoxetine. There is an RCT of fluoxetine for youth with GAD, SAD, and social phobia who were titrated up to a 20-mg dose of fluoxetine for 12 weeks.20 The medication was generally well tolerated compared to placebo, and significant improvements were noted on parent and child reports for the treatment group compared to placebo.20

Fluvoxamine. The Research Units on Pediatric Psychopharmacology Anxiety Study Group conducted an 8-week RCT of youth with SAD, social phobia, and GAD that compared fluvoxamine and placebo.21 It showed significant improvement in the treatment group (76% response in the fluvoxamine group compared with 29% in the placebo group). The medication was well tolerated aside from abdominal discomfort and increased motor activity.21 In the 6-month open-label extension, 94% of fluvoxamine responders maintained response and 71% of the fluvoxamine-treated patients who had not responded to fluvoxamine responded to fluoxetine.22

Serotonin-norepinephrine reuptake inhibitors

There are three RCTs that studied the effectiveness of serotonin-norepinephrine reuptake inhibitors (SNRIs) in youth.

Venlafaxine. Venlafaxine was evaluated in two RCTs in youth ages 6 to 17 years with GAD for 8 weeks. Venlafaxine extended-release was superior to placebo on parent and child rating scales for GAD with pooled results from the two studies. Youth who received the active medication experienced more asthenia, pain, anorexia, somnolence, and weight loss compared to the placebo group.23

Atomoxetine. Atomoxetine is best known for its use in treatment of ADHD. There is an RCT for teens with ADHD and comorbid anxiety including GAD, SAD, and social phobia.24 With a target dose of 1.2 to 1.8 mg/kg per day for 12 weeks, researchers found decreased anxiety in the treatment group (effect size = 0.5) as well as significant improvement in ADHD.24

Safety

Antidepressants are fairly well tolerated, but it is important to discuss potential side effects with patients and parents. Common physical complaints such as headaches, stomachaches, restlessness, and sleep disruption are typically most severe in the first few weeks of treatment and then improve but can lead to treatment discontinuation. Children with anxiety are more likely to be sensitive to potential side effects, but starting at lower doses helps minimize these effects. In addition, antidepressants can cause mood symptoms such as agitation, worsened anxiety or depression, disinhibition, or suicidal ideation/self-harming behaviors. In 2004, the FDA placed a “black-box” warning on SSRIs and SNRIs due to concern for a 2-fold increased risk for suicidal thinking or behavior in children and adolescents taking these medications.25 In 2007, a meta-analysis was completed that included youth taking these medications for any indication.26 The study found a small increased risk for suicidal ideation in the treatment groups (0.7%) with a number needed to harm of 143.26 Of note, there were no completed suicides in any of the studies.27 Clinically, suicidal thoughts appear most commonly when youth experience activation from the SSRI with increased emotional lability and impulsivity. A discussion of the risk of suicidal ideation and the importance of close monitoring for suicidal thoughts and activation should be part of informed consent.

SSRI and SNRI medications take 4 to 8 weeks to reach their full clinical effect at a given dose. It is important for families to be aware of the gradual onset to prevent them from discontinuing prematurely. In addition, abrupt discontinuation of the shorter-acting agents can result in a withdrawal syndrome that resembles the flu.10 For adolescents, who may be self-administering their medications, it is important to monitor frequency of missed doses and discuss ways of improving adherence. For some, this is a reason to choose fluoxetine because the longer half-life reduces side effects from missed doses, and a once-a-week version of fluoxetine is available if taking a medication daily proves too difficult.

Monitoring and Duration of Treatment

Frequent visits and close contact with the treating therapist are recommended when initiating medications. Once an effective dose is achieved, the visits may be spaced out further, but more frequent contact should continue if there is a history of depression, suicidal behaviors, family concern, or when medication compliance is poor. Ongoing monitoring of symptoms with standardized rating scales is recommended to monitor effectiveness of treatment. Once symptom remission is achieved, the medication should be continued for 6 to 12 months before attempting a gradual taper. If symptoms recur, reinstatement of the prior effective dose may be indicated.28

Other Pharmacological Options

Tricyclic antidepressants

With the introduction of SSRI medications, tricyclic antidepressants have fallen from use due to higher safety risk in overdose, need for close cardiac monitoring (must get an electrocardiogram prior to starting), and conflicting results on RCTs of pediatric anxiety disorders. Imipramine and clomipramine are still used as augmenting agents or as a solo agent when there is partial or minimal response to SSRI medications.15 Close monitoring is required for anticholinergic and cardiac side effects.

Buspirone

Buspirone is a partial agonist of serotonin receptors that has some evidence for treatment of GAD in adults but limited data in youth. Buspirone was evaluated in two open-label studies in youth with overanxious disorder (now known as GAD) and showed that during 4 to 6 weeks of treatment anxiety significantly improved.29 However, two RCTs of buspirone for pediatric patients given doses of 15 to 60 mg/day showed no significant differences between buspirone and placebo.29 It is generally well tolerated at doses of 5 to 30 mg twice daily. Common side effects include dizziness, headache, and gastrointestinal complaints.11

Benzodiazapines

Although benzodiazepines are used widely for treatment of anxiety in adults, use of benzodiazepines for children and adolescents with anxiety has not been well researched. In one open-label trial of 12 adolescents with GAD who were treated with alprazolam for 4 weeks, there was significant improvement in anxiety and insomnia.30 However, a double-blind RCT of youth age 8 to 16 years looked at the effect of alprazolam and found no difference between groups for global rating of improvement.31 Given the limited data and risk for addiction or paradoxical disinhibition, benzodiazepines are not commonly used as first-line treatment for anxiety. However, this class of medication may be helpful as an adjunctive treatment to an SSRI during the early phase of treatment when waiting for the SSRI to take effect if anxiety is severe and debilitating.11 Use is contraindicated in youth with substance use abuse. Common side effects include sedation, disinhibition, cognitive dulling, and increased anxiety on discontinuation.29

Alpha-agonists and beta-blockers

There are a few studies to support the use of alpha-agonists and beta-blockers in youth with other anxiety disorders.32,33 Clinically, they are used most commonly when there is a comorbid disorder such as ADHD (an alpha-agonist may address hyperactivity) or SP (beta-blockers block some of the physical effects of autonomic overload).

Antihistamines

There are no data to support the use of these medications for pediatric anxiety disorders. However, they are used clinically for short-term relief of mild anxiety symptoms and may be used on as needed basis. Hydroxyzine may be a useful option for children whose anxiety is fairly well controlled with psychotherapy but are experiencing short-term worsening of their symptoms due to a particular stressor, such as return to school in the fall.

Summary

GAD is an underdiagnosed and undertreated psychiatric diagnosis in the pediatric population. Because youth frequently present with physical complaints, they often undergo significant medical testing for symptoms such as headache and abdominal pain before a diagnosis of anxiety is considered. Left untreated, GAD leads to increased risks of comorbid psychiatric diagnoses and ongoing mood and anxiety problems in adulthood. First-line treatment for GAD is CBT with or without an SSRI. Combination treatment is important for moderate-to-severe anxiety symptoms. Data are limited for second-line treatment options in this population, and most recommendations are extrapolated from adult literature. Further research is needed in treatment-resistant GAD and the long-term outcomes after successful or unsuccessful treatment.

References

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SSRI Treatment Algorithma

Drug Name Usual Starting Dose for Adolescentsb Increase Increment Maximum Dosec Is There an RCT Showing Treatment Benefit in Children? Clinical Pearls FDA Approved
Fluoxetine 10 mg/day 10–20 mg 60 mg/day Yes May be more activating Many drug interactions Long half-life so low side effects from missed dose Side effects: activation, nausea, insomnia For OCD in children>7 years and pediatric MDD
Sertraline 25 mg QHS 25–50 mg 200 mg/day Yes May help with sleep Side effects: sedation, nausea, headaches For OCD in children>6 years
Citalopram 10 mg/day 10–20 mg 40 mg/day Yes Few drug interactions Side effects: sedation, insomnia, diaphoresis For adults
Escitalopram 5 mg/day 5–10 mg 20 mg/day No Active isomer of citalopram Side effects: sedation, insomnia, diaphoresis For adults
Fluvoxamine 25 mg QHS 50 mg 300 mg/day Yes More side effects Many drug interactions Side effects: more sedation For OCD in children>8 years
Paroxetine 10 mg/day 10–20 mg 60 mg/day No Short half-life may cause increased withdrawal effects Generally avoided in children Side effects: sedation, nausea, dry mouth For adultsd
Authors

Erin Dillon-Naftolin, MD, is an Acting Assistant Professor, Seattle Children's Hospital.

Address correspondence to Erin Dillon-Naftolin, MD, Seattle Children's Hospital, 4800 Sand Point Way NE, PO Box 5371, Seattle, WA 98145-5005; email: Erin.Dillon-Naftolin@seattlechildrens.org.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/19382359-20160913-01

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