Pediatric Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is associated with persistent, excessive, and unrealistic worry that is not focused on a specific object or situation.

Children with GAD worry more often and more intensely than other children in the same circumstances. They may worry excessively about their performance and competence at school or in sporting events, about personal safety and the safety of family members, or about natural disasters and future events.

The focus of worry may shift, but the inability to control the worry persists. Because children with GAD have a hard time "turning off" the worrying, their ability to concentrate, process information, and engage successfully in various activities may be impaired. In addition, problems with insecurity that often result in frequent seeking of reassurance may interfere with their personal growth and social relationships. Further, children with GAD often seem overly conforming, perfectionistic, and self-critical. They may insist on redoing even fairly insignificant tasks several times to get them "just right." This excessive structuring of one's life is used as a defense against the generalized anxiety related to the concern about the individual's overall and specific performance. (See Treatment.)

Little empiric data are available regarding the physiologic indicators of anxiety in children.[2] The high cost, lack of normative data, idiosyncratic patterns, and high sensitivity of cardiovascular and electrodermal measures in children contribute to the difficulties in physiologic assessment of anxiety in children.[3] (See Differentials.)

Diagnostic criteria (DSM-5)

The specific DSM-5 criteria for generalized anxiety disorder are as follows:[1]

1. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance).

2. The individual finds it difficult to control the worry.

3. For children, the anxiety and worry are associated with one (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past 6 months):

   1. Restlessness or feeling keyed up or on edge

   2. Being easily fatigued

   3. Difficulty concentrating or mind going blank

   4. Irritability

   5. Muscle tension

   6. Sleep disturbance (difficulty falling or staying asleep, or restlessness, unsatisfying sleep)

4. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

5. The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism).

6. The disturbance is not better explained by another mental disorder.

Complications

Potential complications of GAD include the following (see Prognosis):

• Comorbid depression and other comorbid conditions

• School truancy and withdrawal from other age-appropriate activities

• Strained family relationships when the child's anxiety contributes to irritability, noncompliance, demanding behavior, and/or chronic reassurance seeking

• "Self-medication" leading to substance abuse by adolescents

• Parents' inability to help in the child's treatment or to model adaptive coping/anxiety management because of their own untreated anxiety (or other psychiatric condition)

Multiple factors are thought to contribute to the development of generalized anxiety disorder (GAD) and to the broad category of anxiety disorders. Biologic, familial, and environmental factors are considered important. Behavioral inhibition, an early temperament associated with aversion to novel situations, has been found to be associated with later development of anxiety disorders.

Research has demonstrated an association between parents with anxiety disorders and children with behavioral inhibition. The tendency of anxiety to occur in families also has been established. Anxious parents may genetically predispose their children to anxiety, model anxious behavior, and behave and/or parent in ways that encourage and maintain anxious behavior in the child. 

Genetic studies of pediatric anxiety disorders (including generalized anxiety disorder) reveal heritability estimates from 20% to 65%, consistent with a significant genetic contribution. Earlier onset is thought to represent a more genetically vulnerable population. Nonetheless, studies have had difficulties identifying risk genes due to a complex, multifactorial pattern of inheritance.[4]

Environmental factors, such as other parental emotional problems, disrupted attachment, stressful life events, and traumatic experiences, also may place the child at risk for developing GAD.

The role of the family in understanding child anxiety is important, particularly in situations in which the needs of younger children who are developmentally limited in their ability to benefit from direct individual intervention are considered.

The prevalence of generalized anxiety disorder (GAD) in children and adolescents ranges from 2.9-4.6%. According to the DSM-5, the 12-month prevalence for generalized anxiety disorder is 0.9% among adolescents and 2.9% among adults in the general community of the United states. The 12-month prevalence of the disorder in other countries ranges from 0.4% to 3.6%. The lifetime morbid risk is 9.0%.[1]

In childhood, the sex distribution tends to be equal for females and males. In adolescence, a female-to-male ratio of 6:1 has been suggested; however, epidemiologic study results vary.

The age of onset varies, but GAD is more common in adolescents and older children than in young children. In addition, affected adolescents and older children tend to have more symptoms than do affected younger children.

The prognosis is thought to be relatively good when treatment is implemented early and effectively. However, the child remains at risk for developing generalized anxiety disorder (GAD) or other anxiety disorders.

For example, Last and colleagues reported an 80% recovery rate from overanxious disorder during a 3- to 4-year follow-up period. However, 35% of the children developed a new psychiatric disorder in the same interval.[5]

Mortality and morbidity

Anxiety disorders have a high rate of comorbidity. Children and teens with GAD are also likely to meet criteria for other anxiety disorders and, to a lesser degree, for a depressive or disruptive behavior disorder.

Deaths related to GAD in childhood and adolescence are related more to comorbid conditions, such as depression, than to GAD. Children and adolescents with both depression and an anxiety disorder tend to have more severe forms of depression; therefore, GAD should be viewed as a risk factor for morbidity and mortality. Anxiety disorders tend to be unstable over time. That is, a child may struggle with anxiety for a long period, but it may not necessarily be a result of the same specific anxiety disorder.

Anxiety is a serious problem in children and adolescents. We now understand that, in addition to deleteriously affecting the child's social and academic functioning, anxiety can cause serious long-term consequences. Many children and teens with one of the anxiety disorders suffer intermittently for the rest of their lives. Other serious psychiatric conditions, such as major depressive disorder and substance misuse, are closely associated with pediatric anxiety if not treated in a timely and effective manner.

GAD also may co-occur with conditions associated with stress, such as irritable bowel syndrome and headaches. The long-term physiologic effects of stress are more likely to cause nonpsychiatric gastrointestinal, cardiovascular, or other sequelae later in life.

Psychoeducation should be part of the treatment process. Patients and parents should have a good understanding of the contributing and maintaining factors of anxiety. Also, they should be clear regarding treatment goals, processes, and expectations.

For patient education information, see the Anxiety Center, as well as Anxiety, Panic Attacks, and Hyperventilation.

Children with generalized anxiety disorder (GAD) may experience somatic symptoms such as shortness of breath, rapid heartbeat, sweating, nausea or diarrhea, frequent urination, cold and clammy hands, dry mouth, trouble swallowing, or a "lump in the throat." Problems with muscle tension also can occur, including trembling, twitching, a shaky feeling, and muscle soreness or aches. Patients often complain of stomachaches and headaches. Despite these symptoms, few findings are noted on physical examination.

Association of childhood anxiety and irritability strongly correlate across child gender and age. Pediatric anxiety and irritability were similar across children with and without GAD. This suggests that the anxiety–irritability association remains relevant across pediatric anxiety disorders and not uniquely to GAD.[6]

An evaluation for GAD should include data gathering through diagnostic interviews with the child and parent, direct observation, and questionnaires. Family history of anxiety and mood disorders, the child's early temperament and adjustment to school, and life stressors or disruptions are among important factors to consider in GAD.

Structured interviews yielding DSM diagnoses, such as the Diagnostic Interview Schedule for Children (DISC) and the Anxiety and Related Disorders Interview Schedule for DSM-5 (ADIS-5) - Adult and Lifetime Version can be employed.

Questionnaires, such as the Revised Children's Manifest Anxiety Scale (RCMAS), the Multidimensional Anxiety Scale for Children (MASC),[7] and the Screen for Child Anxiety Related Emotional Disorders (SCARED) child and parent versions, can be used to further assess anxiety symptoms.

As previously mentioned, children with generalized anxiety disorder (GAD) may experience somatic symptoms, including shortness of breath, rapid heartbeat, sweating, nausea or diarrhea, frequent urination, cold and clammy hands, dry mouth, trouble swallowing, or a "lump in the throat." Problems with muscle tension, such as trembling, twitching, a shaky feeling, and muscle soreness or aches, may also occur, and patients often complain of stomachaches and headaches. Despite these symptoms, few findings are noted on physical examination.

Nonetheless, a thorough physical examination is necessary to determine possible physical illnesses indirectly or directly contributing to anxiety manifestations. Somatic complaints and associated anxiety that may be part of an individual’s clinical presentation may also be addressed by reassurance of normal physical examination findings, to include vital signs.

In April 2022, The US Preventive Services Task Force (USPSTF) posted draft recommendation statements on screening for depression and suicide risk in children and adolescents and screening for anxiety in children and adolescents. The USPSTF recommends screening children 12 years and older for depression and, for the first time, recommends screening children ages 8 years and older for anxiety.[8]

Consider urine drug screening (especially with adolescents), thyroid-stimulating hormone level assessment, and less common laboratory tests based on history and physical findings.

Excessive laboratory exclusion of somatic complaints is to be avoided; however, careful interview and physical examination assessment of stress-related symptoms should be repeated if the psychological diagnostic picture is unclear.

Many substances of abuse and even prescribed medications can contribute to anxiety manifestations (eg, stimulants for attention deficit-hyperactivity disorder, beta-2 agonists and corticosteroids for reactive airway disease). Furthermore, both use and/or withdrawal from substances of abuse may contribute to anxiety signs and symptoms.

For patients for whom medication is prescribed, regular appointments with a child and adolescent psychiatrist or developmental-behavioral pediatrician are necessary for the duration of treatment. Parents and patients must be warned of the possible risks of activation and disinhibition and what to do in such circumstances.

Go to Pediatric Obsessive-Compulsive Disorder, Pediatric Panic Disorder, and Anxiety Disorders for complete information on these topics.

Patient therapy

Weekly outpatient therapy for 3–4 months with less frequent follow-up booster sessions may be sufficient.

A cognitive-behavioral approach is likely to be most beneficial. Treatment should consist of individual sessions with family involvement to support the treatment process. Cognitive therapy features may be incorporated into an eclectic approach by highly skilled and experienced therapists.

Psychodynamic therapies, including play therapy, are time-honored modalities, but most outcomes research has focused on the brief or intermediate therapies, which are more structured.

Behavioral and cognitive-behavioral therapies are among the most researched and promising treatments for childhood anxieties. Behavioral techniques (eg, relaxation training, modeling, imagining and visualizing, in vivo exposure) and cognitive techniques (eg, identifying and modifying self-talk, challenging irrational beliefs) often are used in combination with psychoeducation and contingency maintenance. Typically, children are taught to recognize early physiologic and cognitive signs of anxiety and to develop and implement coping techniques.[9, 10]

The importance of parental participation in the treatment process recently has received attention. Adding a family component focused on techniques such as contingency management, communication, and problem solving to individual child cognitive-behavioral therapy has produced favorable long-term treatment benefits in several clinical trials.[11, 12, 13]

Regular exercise promotes a sense of well-being that is particularly beneficial in individuals with anxiety and mood disorders.

Limiting caffeine intake is appropriate.

Prior to a surgical procedure, children with an anxiety disorder are particularly likely to benefit from age-appropriate preparation, including relaxation practice for elective procedures.

The following measures may aid in the prevention of generalized anxiety disorder (GAD) in children:

• Consistent, stable, supportive home environment

• Parenting practices that promote self-confidence, self-esteem, and effective coping skills

• Minimal number of psychosocial stressors or traumatic events

• Adaptive problem solving and coping skills modeled by parents and other significant people in the child's life

• Psychoeducation

• Family-based interventions

Ginsburg conducted a study to determine the effectiveness of preventive intervention in the prevention and/or amelioration of anxiety symptoms in children of parents with anxiety disorders and found evidence to support the concept that family-based intervention may yield benefits in children at risk for anxiety.[14] Forty children and their families were randomized to undergo an 8-week cognitive-behavioral intervention (the Coping and Promoting Strength [CAPS] program; 20 participants) or a wait list control condition (20 participants). After a 1-year follow-up, none of the children in the CAPS program developed an anxiety disorder, while 30% of the children in the wait list group did.

The authors of one study developed a novel prediagnosis intervention, Strongest Families, which includes trained nonprofessionals supervised by mental health professionals for children with disruptive behavior and/or anxiety disorders. The intervention provides care using a handbook, instructional videos, and weekly telephone contacts. The study results noted that these telephone-based treatments resulted in a significant decrease in the proportion of children diagnosed with disruptive behavior or anxiety disorders; this treatment may be an option for those patients who are unable to attend face-to-face sessions.[15]

Given that school and academics represent key components in child and adolescent development, classroom interventions have been increasingly utilized with success. Such programs should also be considered as a treatment along with utilization as a preventive intervention.[16]

Early referral to a psychologist, psychiatrist, or behavioral-developmental pediatrician for evaluation and treatment can alleviate symptoms and stress that may be the early manifestations of a more severe disorder.

Family therapy referral also may be indicated, but that may be best managed by the mental health professional or the developmental and behavioral pediatrician who performs the consultative evaluation.

Studies support the tolerability and safety of selective serotonin reuptake inhibitor (SSRI) treatment for GAD and other pediatric anxiety disorders. These findings further suggest no differences in overall rates of adverse effects. Few differences occurred on specific adverse effect items.[17]

US Preventive Services Task Force

In April 2022, The US Preventive Services Task Force (USPSTF) posted draft recommendation statements on screening for anxiety in children and adolescents. The USPSTF recommends screening children 12 years and older for depression and, for the first time, recommends screening children ages 8 years and older for anxiety.[8]

Medication is ideally adjunctive to psychological treatment of generalized anxiety disorder (GAD). Unfortunately, lack of experienced and qualified therapists may preclude an adequate trial of cognitive-behavioral therapy.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are currently first-line medications in the pharmacotherapy of anxiety disorders in children. These antidepressants are powerful anxiolytics with a broader spectrum that may improve comorbid affective disorders and symptoms of anxiety. 

The FDA approved escitalopram in May 2023 for treatment of GAD in children aged 7–17 years. In a randomized controlled trial, patients received either escitalopram 10–20 mg daily (n = 138) or placebo (n = 137) for 8 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS) for GAD. Escitalopram was superior to placebo in reducing anxiety symptoms of GAD, as seen in the difference in mean change from baseline to week 8 on the PARS severity for GAD score (least squares mean difference = -1.42; p = 0.028).[18]

The selective serotonin/norepinephrine reuptake inhibitor (SNRI), duloxetine, was approved by the FDA in October 2014 for children aged 7 to 17 years for generalized anxiety disorders. Efficacy was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria). The starting dose was 30 mg once daily for 2 weeks. Further dose increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week treatment phase was 57.6 mg/day. Duloxetine (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score.[19]

Benzodiazepines have a relatively favorable adverse effect profile but are generally not chosen as first-line treatments for anxiety in children and adolescents. These agents may cause behavioral disinhibition in young children. They also have street value as drugs of abuse.

Buspirone (BuSpar) is an anxiolytic agent whose efficacy in the treatment of anxiety disorders in children and adolescents has not yet been demonstrated. BuSpar is slow to work in adults but does not cause habituation or disinhibition. Antihistamines and antipsychotics are not recommended for treatment of childhood-onset anxiety disorders.

Pregabalin (Lyrica), an anticonvulsant, has been approved for use in adults by the European Commission (EC) and the US Food and Drug Administration (FDA) for the management of diabetic peripheral neuropathy, postherpetic neuralgia, and adjunctive treatment of partial-onset seizures. On March 27, 2006, the EC approved a new indication for pregabalin, allowing its use in adults for the treatment of GAD in the European Union.

Pregabalin is not FDA approved for treating adult or pediatric GAD in the United States. EC approval was based on a review of data from 5 randomized, double-blind clinical trials in more than 2000 patients, which showed that pregabalin provided rapid and sustained efficacy in treating GAD, yielding significant relief from psychic and somatic symptoms within the first week of treatment.

Most adverse events were mild to moderate in intensity and generally dose-related. Dizziness and drowsiness were most frequently reported.

Pregabalin is a structural derivative of GABA. Its mechanism of action is unknown. It binds with high affinity to the alpha2-delta site (a calcium channel subunit). In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. Pregabalin is FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.

Class Summary

SSRIs are antidepressant agents chemically unrelated to the tricyclic or tetracyclic agents or to other available antidepressants. They inhibit neuronal reuptake of serotonin, thus potentiating serotonergic activity in the brain, with the regulation of hypervigilance and other aspects of anxiety. These changes also may have a weak effect on norepinephrine and dopamine neuronal reuptake. Several SSRIs are now available.

SSRIs are greatly preferred over the other classes of antidepressants. Because the adverse effect profile of SSRIs is less prominent, improved compliance is promoted. SSRIs do not have the cardiac arrhythmia risk associated with tricyclic antidepressants. Arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered when treating a child or adolescent with mood disorder.

Physicians are advised to be aware of the following information and use appropriate caution when considering treatment with SSRIs in the pediatric population.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than age 18 years for treatment of "depressive illness." After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine (Prozac), which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

In 2004, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed, because suicidality occurred in treated and untreated patients with major depression and thus could not be definitively linked to drug treatment.[20]

However, a study of more than 65,000 children and adults treated for depression between 1992 and 2002 by the Group Health Cooperative in Seattle found that suicide risk declined, rather than rose, with the use of antidepressants. This has been the largest study to date to address this issue.

Currently, evidence does not exist to associate obsessive-compulsive disorder (OCD) and other anxiety disorders treated with SSRIs with an increased risk of suicide.

Note that the aforementioned public health advisory by the FDA pertains treatment of depression in the pediatric population and not necessarily isolated anxiety disorders without depression.[21]

Escitalopram (Lexapro)

Indicated for generalized anxiety disorder (GAD) in patients aged 7 years and older. Escitalopram is the S-enantiomer of racemic citalopram. It inhibits the reuptake of serotonin, with little or no effect on norepinephrine or dopamine reuptake. 

Fluoxetine (Prozac)

Off-label for GAD in children aged <18 years. Fluoxetine has the longest history of use in children and adolescents and is now available in generic preparations. The drug's long half-life is an advantage and a drawback. If fluoxetine works well, an occasional missed dose is not a problem; if problems occur, eliminating all active metabolites takes a long time.

Adverse effects of SSRIs seem to be quite idiosyncratic; thus, relatively few reasons exist to prefer one to another at this point if dosing is started at a conservative level and advanced as tolerated.

Fluvoxamine (Luvox CR)

Off-label for GAD in children aged <18 years. Fluvoxamine enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and thus has fewer adverse effects than tricyclic antidepressants.

Fluvoxamine has been shown to reduce repetitive thoughts, maladaptive behaviors, and aggression and to increase social relatedness and language use.

Sertraline (Zoloft)

Off-label for GAD in children aged <18 years. Zoloft selectively inhibits presynaptic serotonin reuptake.

Paroxetine (Paxil, Pexeva)

Off-label for GAD in children aged <18 years. Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake. It also has a weak effect on norepinephrine and dopamine neuronal reuptake. For maintenance dosing, make dosage adjustments to maintain the patient on the lowest effective dosage, and reassess the patient periodically to determine the need for continued treatment.

Class Summary

Selective serotonin/norepinephrine reuptake inhibitors may be considered. 

Duloxetine (Cymbalta, Drizalma Sprinkle)

Duloxetine is FDA approved for GAD in children aged 7 to 17 years. Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Further evidence for duloxetine effectiveness in GAD includes a randomized, placebo-controlled study with duloxetine in treating children and adolescents aged 7–17 years old. Duloxetine was, again, found superior to placebo and consistent with previous study safety profiles.[24]

 

Class Summary

These agents depress all levels of the central nervous system (eg, the limbic and reticular formations), possibly by increasing the activity of gamma-aminobutyric acid (GABA). Benzodiazepines also increase the frequency of chlorine channel opening in response to GABA binding. GABA receptors are chlorine channels that mediate postsynaptic inhibition, resulting in postsynaptic neuron hyperpolarization. The final result is a sedative-hypnotic and anxiolytic effect.

Benzodiazepines have been used in children for a variety of indications, including the reduction of anticipatory or acute situational anxiety. Note the importance of using caution, and use these drugs only in conjunction with psychotherapy aimed at reducing the length of time on benzodiazepines.

Many pediatricians are most familiar with diazepam (Valium), and no particular reason exists to prefer another benzodiazepine in children, because diazepam is available as a generic preparation and has a smooth, longer action that may be advantageous.

Lorazepam (Ativan) has the advantage of being quite short acting in the event of disinhibition, but it is not as useful for the treatment of generalized anxiety disorder (GAD) because of the frequent dosing. Clonazepam (Klonopin) has been studied in severe anxiety disorders but has been anecdotally (incorrectly) noted to have some increased risk of behavioral disinhibition. Alprazolam (Xanax) has been most studied in anxiety disorders in children.

Diazepam (Valium)

Individualize dosage, and increase cautiously to avoid adverse effects. Necessary to use for shortest time possible when abrupt discontinuation is not a risk. Further, should not be continued if patient discontinues psychotherapy.

Class Summary

Buspirone is the anxiolytic in this category. It has a high affinity for serotonin receptors and a moderate affinity for dopamine receptors, and it does not have cross-tolerance with benzodiazepines. No reports of dependence exist. One drawback is that buspirone takes 1-4 weeks to become effective.

Buspirone (Buspirex, BuSpar, Bustab)

This is a 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS. Buspirone hydrochloride has an anxiolytic effect, but it may take up to 2-3 wk to reach full efficacy. A relative disadvantage to the administration of this drug is a lack of official approval for its use in individuals under age 18 years.