http://orcid.org/0000-0003-3359-3191
1. State of art of pediatric Generalized Anxiety Disorder: epidemiology, outcome and treatment options
Generalized Anxiety Disorder (GAD) is characterized by uncontrollable worry, pervasive fear, and excessive anxiety in multiple domains. The most frequent symptoms reported by children and adolescents affected by GAD include feelings of tension, apprehension, the need for reassurance, irritability, negative self-image, and physical complaints [Citation1]. It is a disabling condition, affecting 3–6% of adults and 5% of children and adolescents [Citation1].
Children and adolescents affected by GAD present functional impairment and higher suicide risk throughout their lifespan in comparison to healthy individuals [Citation2]. Moreover, comorbid psychiatric conditions are highly frequent in children affected by GAD, particularly other anxiety disorders (e.g. Separation Anxiety Disorder and Social Anxiety Disorder), mood disorders [Citation3], and Attention Deficit Hyperactivity Disorder (ADHD), thus further increasing the risk of functional impairment, early suicidal attempts or substance abuse compared to healthy controls [Citation3].
The potential clinical severity of pediatric GAD is supported by the evidence that children affected by GAD present dysregulation of the brain fear circuitries that involve the Anterior Limbic Network (ALN), amygdala, ventromedial and ventrolateral prefrontal cortex (VLPFC), rostral insula and the anterior cingulated cortex (ACC). Furthermore, adolescents suffering from GAD have an abnormal activation of the medial PFC and right VLPFC in response to emotional stimuli, and a disrupted connectivity between amygdala/VLPFC and regions involved in mentalization processes (e.g. precuneus or medial PFC) [Citation4].
For what has been mentioned above, pediatric GAD requires early recognition and management. The available treatment strategies for this condition include pharmacotherapy and psychosocial interventions [Citation5]. The authors of a recent review [Citation5] concluded that Selective Serotonin Reuptake Inhibitors (SSRIs) (especially fluoxetine and sertraline) should be the first-line treatment in children and adolescents with GAD, while Selective Serotonin Noradrenalin Inhibitors (SNRIs) should be considered a second-line option, differently from adults. Curiously, the SNRI duloxetine is the only compound to be specifically approved by the Food and Drug Administration (FDA) (in 2014) for children with GAD and only for those of 7 years and older. Psychotherapy appears to ameliorate GAD symptoms especially when used in combination with pharmacotherapy; most of the available studies about psychotherapy in children and adolescents with GAD have demonstrated the efficacy of Cognitive Behavioral Therapy (CBT), while limited data is available for other approaches such as Interpersonal Psychotherapy for adolescents or Mentalization-Based Therapy [Citation6].
In the present article, we list and discuss the most important factors that can direct clinicians to prescribe a pharmacological treatment to children affected by GAD.
2. Factors promoting the initiation of pharmacotherapy
Different factors may promote the initiation of pharmacotherapy in children and adolescents affected by GAD because they are associated with poor prognosis.
The first factor is clinical severity; The Pediatric Anxiety Rating Scale (PARS) is one of the most useful and spread tools to assess severity and functional impairment of children affected by GAD. This rating scale is also one of the most used tools in pharmacological clinical trials, and a total score ≥21 is suggestive of severe GAD symptoms. Other instruments have been specifically developed to assess anxiety in youth and to monitor treatment progress. They may be used in children >8 years, and they include the Multidimensional Anxiety Scale for Children, the Screen for Child Anxiety and Related Emotional Disorders (SCARED), and the Spence Children’s Anxiety Scale (SCAS). Finally, the Preschool Anxiety Scale is a variant of SCAS for parents and it has been developed for children between 2.5 and 6.5 years [Citation7].
Another aspect to be taken into account is medical and psychiatric comorbidity. A recent meta-analysis highlighted that anxiety disorders are three times more frequent in children affected by Asthma than in healthy youth [Citation8]. Furthermore, as mentioned above, pediatric GAD is frequently concomitant with or complicated by other mental conditions including anxiety and mood disorders, and ADHD [Citation3].
A third factor to be considered is the presence of suicidal ideation or high risk of suicidal behavior. A recent study reported that till 34% of children and adolescents with depression or anxiety disorders show suicidal ideation or they have a history of suicidal attempts [Citation9].
Fourth, family history of severe psychiatric disorders (e.g. Bipolar Disorder) or suicide are associated with poor prognosis of children affected by GAD and support early intervention of these patients for the high risk of psychiatric comorbidity, substance abuse especially for adolescents and suicidal attempts.
Finally, previous inefficacy of psychosocial interventions may encourage the initiation of pharmacological treatments.
3. Factors discouraging the initiation of pharmacotherapy
Some aspects have to be carefully evaluated in deciding if a pharmacotherapy has to be started in children affected by GAD.
First, the number of randomized controlled trials in pediatric GAD patients is much lower than in adults and some considerations can be only extrapolated from studies with adults. The evidence of the efficacy of pharmacotherapy (e.g. SSRIs) in children with GAD is, therefore, less robust than in adults [Citation9].
As there are less pharmacological trials in children than in adults, tolerability and side effects can be less predictable in pediatric populations. In addition, children (similarly to the elderly) have clinical specificities and they can be considered more fragile than adults as a consequence of neurodevelopment [Citation2].
SSRIs and SNRIs have been associated with a higher risk of attempted suicide in young people compared to adults, especially in the first months after prescription [Citation9]. For example, even though paroxetine or venlafaxine are two of first-line options for GAD treatment in adults, the administration of these compounds in children or adolescents has been associated with an increased risk of suicidal thinking and behavior.
It is not well established which is the effect of pharmacotherapy (e.g. SSRIs) on brain development; consequently, it is not clearly defined how long pharmacotherapy should be maintained after an acute exacerbation for a full recovery and prevention of relapses in children (even in adults it has not been totally defined a proper duration of maintenance treatment) [Citation7].
In the light of what has been mentioned above, the clinicians should ascertain if an alternative and effective treatment to pharmacotherapy (e.g. CBT) has been previously provided ().
Table 1. Pros and cons of the initiation of pharmacotherapy in children affected by generalized anxiety disorder (GAD).
4. Conclusion
The initiation of pharmacotherapy in children should be carefully assessed taking into account the severity of symptoms, the possible coexistence of medical and psychiatric comorbidities, the onset of adverse events and the ineffectiveness of psychosocial therapies. Available data show that SSRIs and SNRIs improve GAD symptoms in children with a number needed to treat (NNT) ranging from 2.8 to 9.3 and that these compounds are associated with mild treatment-emergent adverse events, consisting mainly of nausea, activation, and headache [Citation10].
5. Expert opinion
A number of pediatric patients affected by GAD may benefit from a pharmacological treatment especially with SSRIs, although evidence of efficacy of pharmacotherapy in children is more limited than in adults. In addition, it has not been totally defined when to start a pharmacotherapy in children with GAD. Some factors may promote the initiation of pharmacotherapy including remarkable severity, presence of psychiatric comorbidity, family history of psychiatric disorders, high risk of suicide, and inefficacy of previous psychological treatments. The presence of two of these factors (e.g. a severe presentation of GAD and comorbidity with a mood disorder or ADHD) may be proposed as guidance for the initiation of pharmacotherapy in these subjects. Obviously, children taking a psychopharmacological treatment should be carefully monitored to have an accurate risk/benefit ratio because, as mentioned above, children (more than adults) may develop unpredictable side effects or have an increased risk of suicidal ideation or behavior during antidepressant treatment. However, it must also be said that data on the association between SSRIs and completed suicide derive from retrospective analysis. A meta-analysis of randomized controlled trials with antidepressants in children reported no completed suicide and a slightly increased risk of suicidal ideation or attempt (number needed to harm-NNH: 143) [Citation11]. Of note, the suicidal aspects appear to be closely related to the severity and type of psychiatric illness; in this sense, anxiety disorders would not be associated with a significant increased suicidal risk in children differently from depressive disorders. In addition, antidepressants have shown to be more beneficial in children affected by anxiety disorders than in those affected by depressive disorders [Citation12].
Children may need lower doses of antidepressants depending on weight, or alternatively, the compounds may not be available in formulations suited for children (e.g. solution or suppository). It is true that there is limited data about the opportunity to adjust doses of antidepressants in children; however, preliminary data indicate that pharmacokinetics may be different and that this may have contributed to the safety and tolerability concerns of antidepressant treatment in the youngest patients [Citation13].
Duloxetine is the only compound approved for pediatric GAD by the FDA [Citation14], but other organizations such as European Medicines Agency (EMA) do not recommend any pharmacological treatment for these patients. SSRIs would represent the first option for GAD treatment in children [Citation5], but in case of comorbidity, it would be advisable to select a compound with data of efficacy for both the disorders to avoid poly-therapy that in turn may increase the risk of side effects. Duloxetine, sertraline, and fluoxetine might be preferred in case of comorbid Major Depression; fluoxetine and sertraline in case of comorbidity with Obsessive-Compulsive Disorder; fluoxetine for concomitant Panic Disorder and sertraline in case of comorbidity with Social Anxiety Disorder. The old antihistamine compound hydroxyzine could improve anxiety symptoms in children affected by Rhinitis or Grass Pollen-Sensitive Asthma, and it could be considered as an alternative in the case of inefficacy of SSRIs and SNRIs. Similar considerations may be done for imipramine prescribed to treat Enuresis ().
Table 2. What is the evidence of efficacy on GAD symptoms of compounds used in comorbid medical and psychiatric conditions?
The last issue to be considered is that GAD frequently does not occur alone in children and adolescents. In light of the high frequent comorbidity of GAD with Social Anxiety Disorder and Separation Anxiety Disorder, some authors have hypothesized a unique anxiety disorder with different clinical manifestations [Citation15]. This aspect may make future clinical trials more complicated in terms of the selection of patients with pure GAD as well as in terms of comparing the results from those of currently available studies.
Declaration of interest
M Buoli has been a consultant for Mylan and Lundbeck AS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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