When is it appropriate to treat children with social anxiety, pharmacologically?

1. Introduction

Social anxiety disorder (SAD) represents one of the most common forms of psychopathology among children and adolescents, but often goes undetected or untreated. The core symptom of SAD is a marked and persistent fear of one or more social or performance situations, leading to excessive anxiety or avoidance of such situations [1]. In children and adolescents, school and peer settings are commonly the focus of the child’s concern, which can cause significant distress and functional impairment that may impair peer relationships and school attendance and performance. The onset of SAD is typically mid-adolescence and commonly persists into adulthood [2]. For treatment to be most effective, it should ideally include a multimodal approach, comprising psychotherapy (especially exposure-based cognitive behavior therapy, or CBT), family and patient education, consultation with school personnel and primary care physicians, and/or use of pharmacotherapy if indicated [3].

It is important to note that SAD is highly comorbid with other disorders, such as depression or other anxiety disorders [4] This paper will focus on specific treatment options for SAD, however much of what is discussed could be applied to similar anxiety disorders as well. Comorbid diagnoses are important to note, however these should not negate treatment options discussed here.

Before choosing pharmacotherapy, the following questions should be addressed: (1) Has CBT been properly used as treatment? (2) When is it appropriate to use pharmacotherapy? (3) Is pharmacotherapy safe and effective? and (4) How acceptable is pharmacotherapy? We will offer venues for future research and discuss research-based guidelines for clinicians (pediatricians and psychiatrists) who are facing difficult decisions, while aiming to provide children with SAD the safest and effective care.

2. Has CBT been properly used as treatment?

Research indicates that treatment for SAD in children and adolescents should be psychotherapy, especially exposure-based CBT, combined with family and patient education and the inclusion of school personnel as needed. The most extensively studied nonpharmacologic treatment for SAD is CBT, particularly with an emphasis on exposure therapy [5] Recent meta-analyses have found strong support for CBT for anxiety disorders in children, with large effect sizes. In addition, CBT was found to be superior to selective reuptake inhibitors due to lesser side effects and greater cost-effectiveness [6]. Randomized controlled trials of adolescents with SAD have also found cognitive therapy for SAD (CT-SAD) to be highly effective treatment at low cost [7].

3. When is it appropriate to use pharmacotherapy?

Children and adolescents with symptoms of SAD commonly present in primary care settings. Signs and symptoms of anxiety include cognitive, physiological, and behavioral manifestations. Diagnosis of SAD is typically made via a clinical interview of the child and his or her parents. According to the DSM-5, SAD can be reliably diagnosed in children as young as age six, with the same diagnostic criteria across age groups, and with a minimum duration of six months, regardless of age [8].

Behavioral treatment modalities are the mainstay and have been shown to be efficacious in the treatment of SAD in children and adolescents [9]. Still, pharmacotherapy alone or in combination with psychotherapy is indicated when one or more of the conditions below is present:

1. For many children and adolescents, the symptoms of anxiety are severe enough to preclude effective participation in psychotherapy. In these cases, medications are indicated in order to ameliorate anxiety symptoms to a sufficient level, allowing for effective participation in the behavioral treatment.

2. Even when psychotherapy is provided, severity of symptoms and interference in the child’s functionality might indicate the use of medications along with the psychological treatment. This is especially true if children need to first reach certain developmental, cognitive, and/or educational milestones before certain forms of psychological strategies (such as certain cognitive interventions) can have their intended effect.

3. When behavioral treatment is provided but only shows partial results or does not bring the desired improvements, it is important to evaluate if best practice behavioral treatment has been given. If this is the case, pharmacotherapy may then be indicated to support psychotherapy, allowing more effective participation with the goal to improve treatment outcomes.

4. Unfortunately, psychotherapy is not always accessible to children for various reasons (i.e. lack of mental health providers in some areas, long waiting lists in treatment centers, or inability of the family to support and participate in psychotherapy). In those cases, primary care physicians are left with few alternatives to pharmacotherapy.

There is good evidence to suggest that a combined approach (i.e. psychotherapy and pharmacotherapy) can be an effective strategy [10]. However, sometimes medication alone is used as treatment of SAD in children, when other modalities are not accessible. As a result, it is important that public health policies and treatment guidelines are based on the best available evidence.

4. Is pharmacotherapy safe and effective?

In children and adolescents who might benefit from the use of medications, selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice [10]. SSRIs act by blocking the reuptake of serotonin by pre-synaptic neurons and enhance serotonergic neurotransmission. A series of randomized, placebo-controlled trials examining the efficacy of SSRIs have established a short-term benefit of SSRIs for treating childhood anxiety disorders, including SAD. Well-researched medications are sertraline [11], paroxetine [12], fluvoxamine, and fluoxetine [13].

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may also be considered when first-line treatments (usually SSRIs) have been ineffective. SNRIs act by blocking both serotonin and norepinephrine reuptake and inhibit dopamine reuptake. Drugs such as venlafaxine and duloxetine are effective in anxiety disorders in children and adolescents, but have been rarely tested in pediatric SAD samples [14].

As a general guideline, SSRIs and SNRIs should be administrated for an initial period of at least one year. Once a patient has been on a stable dose for a year, treatment may be discontinued while monitoring the patient for reemergence of anxiety symptoms [15]. However, little is known about the long-term benefits of these medications, especially in children and adolescents. Dosage recommendations indicate a period of four weeks before considering an increase in the dose or changing to a different SSRI agent [16]. For SNRIs, only 40% of the treatment response observed for SSRIs was observed at week 8. Thus, clinicians might preferentially use SSRIs as first-line psychopharmacologic interventions in pediatric patients with anxiety disorders [17].

The general generic guideline is to start at a low dose, closely monitoring the side effects, and then slowly increasing the dose based on guidelines by the drug manufacturer, treatment response, and tolerability [15,18]. To our knowledge, there are no long-term studies that examined the effects of treatment duration and dosing, to guide clinicians’ decision-making for treating children and adolescents with SAD, so further research needs to be conducted in this area.

Compared to placebo, SSRIs are moderately effective and well tolerated for treating pediatric anxiety disorders [17]. Early identification and effective treatment may reduce the impact of anxiety on academic and social functioning in youths and may reduce the persistence of anxiety disorders into adulthood. Carefully outweighing the risks and benefits in any individual case should guide the clinician to decide which treatment to initiate.

To date, aside from SSRIs and SNRIs, data are insufficient to categorically recommend other classes of anti-anxiety drugs in children over another. Other types of medications, including tricyclic antidepressants [TCAs], buspirone, and benzodiazepines are rarely used for children with anxiety disorders. To date, the literature does not clearly support the effectivity and tolerability of these medications in pediatric populations. Specifically, no randomized control trial has examined these treatments for social anxiety disorder among children. Benzodiazepines, for example, showed promising results in open label trials, but failed to show superiority over placebo in more rigorous studies (Witek et al., 2005) [19]. Similarly, TCAs and buspirone showed inconsistent results (for a review, see Strawn et al., 2018, Kuang, Johnson, Mulqueen & Bloch, 2017) [20,21]. Therefore, clinicians rarely recommend them as alternatives, either alone or in combination with SSRIs, in cases of partial or non-response to other therapeutic attempts [22].

Although beneficial in many cases, SSRIs and some SNRIs are associated with several concerning side effects, significantly more treatment-emergent and even serious adverse events, as well as family and patient’s compliance difficulties and treatment discontinuation. Common side effects are gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, and behavioral activation (i.e. alteration in mood, dysphoria, altered cognition, nervousness, agitation, irritability) [23]. Although side effects are often mild, even these mild side effects may be problematic for anxious children, as they are often sensitive to any worsening in the somatic symptoms or emergence of even transient side effects of medications. However, it is important to note that most SSRI side effects are dose related. For example, nausea, a common symptom, can often be alleviated by reducing the SSRI dosage [23].

An especially concerning side effect is depression and suicidality associated with SSRIs and SNRIs [24]. In February 2004, the U.S Food and Drug Administration issued a black-box warning and advised clinicians to carefully monitor pediatric patients receiving SSRIs for worsening depression, agitation, or suicidality, particularly at the beginning of medication treatment or during dose changes. However, this was based on evidence from adolescents whose primary diagnosis was depression, not SAD or other anxiety disorders, thus further research needs to be conducted. Even though the evidence supports the efficacy of antidepressant medications for anxiety disorders, FDA labeling is lacking. Some SSRIs are FDA approved for pediatric OCD (e.g. Fluoxetine, Fluvoxamine IR) or for GAD (e.g. Duloxetine; for the full FDA approved medications for pediatric anxiety disorders see Patel et al. [3]). Although research supports the efficacy and safety of SSRIs/SNRI’ in pediatric SAD, clinicians are still forced to prescribe these medications off-label. While off-label use of medications is not uncommon, it can be problematic in vulnerable populations, such as children. Importantly, a recent metanalysis suggested that adverse events are rarely serious and generally do not require discontinuation of treatment [25].

5. How acceptable is pharmacotherapy?

Treatment acceptability is the individual’s belief that a treatment is appropriate for use. It is influenced by various factors (i.e. knowledge, alliance with the therapist, treatment intrusiveness) and is strongly associated with better compliance and efficacy. Studies have shown that parents are more accepting of psychotherapy for SAD and for depression, compared to pharmacological approaches [26]. Additionally, in some ethnic minority (African and Latino parents) help seeking behavior and specifically use of SSRIs among children is consistently lower compared to the white Americans population [27]. Treatment acceptability effect compliance rates and treatment outcomes. Accordingly, it is highly important devote resources for raising awareness and providing updated information about the available treatments for anxiety and to enhance open communication with health care providers to address parental concerns and to increase acceptability.

In SAD, as in other psychiatric conditions, problems tend to emerge in more complex cases when first-line treatments fail and other obstacles for treatment are present. These may include symptom severity, multiple comorbidities, conflictual or dysfunctional family dynamics, low resources and low accessibility to mental health providers. It is in these cases that combination treatments are recommended. There may be other situations as well where combination treatment offers significantly higher rates of remission. These cases call for further clinical and research attention, to assure the delivery of responsible and evidence guided therapy for children and their families.

6. Expert opinion

As CBT has fewer side effects than pharmacotherapy, it may be considered as the first-line treatment. At the same time, enough evidence is supporting the efficacy of pharmacotherapy, especially SSRIs, in socially anxious youth, suggesting that a combination with psychotherapy may be a viable treatment option. Furthermore, in terms of symptomatic relief pharmacotherapy often provide short-term improvements which could be extremely valuable in moderate and severe cases.

More research is needed to elucidate the effects of the consequences of prolonged use of this type of medication for children’s developing brains. However, we recognize that long-term randomized controlled trials with placebo is not feasible from an ethical perspective. Our hope, however, is that more research can demonstrate the safety and efficacy of long-term use. Additionally, variability in treatment outcomes (both psychotherapy and pharmacotherapy) calls for new, evidence-based interventive tools. We recommend that clinicians treating SAD in children closely monitor the symptoms and use a conservative approach ensuring safety for patients. In addition, pediatricians and psychiatrists need to facilitate communication with parents about attitudes toward mental health treatments and focus on addressing parental concerns. It is necessary to provide families with information regarding proper medications use, change mechanisms, expected outcomes and side effects. Building strong long-term alliances with patients and their families can increase treatment acceptability, minimize the risks and increase treatment effectivity.

Declaration of interest

Dr. Hofmann receives financial support from the Alexander von Humboldt Foundation, NIH/NIMH (R01MH099021, U01MH108168), and the James S. McDonnell Foundation. He receives compensation for his work as editor from SpringerNature, and as an advisor from the Palo Alto Health Sciences, Otsuka Pharmaceuticals, Jazz Pharmaceuticals. and for his work as a Subject Matter Expert from John Wiley & Sons, Inc., Wolters Kluwer, and SilverCloud Health, Inc. He also receives royalties and payments for his editorial work from various publishers.

Dr. Snir and Ms. Moskow 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

A referee declares receiving royalties from Wolters Kluwer for working with UptoDate on Pediatric Anxiety Disorders. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

Dr. Hofmann was supported for this work by the James S. McDonnell Foundation via a Collaborative Activity Award (ID: 220020479).