Psychiatric Annals

Psychopharmacology of Child and Adolescent Anxiety Disorders

David R Rosenberg, MD; S Preeya Banerjee, PhD; Jennifer L Ivey, BS; Elisa R Lorch, MA

Abstract

In recent years, anxiety disorders in children have been recognized as severe, highly prevalent, and chronically disabling illnesses over which a child usually has little, if any, control. Lifetime prevalence rates for pediatric anxiety disorders are comparable with prevalence rates observed for common pediatric conditions including asthma and diabetes.

Treatment studies of pediatric anxiety disorders have lagged far behind studies of adults with anxiety disorders. However, this has changed since the Food and Drug Administration (FDA) mandated testing of medications being used in pediatric populations. In years past, pharmaceutical companies typically developed compounds and tested them exclusively in adults and then promoted their use in children in a top-down fashion.

The FDA mandate that medications used in pediatric populations undergo rigorous testing has resulted in several multicenter controlled studies in various pediatric anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are the drugs of first choice for anxiety disorders in both adults and children. This is largely due to their favorable side effect profile and their being far less lethal in overdose. Newer nontricylic agents, eg, venlafaxine and bupropion, are also being used increasingly in pediatric anxiety disorders.

Psychotherapy, particularly cognitive behavioral therapy (CBT), is a viable treatment for pediatric anxiety disorders with controlled data supporting acute and long-term efficacy.1 Indeed, many health care professionals consider CBT the treatment of choice for pediatric patients with anxiety disorders. Clearly, its use (with or without medication) should be considered in the treatment plan for any child or adolescent diagnosed with an anxiety disorder.

In this article we synthesize available data to provide the reader with the best clinical judgment and practice for use of psychotropic medications in pediatric anxiety disorders.

PHARMACOTHERAPY FOR OBSESSIVE-COMPULSIVE DISORDER

Obsessive-compulsive disorder (OCD) is a severe, prevalent, and chronically disabling illness with frequent onset during childhood and adolescence. In contrast to many pediatric neuropsychiatrie disorders, the clinical phenomenology, nosology, and empirical treatment for pediatric OCD have been well delineated. Obsessive-compulsive disorder is also less vulnerable to ambiguities in expression across the lifetime compared to other disorders such as major depressive disorder and bipolar disorder.

Serotonin reuptake inhibitors (SRIs) are now widely used in pediatric patients with OCD and are the most commonly used initial treatment for OCD across the lifespan.2 Controlled trials in adults with OCD clearly demonstrate the efficacy and safety for the nonselective SRI clomipramine3 and the SSRIs paroxetine, fluvoxamine, sertraline, fluoxetine, and Citalopram.45

Previously published meta-analyses have suggested that the SRI clomipramine may have superior efficacy compared to SSRIs in OCD.4 However, head-to-head, controlled, comparative trials of SSRIs and clomipramine6,7 have reported comparable therapeutic efficacy and there is no clear superiority of one compound (SSRI or SRI) over another to date.8

The clomipramine multicenter study9 led to the first FDA approval of a psychotropic medication for pediatric OCD. Since then, fluvoxamine (aged 8 to 18 years) and sertraline (aged 6 to 1 8 years) have also received FDA approval for the treatment of children and adolescents with OCD.10,11 A large multicenter, double-blind, placebo-Controlled trial of fluoxetine and placebo in 103 pediatric patients with OCD, aged 7 to 17 years, demonstrated significantly greater reduction in OCD symptoms with fluoxetine compared to placebo.12

The SSRI paroxetine has been evaluated in several industry-sponsored, multi-site, controlled trials for the treatment of both pediatric OCD and pediatric major depressive disorder. The results of the two multicenter studies of paroxetine in pediatric OCD clearly demonstrate both its efficacy (superior to placebo) and safety.12"14 The total number of 537 pediatric patients with OCD enrolled in the two multicenter studies of paroxetine represents the largest trial of any SRI or SSRI for any pediatric…

In recent years, anxiety disorders in children have been recognized as severe, highly prevalent, and chronically disabling illnesses over which a child usually has little, if any, control. Lifetime prevalence rates for pediatric anxiety disorders are comparable with prevalence rates observed for common pediatric conditions including asthma and diabetes.

Treatment studies of pediatric anxiety disorders have lagged far behind studies of adults with anxiety disorders. However, this has changed since the Food and Drug Administration (FDA) mandated testing of medications being used in pediatric populations. In years past, pharmaceutical companies typically developed compounds and tested them exclusively in adults and then promoted their use in children in a top-down fashion.

The FDA mandate that medications used in pediatric populations undergo rigorous testing has resulted in several multicenter controlled studies in various pediatric anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are the drugs of first choice for anxiety disorders in both adults and children. This is largely due to their favorable side effect profile and their being far less lethal in overdose. Newer nontricylic agents, eg, venlafaxine and bupropion, are also being used increasingly in pediatric anxiety disorders.

Psychotherapy, particularly cognitive behavioral therapy (CBT), is a viable treatment for pediatric anxiety disorders with controlled data supporting acute and long-term efficacy.1 Indeed, many health care professionals consider CBT the treatment of choice for pediatric patients with anxiety disorders. Clearly, its use (with or without medication) should be considered in the treatment plan for any child or adolescent diagnosed with an anxiety disorder.

In this article we synthesize available data to provide the reader with the best clinical judgment and practice for use of psychotropic medications in pediatric anxiety disorders.

PHARMACOTHERAPY FOR OBSESSIVE-COMPULSIVE DISORDER

Obsessive-compulsive disorder (OCD) is a severe, prevalent, and chronically disabling illness with frequent onset during childhood and adolescence. In contrast to many pediatric neuropsychiatrie disorders, the clinical phenomenology, nosology, and empirical treatment for pediatric OCD have been well delineated. Obsessive-compulsive disorder is also less vulnerable to ambiguities in expression across the lifetime compared to other disorders such as major depressive disorder and bipolar disorder.

Serotonin reuptake inhibitors (SRIs) are now widely used in pediatric patients with OCD and are the most commonly used initial treatment for OCD across the lifespan.2 Controlled trials in adults with OCD clearly demonstrate the efficacy and safety for the nonselective SRI clomipramine3 and the SSRIs paroxetine, fluvoxamine, sertraline, fluoxetine, and Citalopram.45

Previously published meta-analyses have suggested that the SRI clomipramine may have superior efficacy compared to SSRIs in OCD.4 However, head-to-head, controlled, comparative trials of SSRIs and clomipramine6,7 have reported comparable therapeutic efficacy and there is no clear superiority of one compound (SSRI or SRI) over another to date.8

The clomipramine multicenter study9 led to the first FDA approval of a psychotropic medication for pediatric OCD. Since then, fluvoxamine (aged 8 to 18 years) and sertraline (aged 6 to 1 8 years) have also received FDA approval for the treatment of children and adolescents with OCD.10,11 A large multicenter, double-blind, placebo-Controlled trial of fluoxetine and placebo in 103 pediatric patients with OCD, aged 7 to 17 years, demonstrated significantly greater reduction in OCD symptoms with fluoxetine compared to placebo.12

The SSRI paroxetine has been evaluated in several industry-sponsored, multi-site, controlled trials for the treatment of both pediatric OCD and pediatric major depressive disorder. The results of the two multicenter studies of paroxetine in pediatric OCD clearly demonstrate both its efficacy (superior to placebo) and safety.12"14 The total number of 537 pediatric patients with OCD enrolled in the two multicenter studies of paroxetine represents the largest trial of any SRI or SSRI for any pediatric population or condition. Application for an FDA indication for paroxetine has been submitted to the FDA.

No double-blind, placebo-controlled trials of Citalopram have been conducted in pediatric OCD patients. Subsequent investigations to determine the long-term efficacy and safety of (1) fluvoxamine (for 12 months) in 99 children and adolescents aged 8 to 17 years with OCD,15 and (2) sertraline (for 12 months) in 137 pediatric patients with OCD aged 6 to 18 years11 resulted in marked additional improvement in OCD symptom severity than was seen during acute treatment. Thus, full treatment effects of SRIs may be delayed several months, with added benefit achieved after more chronic administration of medication.

Dosing ranges for SRIs vary Utile across the lifespan.8 Consensus guidelines among experts for treatment of OCD advise initiating SRIs at a low dose, waiting 2 to 3 weeks before increasing the dose, targeting therapeutic doses by 6 to 8 weeks of treatment, and allowing 10 to 12 weeks for adequate acute dose titration.8 Pharmacokinetic studies in children and adolescents show no difference in dosing strategy for SRIs by age grouping is necessary.16,17 Serum drug levels of SRIs also do not predict behavioral/symptomatic response. ' ' Because of the more benign side effect profile of SSRIs compared to clomipramine, SSRIs are considered first-line agents in pediatric OCD. Clomipramine is typically used in pediatric patients with OCD only when two or more SSRIs fail to achieve sufficient amelioration of symptoms.

Up to one third of patients with OCD do not respond at all, even to adequate trials of SRIs.'8 Respondéis to SRIs often respond incompletely with continued functional impairment. Double-blind, placebo-controlled studies adding Uthium and thyroid hormone,19 buspirone,20 clonazepam,21 and trazodone22 to SRI therapy have been disappointing and have not demonstrated superiority to augmentation with pill placebo. Augmentation strategies of SRI with haloperidol23'24 and pimozide24 have, however, been found to be effective and superior to placebo in adult OCD patients with coexisting tic disorders or schizotypal personality disorder but not in OCD patients without these comorbid conditions.

The potentially irreversible side effects of traditional neuroleptics, eg, tardive dyskinesia, further limits their use, particularly in pediatric populations. Atypical neuroleptics are, therefore, being used more commonly to augment SRI therapy in both adult and pediatric patients with OCD. McDougle et al.25 found augmentation of SSRl treatment with risperidone superior to augmentation with placebo in treatment-refractory adult OCD patients with and without comorbid tic disorders. Open-label investigation also suggests that augmentation of SRI treatment with risperidone26 or clomipramine27,28 may be effective in pediatric patients with OCD, including patients without comorbid tic disorders. Placebo-controlled investigation is clearly warranted.

Cognitive behavioral therapy is an effective treatment in pediatric patients who only have OCD or who have a combination of OCD and other psychiatric disorders.29 Children with OCD should never be considered treatmentrefractory until an adequate trial of CBT has been attempted. In some children with severe illness, CBT may not be feasible until pharmacotherapy decreases symptoms to a level where this technique can be effectively implemented. Drs. John March (Duke University) and Edna Foa (University of Pennsylvania) have nearly completed a 5-year, National Institute of Mental Health-funded, randomized, controlled trial comparing initial treatments of sertraline, CBT, and combination CBT and sertraline versus pill placebo (personal communication, Dr. John March). When the results of this study are published, practitioners may benefit from better-delineated guidelines to answer the clinically salient question: which treatment(s) should be used for individual patients with OCD?

PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS ASSOCIATED WITH GROUP A β-HEMOLYTIC STREPTOCOCCAL INFECTIONS

Recent identification of children with streptococcal-precipitated OCD has spurred intense investigation. Although these children may have distinct neurobiologie profiles and require different treatment(s), there are no clearly established guidelines for treatment. (See Swedo et al.30 and Leonard et al.31 for two excellent reviews.)

The base rate of OCD associated with pediatric autoimmune neuropsychiatrie disorders associated with group A β-hemolytic streptococcal infections (PANDAS) is currently unknown and the diagnosis cannot be made retrospectively at this time. Current diagnostic criteria for PANDAS include at least two prospectively documented exacerbations of OCD symptoms associated with group A β-hemolytic streptococcal infection. A definitive retrospective diagnosis of PANDAS is practically impossible in clinically referred pediatric patients with OCD (personal communication, Dr. John March).

GENERALIZED ANXIETY DISORDER

Selective serotonin reuptake inhibitors are now also first-line treatments for all non-OCD anxiety disorders including generalized anxiety disorder (GAD). Benzodiazepines are often prescribed during the initial titration phase since response to SSRI treatment can be delayed. While this may be necessary, careful screening for history of substance abuse in the patient and family is indicated when prescribing these agents with SSRIs. It is also advisable to alert the patient and parents that the benzodiazepine will be prescribed short-term with efforts to taper and discontinue the benzodiazepine after SSRI anti-anxiety effectiveness is established. This is best done before prescribing the benzodiazepine.

A double-blind, placebo-controlled study demonstrated the efficacy and safety of sertraline in treating 22 children and adolescents with GAD, aged 5 to 17 years.32 The medication was initiated at 25 mg/d for the first week of the study and then increased to 50 mg/d for weeks 2 through 9. By 4 weeks, differences in treatment favoring sertraline versus placebo were noted. Sertraline was comparably effective in reducing both psychiatric and somatic anxiety symptoms at 50 mg/d.32

The Research Unit on Pediatric Psychopharmacology (RUPP) Anxiety Study Group33 recently completed a double-blind, placebo-controlled study of fluvoxamine in 128 children with GAD, separation anxiety disorder, and social phobia. Fluvoxamine was superior to placebo, with 79% of pediatric patients with anxiety disorders responding to fluvoxamine compared to fewer than 30% of patients receiving pill placebo. This improvement with fluvoxamine was greater than improvement reported in adults with anxiety disorders treated with tricyclic antidepressants and benzodiazepines. Long-term treatment with fluvoxamine resulted in additional benefit after the initial 8-week, acute SSRI trial in pediatric patients with non-OCD anxiety disorders.34

There are ongoing industry-sponsored, double-blind, placebo-controlled trials of sustained release venlafaxine ER and the 5-HT1A agonist buspirone for GAD in children and adolescents. The results of these studies have not yet been analyzed or reported.

SEPARATION ANXIETY DISORDER, SCHOOL REFUSAUAND PHOBIA

Earlier studies suggested that the tricyclic antidepressant Imipramine may be effective for treating children with separation anxiety disorder34 although contradictory reports exist.35 Bernstein et al.36 compared Imipramine and placebo in combination with CBT in children with school refusal. Significantly more patients treated with Imipramine plus CBT (50%) achieved symptom remission compared to only 16% of patients treated with CBT plus placebo. In contrast, no superiority of the tricyclic antidepressant clomipramine versus placebo was demonstrated in children with school phobia.37

Graee et al.38 conducted a 4-week, double-blind, placebo-controlled study of clonazepam in 15 children with separation anxiety disorder and found that clonazepam treatment (0.5-2.0 mg/d) was not more effective than placebo. There are no controlled studies of buspirone in separation anxiety disorder. Nonetheless, it is often used alone or in combination with other pharmacologic and psychotherapeutic treatments of separation anxiety disorder. Controlled study is clearly warranted.

Despite the potential benefit of Imipramine, many practitioners are loath to prescribe this medication in children and adolescents because of its tricyclic side effect profile and possible rare association with sudden cardiac death.39 As described previously, SSRIs have become the first-line agents for all non-OCD anxiety disorders including separation anxiety disorder. Aside from the RUPP study of fluvoxamine in several pediatric anxiety disorders including separation anxiety disorder, there are no controlled studies of other SRIs in patients with separation anxiety disorder, school phobia, or school refusal.

ANXIETY DISORDER AND SOCIAL PHOBIA

Selective serotonin reuptake inhibitors are also the treatment of choice for social anxiety disorder and social phobia. The RUPP Anxiety Study Group33 reported that fluvoxamine is superior to placebo in children and adolescents with non-OCD anxiety disorders including social phobia. There are ongoing industry-sponsored, multi-center, double-blind, placebo-controlled studies of the SRI venlafaxine ER and the SSRI paroxetine (recently approved by the FDA for treating social phobia in adults) in pediatric patients with social phobia. Although buspirone is not uncommonly used in pediatric patients with social phobia, there is no controlled investigation of its use in this population.

Benzodiazepines are typically not recommended for social phobia because of their sedative side effects. Betablockers such as propranolol and atenolol are, however, not uncommonly used to treat patients with social phobia, particularly patients suffering from performance-related anxiety. Nonetheless, there is no controlled study in children and adolescents with social phobia, and these agents do not have FDA approval for any psychiatric condition in either children or adults.

PANIC DISORDER

Although SSRIs have been demonstrated to be effective in adults with panic disorder, there are no controlled data in pediatric patients with panic disorder. Open-label studies with fluoxetine, paroxetine, and sertraline suggest that SSRI treatment may be safe and effective in pediatric patients with panic disorder.40

Many clinicians prescribe benzodiazepines in addition to SRIs when treating pediatric patients with panic disorder, particularly in the acute phase. As-needed doses are also often prescribed for these patients. Although this is often necessary clinically, caution about the potential addictive effects of benzodiazepines is warranted. Longer-acting benzodiazepines such as clonazepam are recommended. For as-needed use, lorazepam can be effective. Careful monitoring of cumulative doses is critical.

SPECIFIC PHOBIA

There are no data supporting the efficacy of pharmacologic intervention for specific phobias (eg, fear of specific objects or situations such as storms, animals, etc). Cognitive behavior therapy is considered the most effective treatment for specific phobias.41 Selective serotonin reuptake inhibitors such as fluvoxamine may, however, be useful in cases of severe specific phobias.42

POSTTRAUMATIC STRESS DISORDER

In contrast to adults, for whom SSRIs now have FDA approval for the specific treatment of posttraumatic stress disorder, there are no controlled studies of psychotropic medications in children and adolescents with posttraumatic stress disorder. Associated symptoms, eg, anxiety, depression, and psychosis, are typically treated with appropriate agents, eg, SRIs and neuroleptics (most commonly atypical agents). Controlled investigation is warranted for this debilitating and under-studied condition in pediatric patients.

CONCLUSION

Although considerable advances in the psychopharmacology of pediatric anxiety disorders have been made in recent years, much work needs to be done. One reason for this is that until recently, specific diagnoses of anxiety have not been well defined or characterized in children and adolescents. We also know that anxiety disorders, if first seen and treated in childhood or adolescence, are likely to respond to similar treatments demonstrated to be effective in adults with appropriate developmental modifications. The FDA mandate requiring study of medications in pediatric populations will spur further advances in the psychopharmacology of pediatric anxiety disorders.

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