Medication Summary
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 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. [18]
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.
Selective serotonin reuptake inhibitors
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. [19]
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. [20]
Fluoxetine (Prozac)
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)
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)
Zoloft selectively inhibits presynaptic serotonin reuptake.
Paroxetine (Paxil, Pexeva)
This is unlabeled use. 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.
Antidepressants, SNRIs
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]
Benzodiazepines
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.
Antianxiety Agents
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.
