Anxiety disorders are common in young people, affecting 4%–7% of children (Ipser JC et al, Cochrane Review 2010;Issue 6), and can cause a plethora of symptoms and impairments—from aggression and suicide to social withdrawal, school failure, and poor physical health. While OCD and PTSD have been addressed in previous issues (see CCPR, June 2011 and CCPR, November 2011), there are still plenty of disorders left to discuss, and a review of the literature for medication interventions for anxiety is in order. Indeed, most children who present with some form of anxiety meet criteria for several formal disorders (Rienblatt SP and Riddle MA, Psychopharmacology 007;191(1):67–86).

It appears that the majority of “adult” anxiety disorders begin in childhood and are stable and often chronic conditions (Ipser op.cit), so an effective intervention can have lifelong benefits. To this end, psychotherapy has been the traditional treatment, and for good reason: it is safe and it works…most of the time. However, therapy doesn’t work for everyone or in every situation.

Is Medication Effective for Anxiety?
Looking at pharmacological treatments for DSM-III or IV anxiety disorders, Ipser et al found an overall response rate to medication of 58.1%, a statistically significant difference from the 31.5% response rate for placebo. The number needed to treat as compared with placebo was a respectable four. Put simply, this means you need to treat four patients with medication to get one patient effectively treated. (For a good review of NNT and number needed to harm (NNH) see CCPR, September 2010.) The majority of medications studied were SSRIs and venlafaxine (Effexor XR). The review found little evidence of difference among them. Behavioral side effects and activation were common.

In a meta-analysis by Hidalgo et al, effect sizes were calculated for several classes of anxiolytics for the treatment of GAD in adults (19 studies) and children (2 studies). The spectrum of research was limited a bit by the fact that all studies had the Hamilton Anxiety Scale as the outcome measure. Two surprising findings were revealed: first, pregabalin (Lyrica) and hydroxyzine (Atarax, Vistaril) had the highest effect sizes overall, at 0.50 and 0.48 respectively; and second, the effect sizes were higher for children than adults in the two studies that included children (Hidalgo RB et al, J Psychopharmacol 2007;21(8):864–872).

Which Medications are Best?
Buspirone (BuSpar) has some evidence of helping focus (Davari-Ashtiani R, Child Psychiatry Hum Devel 2010;41(6):641–648) and so may have some benefit for the anxious ADHD sufferer, as the SSRIs are generally not helpful and may actually impair focus. Many patients find Buspirone difficult to take, both because of the frequency of dosing (TID) and because it can make kids feel dizzy. There is evidence in both adults and children to support its use, but the effect size is not large (Hidalgo op.cit).

Antipsychotics are probably too risky to use as first or second line for anxiety, although there is evidence for their use as an augmentation agent in OCD and PTSD.

Benzodiazepines have remarkably little evidence of effectiveness in children (Witek MW et al, Psychiatric Quarterly 2005;76(3):283–296). In addition, there is concern that they may cause cognitive impairment with long term use, as well as disruption of short term memory. They can be quite effective for individual patients, however, especially in the situations where an immediate fix is required. They are probably best left as short term medications.

Gabapentin (Neurontin) and pregabalin (Lyrica) have small RCTs in the adult literature that suggest benefit, and the risks of adverse events are fairly low. Further, they may be tolerated in kids who can’t tolerate SSRIs, either because of comorbid bipolar disorder or because of serotonin induced anxiety or activation. They tend to act relatively quickly as well. Lyrica is the more promising of the two.

Diphenhydramine (Benadryl) and hydroxyzine (Atarax, Vistaril) have some evidence of effectiveness for both acute and longer term treatment of anxiety in children and adolescents. However, chronic use can cause side effects such as dry mouth that leads to dental cavities—a problem for a number of different medications—and they often have a “hangover effect” the next morning.

What’s on the Horizon?
As Dr. Moira Rynn points out in her interview in this issue, there are some interesting approaches in development. D-cycloserine is under study as a means of enhancing cognitive behavioral therapy for OCD, specific phobias, social phobias, and panic. Specifically, it is to be dosed an hour before the therapy session (given its short half life) and appears to increase the exposure-based learning that happens during therapy (Hofmann SG et al, CNS Drug Rev 2006;12(3–4):208–217). Dosing in this study was a single 50 mg dose prior to each session—much lower than the dosing for tuberculosis.

The glutamatergic agent rizulole (Rilutek) has shown promise in case reports and small open-label studies of adults with OCD, trichotillomania, disordered eating, skin picking, and GAD and one open-label study of children with OCD (doses to 120 mg daily) (Grant P, J Child Adolesc Psychopharmacol 2007;17(6):761–67). It was well tolerated and is under study by the NIMH for use in children with OCD (Clinical Trials identifier: NCT00251303). See the table (link below) for a review of meds most commonly used to treat anxiety in children and adolescents.