Treatment with Adjunctive N -Acetylcysteine in an Adolescent with Selective Serotonin Reuptake Inhibitor-Resistant Anxiety

To the Editor:

S elective serotonin reuptake inhibitors (SSRIs) are a mainstay of psychopharmacologic treatment for pediatric anxiety disorders (Strawn et al. 2012); however, 20–35% of SSRI-treated youth with anxiety disorders do not achieve significant benefit from these treatments (Walkup et al, 2008). Nonetheless, there is currently limited evidence for adjunctive pharmacologic interventions in children and adolescents with who have not responded to initial SSRI medications. Recently, however, several studies of anxiety-spectrum disorders in adults have noted increased central glutamate concentrations, and glutamatergic hyperactivity is implicated in the pathophysiology of anxiety disorders (Phan et al. 2005). Among available glutamate modulators is the over-the-counter antioxidant, N-acetylcysteine (NAC), which is converted into cysteine and—through its action at the glial cysteine–glutamate antiporter—increases extrasynaptic glutamate and, in doing so, stimulates inhibitory metabotropic glutamate receptors and decreases synaptic glutamate (Lafleur et al., 2006). This decrease in synaptic glutamate has been hypothesized to confer benefit in anxiety treatment. Herein, we report a case of a 17-year-old adolescent boy with functionally-impairing generalized anxiety disorder (GAD) and social phobia (SoP),who partially responded to high-dose sertraline, but whose response was accentuated by adjunctive NAC.

A. is a 17-year-old white boy with a history of GAD and generalized SoP. At initial outpatient presentation, A. described persistent fear of social situations, was preoccupied by perceived evaluation by peers and social situations, and he avoided most social situations, including school. He had demonstrated limited improvement in school avoidance and withdrawal from social situations, despite ongoing cognitive-behavioral psychotherapy and fluoxetine, which had been titrated to 20 mg daily and reportedly worsened his anxiety. A. also described intense anxiety related to the future, a constant sense of inner tension and restlessness, and anxious ruminations that were associated with initial and middle insomnia. Moreover, he described recurrent headaches in times of anxiety, and secondary to his significant anxiety, A. had recently terminated his part-time employment at a local restaurant.

Fluoxetine was discontinued and, over the next 8 weeks, sertraline monotherapy was initiated and titrated to 150 mg daily, yielding a decrease in his anxiety. However, although there was some improvement in his subjective anxiety, A. reported persistent social anxiety and his Clinical Global Impressions-Severity (CGI-S) score remained a 5. At that time, adjunctive NAC was initiated (600 mg capsules by mouth twice daily) and, over the next 4 weeks, A. experienced a decrease in his anxiety and his CGI-S decreased to a 4. To target A.'s significant anxiety symptoms, NAC was increased to 1200 mg twice daily and, over the subsequent 4 weeks, he noted a decrease in anxiety and became able to attend several social activities with friends at a local coffee shop, was less concerned about others' perceptions of him, and was able to attend church and begin applying for a part-time job. A. also reported improvement in his anxiety-related insomnia, a decrease in his sense of inner tension and restlessness, and diminished somatic symptoms. At that time, his CGI-S had decreased to 2, he reported that adjunctive NAC was well tolerated, and he denied any side effects.

This case highlights the potential efficacy of adjunctive NAC (1200 mg twice daily) in adolescents with anxiety disorders who have experienced partial responses to SSRI pharmacotherapy. The onset of action was rapid, with reduction of psychic and somatic anxiety symptoms; onset of efficacy occurred within 1 week of the target dose (1200 mg twice daily), and the effect was sustained over the treatment period. Importantly, NAC was well tolerated, as has been the case in children with autism (Hardan et al. 2012), in adolescents with cannabis dependence (Gray et al. 2012), in adults with trichotillomania (Grant et al. 2009), and when used adjunctively with SSRIs, in adults with SSRI-resistant anxiety disorders (Lafleur et al. 2006). Additional, prospective trials are urgently needed to assess the potential role of glutamate modulators, such as NAC, in youth with anxiety disorders, including those who have had partial responses to “first-line” psychopharmacologic and psychotherapeutic interventions.