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

Abstract

elective serotonin reuptake inhibitors (SSRIs) are amainstay of psychopharmacologic treatment for pediatricanxiety disorders (Strawn et al. 2012); however, 20–35% of SSRI-treated youth with anxiety disorders do not achieve significantbenefit from these treatments (Walkup et al, 2008). Nonetheless,there is currently limited evidence for adjunctive pharmacologicinterventions in children and adolescents with who have notresponded to initial SSRI medications. Recently, however, severalstudies of anxiety-spectrum disorders in adults have noted increasedcentral glutamate concentrations, and glutamatergic hyperactivity isimplicated 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 convertedinto cysteine and—through its action at the glial cysteine–glutamateantiporter—increases extrasynaptic glutamate and, in doing so,stimulates inhibitory metabotropic glutamate receptors and de-creases synaptic glutamate (Lafleur et al., 2006). This decrease insynaptic glutamate has been hypothesized to confer benefit in anx-iety treatment. Herein, we report a case of a 17-year-old adolescentboywithfunctionally-impairinggeneralizedanxietydisorder(GAD)and social phobia (SoP),who partially responded to high-dose ser-traline, but whose response was accentuated by adjunctive NAC.A. is a 17-year-old white boy with a history of GAD andgeneralized SoP. At initial outpatient presentation, A. describedpersistent fear of social situations, was preoccupied by perceivedevaluation by peers and social situations, and he avoided mostsocial situations, including school. He had demonstrated limitedimprovement in school avoidance and withdrawal from socialsituations, despite ongoing cognitive-behavioral psychotherapyand fluoxetine, which had been titrated to 20mg daily and report-edly worsened his anxiety. A. also described intense anxiety relatedto the future, a constant sense of inner tension and restlessness, andanxious ruminations that were associated with initial and middleinsomnia. Moreover, he described recurrent headaches in times ofanxiety, and secondary to his significant anxiety, A. had recentlyterminated his part-time employment at a local restaurant.Fluoxetine was discontinued and, over the next 8 weeks,sertraline monotherapy was initiated and titrated to 150mg daily,yielding a decrease in his anxiety. However, although there wassome improvement in his subjective anxiety, A. reported persistentsocial anxiety andhisClinicalGlobalImpressions-Severity(CGI-S)score remained a 5. At that time, adjunctive NAC was initiated(600mg capsules by mouth twice daily) and, over the next 4 weeks,A.experiencedadecreaseinhisanxietyandhisCGI-Sdecreasedtoa4. To target A.’s significant anxiety symptoms, NAC was increasedto 1200mg twice daily and, over the subsequent 4 weeks, he noted adecreaseinanxietyandbecameabletoattendseveralsocialactivitieswith friends at a local coffee shop, was less concerned about others’perceptionsofhim,andwasableto attendchurchandbeginapplyingfor a part-time job. A. also reported improvement in his anxiety-related insomnia, a decrease in his sense of inner tension and rest-lessness, and diminished somatic symptoms. At that time, his CGI-Shad decreased to 2, he reported that adjunctive NAC was welltolerated, and he denied any side effects.This case highlights the potential efficacy of adjunctive NAC(1200mg twice daily) in adolescents with anxiety disorders whohave experienced partial responses to SSRI pharmacotherapy. Theonset of action was rapid, with reduction of psychic and somaticanxiety symptoms; onset of efficacy occurred within 1 week of thetarget dose (1200mg twice daily), and the effect was sustained overthe treatment period. Importantly, NAC was well tolerated, as hasbeen the case in children with autism (Hardan et al. 2012), in ad-olescents with cannabis dependence (Gray et al. 2012), in adultswith trichotillomania (Grant et al. 2009), and when used adjunc-tively with SSRIs, in adults with SSRI-resistant anxiety disorders(Lafleur et al. 2006). Additional, prospective trials are urgentlyneeded to assess the potential role of glutamate modulators, such asNAC, in youth with anxiety disorders, including those who havehad partial responses to ‘‘first-line’’ psychopharmacologic andpsychotherapeutic interventions.DisclosuresDrs. Strawn and Saldan˜a disclosed no competing financial in-terests. Dr. Strawn has received research support from Eli Lilly,Shire, and the American Academy of Child & Adolescent Psy-chiatry; these are noted in the spirit of full disclosure and are notdirectly related to the work or results presented herein.References