Faculty Bibliography

OBJECTIVE: This is the first trial examining duloxetine for generalized social anxiety disorder (GSAD) and the effect of increased dose for those without early remission. METHODS: Individuals (n=39) with GSAD received 6 weeks of open-label duloxetine 60 mg/day; those with a Liebowitz Social Anxiety Disorder Scale (LSAS) score >30 at week 6 were randomized in double-blind fashion to an additional 18 weeks of continued duloxetine 60 mg/day or to duloxetine 120 mg/day. RESULTS: Duloxetine was associated with a significant LSAS reduction at week 6 (91.3 [17.7] to 69.8 [28.5], paired t [df]=5.2 [38], P<.0001), and randomized participants overall continued to improve at week 24 (74.6 [23.9] to 60.3 [29.7]; paired t [df]=3.3 [27], P=.0026). Though the increased dose strategy was associated with a moderate effect size (Cohen's d=.57), there was no significant difference at week 24 endpoint in LSAS reduction (20.5 [26.0] versus 7.3 [17.2], t [df]=1.6 [26], P=.13) nor remission (33% versus 8%) for duloxetine with dose increased to 120 mg/day compared to duloxetine continued at 60 mg/day. Overall, 44% (17/39) discontinued prior to week 24. CONCLUSIONS: Though with limited power, these data provide preliminary support for the efficacy of duloxetine for GSAD, and suggest continued improvement but limited remission overall at 24 weeks for individuals remaining symptomatic at week 6. These observations warrant further controlled study.

Despite its acute efficacy for the treatment of panic disorder, benzodiazepines (BZs) are associated with a withdrawal syndrome that closely mimics anxiety sensations, leading to difficulty with treatment discontinuation and often disorder relapse. An exposure-based cognitive-behavioral treatment for BZ discontinuation, Panic Control Treatment for BZ Discontinuation (CBT) targets the fear of these sensations and has demonstrated efficacy in preventing disorder relapse and facilitating successful BZ discontinuation among patients with panic disorder. In this randomized controlled trial, CBT was compared to taper alone and a taper plus a relaxation condition to control for the effect of therapist contact and support among 47 patients with panic disorder seeking taper from BZs. Based on the primary outcome of successful discontinuation of BZ use, results indicate that adjunctive CBT provided additive benefits above both taper alone and taper plus relaxation, with consistently medium and large effect sizes over time that reached significance at the six month follow-up evaluation. The efficacy of CBT relative to either of the other taper conditions reflected very large and significant effect sizes at that time. These findings suggest that CBT provides specific efficacy for the successful discontinuation from BZs, even when controlling for therapist contact and relaxation training.

BACKGROUND: Traditional combination strategies of cognitive-behavior therapy plus pharmacotherapy have met with disappointing results for anxiety disorders. Enhancement of cognitive-behavior therapy with d-cycloserine (DCS) pharmacotherapy represents a novel strategy for improving therapeutic learning from cognitive-behavior therapy that remains untested in panic disorder. METHOD: This is a randomized, double-blind, placebo-controlled augmentation trial examining the addition of isolated doses of 50 mg d-cycloserine or pill placebo to brief exposure-based cognitive-behavior therapy. Randomized participants were 31 outpatients meeting DSM-IV criteria for panic disorder with or without agoraphobia, who were offered five sessions of manualized cognitive-behavior therapy emphasizing exposure to feared internal sensations (interoceptive exposure) but also including informational, cognitive, and situational exposure interventions. Doses of study drug were administered 1 hour before cognitive-behavior therapy sessions 3 to 5. The primary outcome measures were the Panic Disorder Severity Scale (PDSS) and Clinicians' Global Impressions of Severity. RESULTS: Results indicated large effect sizes for the additive benefit of d-cycloserine augmentation of cognitive-behavior therapy for panic disorder. At posttreatment and 1 month follow-up, participants who received d-cycloserine versus placebo had better outcomes on the PDSS and global severity of disorder and were significantly more likely to have achieved clinically significant change status (77% vs. 33%). There were no significant adverse effects associated with DCS administration. CONCLUSIONS: This pilot study extends support for the role of d-cycloserine in enhancing therapeutic learning from exposure-based cognitive-behavior therapy and is the first to do so in a protocol emphasizing exposure to feared internal sensations of anxiety in panic disorder.

OBJECTIVE: This multicenter, double-blind, placebo-controlled, 2-arm, parallel-group study was carried out to determine the effectiveness and safety of the novel anticonvulsant levetiracetam for the treatment of generalized social anxiety disorder (GSAD). METHOD: After a 1-week, single-blind, placebo run-in period, 217 adult outpatients meeting DSM-IV criteria for social anxiety disorder, generalized type, were randomly assigned (1:1) to 12 weeks of double-blind treatment with either levetiracetam (n = 111) or placebo (n = 106). Participants were required to have scores of >or= 60 on the Liebowitz Social Anxiety Scale (LSAS) and a total score of or= 30% reduction in LSAS score) were similar with 41.3% (levetiracetam) and 46.6% (placebo). No significant between-group differences were found on secondary outcome measures, which included changes in Sheehan Disability Scale, Clinical Global Impression of Change, and HDRS scores. CONCLUSIONS: Although well-tolerated, levetiracetam failed to separate from placebo in this trial for the treatment of moderate to severe GSAD.

Panic disorder with or without agoraphobia is a common, often chronic and refractory anxiety disorder. Although a number of pharmacotherapies are now indicated for panic disorder, many patients do not respond to available interventions. We hypothesized that duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI) that has greater initial noradrenergic effects than venlafaxine, would have broad efficacy for individuals with panic disorder. Fifteen individuals with panic disorder with or without agoraphobia received 8 weeks of open label duloxetine flexibly dosed from 60 to 120 mg per day. Duloxetine treatment resulted in significant anxiolysis as measured by the primary outcome measure, the Panic Disorder Severity Scale (PDSS) (paired t(df) = 4.02(14), P= 0.0013), as well as measures of generalized anxiety, depression and quality of life (all P < 0.05). Although definitive conclusions are limited due to its small open-label nature, this first prospective study provides preliminary support for the efficacy of duloxetine for panic disorder and suggests larger randomized controlled study is warranted.