Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. Quetiapine augmentation of paroxetine CR for the treatment of refractory generalized anxiety disorder: preliminary findings. Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Efficacy of olanzapine in social anxiety disorder: a pilot study. Quetiapine as monotherapy for social anxiety disorder: a placebo-controlled study.
Although significant advances have been made in recent years in the treatment of generalized anxiety disorder (GAD), many patients remain symptomatic despite ongoing treatment, underscoring the need for adjunctive new treatments to help improve response.
                Forty patients with a primary diagnosis of DSM-IV GAD, who continued to experience GAD symptoms despite current anxiolytic treatment of at least 4 weeks' duration, as evidenced by Hamilton Rating Scale for Anxiety (HAM-A) total score > or = 18 and Clinical Global Impressions-Severity of Illness scale score of moderate or greater, completed a 1-week screening phase and were then randomly assigned to 5 weeks of double-blind adjunctive treatment with placebo or risperidone at flexible doses of 0.5 to 1.5 mg/day. Patients continued to take their anxiolytics throughout the study. The study was conducted from June 2001 through March 2003.
                Adjunctive risperidone was associated with statistically significant improvements in core anxiety symptoms, as demonstrated by greater reductions in HAM-A total scores (p = .034) and HAM-A psychic anxiety factor scores (p = .047) compared with placebo. Although change scores on other outcome variables, including response rates, were higher in the risperidone group, differences did not achieve statistical significance.
                Study findings suggest that risperidone at low doses may represent a useful tool in the management of symptomatic GAD patients. More data are needed to guide "next step" strategies for patients with generalized anxiety disorder (GAD) remaining symptomatic despite initial pharmacotherapy.
                This study prospectively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD remaining symptomatic with initial paroxetine CR pharmacotherapy.
                Adult outpatients with GAD were recruited from 2004 to 2007 at two academic centers. Phase 1 consisted of 10 weeks of open-label paroxetine CR flexibly dosed to a maximum of 62.5 mg/day. Those remaining symptomatic (Hamilton Anxiety Scale [HAM-A] >or= 7) at week 10 were randomized to quetiapine or placebo augmentation flexibly dosed from 25 to 400 mg/day.
                For participants receiving paroxetine CR (n = 50), there was a significant reduction in HAM-A scores (baseline mean +/- SD = 22.4 +/- 4.2 to endpoint mean +/- SD = 11.2 +/- 6.9; paired t = 12.1, df = 49, t < 0.0001) with 40% (n = 20) achieving remission. Counter to our hypothesis, we did not find significant benefit for quetiapine augmentation of continued paroxetine CR (HAM-A reduction mean +/- SD = 2.6 +/- 5.8 points quetiapine, 0.3 +/- 5.5 points placebo; t = 0.98, df = 20, p = n.s.) in the randomized sample (n = 22) with relatively minimal additional improvement overall in phase 2.
                Although conclusions are considered preliminary based on the relatively small sample size, our data do not support the addition of quetiapine to continued paroxetine CR for individuals with GAD who remain symptomatic after 10 weeks of prospective antidepressant pharmacotherapy and suggest that further research examining strategies for GAD refractory to antidepressants is needed. Residual symptoms despite treatment are common in generalized anxiety disorders (GAD). The Patient-Rated Troubling Symptoms for Anxiety (PaRTS-A) is a newly created and validated instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms.
                Primary care and psychiatry clinicians enrolled adults (n = 417) with GAD and a Clinical Global Impressions of Severity rating ≥ 4 despite ≥ 8 weeks of anxiolytic treatment. Subjects were randomized to adjunctive risperidone or placebo. The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A.
                Improvement from baseline to week 4 endpoint in PaRTS-A total score (mean +/-SE) was similar between treatment groups (-8.54 [0.63] and -7.61 [0.64] for adjunctive risperidone and placebo, respectively; P = .265). Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures. A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo (P = .04). Headache, weight increase, and increased appetite were the most frequently reported adverse events in both groups.
                Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo. Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinically meaningful information on patient-rated symptoms. Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated. There has been little systematic study of "next-step" interventions for patients with generalized anxiety disorder (GAD) who remain symptomatic despite initial pharmacotherapy. We present one of the first randomized controlled trials for refractory GAD, comprising double blind augmentation with olanzapine or placebo for patients remaining symptomatic on fluoxetine.
                Patients remaining symptomatic after 6 weeks of fluoxetine (20 mg/day) were randomized to 6 weeks of olanzapine (mean dose 8.7 +/- 7.1 mg/day) or placebo augmentation.
                Twenty-four of 46 fluoxetine-treated patients were randomized. Olanzapine resulted in a greater proportion of treatment responders based on a Clinical Global Impression-Severity Scale (CGI-S) end point score of 1 or 2 (Fisher's exact test [FET] p < .05) or a 50% reduction in Hamilton Anxiety Scale (HAMA-A) score (FET p < .05). There were no other statistically significant differences for olanzapine compared with placebo augmentation in outcome measures, though rates of remission (HAM-A <or= 7) on olanzapine were higher at the level of a trend (FET, p = .1). Average weight gain for completers was greater with olanzapine than placebo augmentation (11.0 +/- 5.1 vs. -0.7 +/- 2.4 pounds: t = 6.32, p < .001).
                Olanzapine may have a salutary effect on anxiety for some GAD patients remaining symptomatic despite initial serotonin selective reuptake inhibitor (SSRI) therapy, but the emergence of significant weight gain represents an important clinical consideration. Based on evidence suggesting anxiolytic properties of the atypical antipsychotic olanzapine, this study was conducted to evaluate whether olanzapine may be efficacious in treating social anxiety disorder (SAD). This study was an 8-week, double-blind, placebo-controlled evaluation of olanzapine as monotherapy in which 12 patients with the DSM-IV diagnosis of SAD were randomized to either olanzapine (n = 7) or placebo (n = 5). An initial dose of 5 mg/day was titrated to a maximum of 20 mg/day. Baseline to endpoint scores from the Brief Social Phobia Scale (BSPS), Social Phobia Inventory (SPIN), Liebowitz Social Anxiety Scale and Sheehan Disability Scale, as well as Clinical Global Impression-Improvement ratings, were compared for olanzapine versus placebo. Seven subjects completed all 8 weeks of the study, four in the olanzapine group and three in the placebo group. In the intent-to-treat analysis, olanzapine yielded greater improvement than placebo on the primary measures: BSPS (p = 0.02) and SPIN (p = 0.01). Both treatments were well tolerated, although the olanzapine group had more drowsiness and dry mouth. Olanzapine and placebo were both associated with negligible weight gain. Olanzapine was superior to placebo on the primary outcome measures in this preliminary study of SAD. Additional studies of olanzapine as a treatment for SAD are warranted. Social anxiety disorder (SAD) is one of the most common anxiety disorders. Reports have suggested an effect of the atypical antipsychotic quetiapine in anxiety disorders. Given these considerations, we conducted a controlled trial of quetiapine monotherapy in SAD. Fifteen patients were randomized to quetiapine (up to 400 mg/day) or placebo for 8 weeks. The Brief Social Phobia Scale (BSPS) and the Clinical Global Impression of Improvement Scale (CGI-I) were the primary outcome measures, while the Social Phobia Inventory (SPIN) and the Sheehan Disability Inventory (SDI) were secondary measures. There was no significant difference on the BSPS score at endpoint between the quetiapine and placebo groups. There was a significant time effect but not a significant time x treatment group interaction, indicating that both the quetiapine and placebo patients did better over the course of the trial. 20% of the quetiapine patients had a 50% or greater drop in BSPS score at the end of the trial compared to baseline, while 0% had such a drop in the placebo group. There was no significant difference in responders (CGI-I score of 1 or 2) versus non-responder (CGI-I score of 3 or more) across the groups. However, 40% of quetiapine patients and 0% of the placebo patients showed much or very much improvement on the CGI-I. The Number Needed to Treat (NNT) to be a responder on the CGI-I was 3. Significant time effects were noted for the SPIN and SDI, as well as a significant time x treatment effect in favor of quetiapine on the SPIN. Additionally, quetiapine showed a large effect size on the SPIN.