Faculty Bibliography

Emotional regulation deficits are described as a core component of anxiety disorders (ADs), yet there remains a paucity of data examining this issue in patients diagnosed with ADs. We hypothesized that help-seeking individuals with ADs would report lower levels of emotional approach coping (EAC), which includes emotional processing (EP) and emotional expression (EE), than nonanxious controls. Diagnostic interviews and a validated self-report scale assessing emotional approaches to coping (emotional approach coping scale [EACS]) were administered to 101 nonanxious controls and 92 patients with a primary AD (29 generalized anxiety disorder, 40 social anxiety disorder, and 23 panic disorder). Patients with each AD demonstrated significantly lower EAC, including both EP and EE, than nonanxious controls. Lower EAC was also associated with higher anxiety sensitivity and higher anxiety symptom severity. Overall, gender did not moderate the anxiety-EAC effect, but the results suggested that women utilize EAC to a greater degree than men. Clinical techniques designed to improve emotional coping may be beneficial to individuals with ADs.

Impulsivity and anxiety, common features of bipolar disorder (BD), are each associated with a number of negative outcomes in BD. The relationship between anxiety and impulsivity, however, has not been a focus of study in BD. In this paper, we present data regarding the association between anxiety and impulsivity as measured by the Barratt impulsiveness scale (BIS-11) in 114 outpatients with BD. Results revealed that patients with a comorbid anxiety disorder displayed significantly higher levels of impulsivity relative to patients without an anxiety disorder. Moreover, a broad range of anxiety-related symptom domains was associated with greater impulsivity. Exploratory analyses also revealed that baseline anxiety symptoms were associated with elevated impulsivity at 9-month follow-up, although these relationships were less robust after covariate adjustment. These data demonstrate that anxiety is positively associated with impulsivity in patients with BD. Further studies are needed to elucidate the implications of and reasons for this association.

INTRODUCTION: Individuals with anxiety disorders often remain symptomatic despite treatment with a first-line pharmacologic agent. More research examining pharmacotherapy augmentation strategies to improve outcomes is needed. METHODS: In an 8-week, open-label, prospective augmentation study, we examined the efficacy and tolerability of the novel antipsychotic agent aripiprazole for adult outpatients with generalized anxiety disorder (n=13) or panic disorder (n=10) who remained symptomatic despite treatment for at least 8 weeks with an adequate (or maximally tolerated) dose of typical pharmacotherapy. RESULTS: Aripiprazole augmentation was associated with a significant reduction in Clinical Global Impressions-Severity scores (paired t=4.41, df=22, P<.001) in the intent-to-treat sample of 23 individuals. Three subjects (13%) discontinued due to sedation, chest discomfort, and restlessness, respectively. CONCLUSION: These data provide preliminary evidence that aripiprazole may be a useful augmentation strategy for individuals with generalized anxiety disorder or panic disorder who show a limited response to initial pharmacotherapy.

Complicated grief (CG) is a debilitating syndrome that can be reliably identified, but there is a paucity of research examining treatment of CG. A targeted psychotherapy for complicated grief (CGT) was recently shown to be efficacious [Shear, K., Frank, E., Houck, P.R., Reynolds, C.F., 3rd, 2005. Treatment of complicated grief: a randomized controlled trial. Journal of the American Medical Association 293, 2601-2608]. We provide a detailed examination of the association of naturalistic pharmacotherapy use with treatment response and study completion in the psychotherapy study. Patients on an antidepressant medication were more likely to complete a full course of CGT (91% vs. 58% completed), while antidepressant use had no effect on completion rates for the comparator, interpersonal psychotherapy (70% vs. 77%). Our naturalistic data underscore the need for prospective, randomized controlled studies of CG pharmacotherapy and psychotherapy alone and in combination.

RATIONALE: More data are needed to guide "next step" strategies for patients with generalized anxiety disorder (GAD) remaining symptomatic despite initial pharmacotherapy. OBJECTIVE: This study prospectively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD remaining symptomatic with initial paroxetine CR pharmacotherapy. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

OBJECTIVE: Abnormalities in brain gamma-aminobutyric acid (GABA) and glutamate may be relevant to the underlying pathophysiology of anxiety disorders including social anxiety disorder (SAD). METHODS: We used proton magnetic resonance spectroscopy (pMRS) to examine whole brain and regional GABA, glutamate and glutamine in patients (N=10) with SAD at baseline compared to a matched group of healthy controls (HC), and changes following 8 weeks of pharmacotherapy with levetiracetam. RESULTS: For SAD subjects, there were significantly higher whole brain levels of glutamate and glutamine, though no significant differences in GABA. In the thalamus, glutamine was higher and GABA lower for SAD subjects. There was a significant reduction in thalamic glutamine with levetiracetam treatment. CONCLUSION: Our findings provide preliminary support for impaired GABAergic and overactive glutamatergic function in social anxiety disorder and the potential relevance of changes in these systems for the anxiolytic response to levetiracetam.

OBJECTIVE: Little is known about the efficacy of "next step" strategies for patients with post-traumatic stress disorder (PTSD) who remain symptomatic despite treatment. This study prospectively examines the relative efficacy of augmentation of continued prolonged exposure therapy (PE) with paroxetine CR versus placebo for individuals remaining symptomatic despite a course of PE. METHOD: Adult outpatients meeting DSM-IV criteria for PTSD were recruited from February 2003 to September 2005 at 4 academic centers. Phase I consisted of 8 sessions of individual PE over a 4- to 6-week period. Participants who remained symptomatic, defined as a score of >or= 6 on the Short PTSD Rating Interview (SPRINT) and a Clinical Global Impressions-Severity of Illness scale (CGI-S) score >or= 3, were randomly assigned to the addition of paroxetine CR or matched placebo to an additional 5 sessions of PE (Phase II). RESULTS: Consistent with prior studies, the 44 Phase I completers improved significantly with initial PE (SPRINT: paired t = 7.6, df = 41, p < .0001; CGI-S: paired t = 6.37, df = 41, p < .0001). Counter to our hypothesis, however, we found no additive benefit of augmentation of continued PE with paroxetine CR compared to pill placebo for the 23 randomly assigned patients, with relatively minimal further gains overall in Phase II. CONCLUSION: Although replication with larger samples is needed before definitive conclusions can be drawn, our data do not support the addition of paroxetine CR compared with placebo to continued PE for individuals with PTSD who remain symptomatic after initial PE, suggesting that the development of novel treatment approaches for PTSD refractory to PE is needed. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00215163.

Pharmacotherapy is an effective treatment for generalized anxiety disorder (GAD), but few studies have examined the nature of decline of anxiety and depression during pharmacotherapy for GAD and even fewer studies have examined predictors of symptom decline. This study examined the decline in symptoms of anxiety and depression in patients with GAD during a 6-week open trial of fluoxetine. Growth curve analyses indicated that pharmacotherapy with fluoxetine led to significant declines in symptoms of anxiety and depression over the 6 weeks of treatment. However, the decay slope observed for anxiety symptoms was significantly greater than that for depressive symptoms. Further analyses revealed that the decline in anxiety remained significant after accounting for the changes in symptoms of depression. However, the effect of treatment on depression was no longer significant after controlling for the reduction in anxiety symptoms. Overall anxiety sensitivity (AS) did not moderate the level of reduction in symptoms of anxiety or depression during pharmacotherapy. However, AS specific to physical concerns demonstated a marginal negative association with decline in anxiety and depression. AS specific to social concerns also demonstrated a marginal negative association with decline in anxiety symptoms. These findings suggest that the decline in anxiety symptoms is independent of the decline in symptoms of depression during pharmacotherapy for GAD and specific AS dimensions may predict symptom change in GAD.

The Anxiety Disorders Association of America convened a conference of experts to address treatment-resistant anxiety disorders and review promising novel approaches to the treatment of refractory anxiety disorders. Workgroup leaders and other participants reviewed the literature and considered the presentations and discussions from the conference. Authors placed the emerging literature on new therapeutic approaches into clinical perspective and identified unmet needs and priority areas for future research. There is a relative paucity of efforts addressing inadequate response to anxiety disorder treatment. Systematic efforts to exhaust all therapeutic options and overcome barriers to effective treatment delivery are needed before patients can be considered treatment refractory. Cognitive behavioral therapy, especially in combination with pharmacotherapy, must be tailored to accommodate the effects of clinical context on treatment response. The literature on pharmacologic treatment of refractory anxiety disorders is small but growing and includes studies of augmentation strategies and non-traditional anxiolytics. Research efforts to discover new pharmacologic targets are focusing on neuronal systems that mediate responses to stress and fear. A number of clinical and basic science studies were proposed that would advance the research agenda and improve treatment of patients with anxiety disorders. Significant advances have been made in the development of psychotherapeutic and pharmacologic treatments for anxiety disorders. Unfortunately, many patients remain symptomatic and functionally impaired. Progress in the development of new treatments has great promise, but will only succeed through a concerted research effort that systematically evaluates potential areas of importance and properly uses scarce resources.