Faculty Bibliography

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.

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.

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.

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.

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.

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.

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.

BACKGROUND: Prior studies suggest an association between anxiety comorbidity and suicidal ideation and behaviors in bipolar disorder. However, the nature of this association remains unclear. METHODS: We examined a range of anxiety symptoms, including panic, phobic avoidance, anxiety sensitivity, worry and fear of negative evaluation, in 98 patients with bipolar disorder. We predicted that each anxiety dimension would be linked to greater suicidal ideation and behavior as measured by Linehan's Suicide Behaviors Questionnaire (SBQ), greater depressive rumination, and poorer emotional processing and expression. RESULTS: Each anxiety dimension except fear of negative evaluation was associated with greater SBQ score, greater rumination, and lower levels of emotional processing in univariate analyses. Depressive rumination was a significant predictor of higher SBQ scores in a stepwise multivariate model controlling for age, gender, bipolar subtype, and bipolar recovery status; the association between the anxiety symptom dimensions and SBQ score was found to be redundant with depressive rumination. Emotional processing emerged as protective against suicidal ideation and behaviors in men only, while emotional expression was a significant predictor of lower SBQ scores for women and for the full sample; however, emotional expression was not significantly correlated with anxiety symptoms. Confirmatory analyses examining only those in recovery or recovered (n=68) indicated that the link between rumination and suicidality was not explained by depression. LIMITATIONS: Interpretation is limited by the cross-sectional study design. CONCLUSIONS: These findings indicate that increased ruminations may mediate the association between anxiety and suicidal ideation/behavior. In men, lower emotional processing may also play a role in this relationship.

To date, no large-scale, controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported. This double-blind study compares the efficacy of venlafaxine extended-release (ER) and paroxetine with placebo. A total of 664 nondepressed adult outpatients who met DSM-IV criteria for panic disorder (with or without agoraphobia) were randomly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER (75 mg/day or 150 mg/day), or paroxetine 40 mg/day. The primary measure was the percentage of patients free from full-symptom panic attacks, assessed with the Panic and Anticipatory Anxiety Scale (PAAS). Secondary measures included the Panic Disorder Severity Scale, Clinical Global Impressions--Severity (CGI-S) and--Improvement (CGI-I) scales; response (CGI-I rating of very much improved or much improved), remission (CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks); and measures of depression, anxiety, phobic fear and avoidance, anticipatory anxiety, functioning, and quality of life. Intent-to-treat, last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo. No significant differences were observed between active treatment groups. Panic-free rates at end point with active treatment ranged from 54% to 61%, compared with 35% for placebo. Approximately 75% of patients given active treatment were responders, and nearly 45% achieved remission. The placebo response rate was slightly above 55%, with remission near 25%. Adverse events were mild or moderate and similar between active treatment groups. Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder.

Individuals with bipolar disorder are at increased risk for suicide attempts and completion. Although anxiety may be a modifiable suicide risk factor among bipolar patients, anxiety disorder comorbidity has not been highlighted as critical in identification of high-risk individuals nor has its treatment been integrated into suicide prevention strategies. In this study, ancillary to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 120 outpatients with bipolar disorder completed detailed assessment of suicidal ideation and behaviors. We examined the association of current and lifetime comorbid anxiety disorders with suicidal ideation and behaviors univariately and with adjustment for potential confounders in regression models. Lifetime anxiety disorders were associated with a more than doubling of the odds of a past suicide attempt, and current anxiety comorbidity was associated with a more than doubling of the odds of current suicidal ideation. Individuals with current anxiety disorders had more severe suicidal ideation, a greater belief suicide would provide relief, and a higher expectancy of future suicidal behaviors. However, some of these associations appeared to be better accounted for by measures of bipolar severity including an earlier age at bipolar onset and a lack of current bipolar recovery. Comorbid anxiety disorders may play a role in characteristics of bipolar disorder that then elevate risk for suicidal ideation and attempts. While further research is needed to establish the precise nature of these associations, our data support that the presence of comorbid anxiety disorders in individuals with bipolar disorder should trigger careful clinical assessment of suicide risk.