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The Panic Disorder Severity Scale (PDSS) is a clinician-administered measure of panic disorder symptom severity widely used in clinical research. This investigation sought to provide clinically meaningful anchor points for the PDSS both in terms of clinical severity as measured by the Clinical Global Impression-Severity Scale (CGI-S) and to extend its clinical meaningfulness by examining its association with quality of life. A total of 63 individuals with a primary diagnosis of panic disorder were assessed on completion of a 6- or 8-week psychotherapy or pharmacotherapy trial for the treatment of panic disorder. As expected, the PDSS was correlated with both the CGI-S and quality of life. These results provide further support for the validity and clinical utility of the PDSS and provide simple anchors to help guide the potential use of the PDSS scale to measure treatment progress in clinical practice.

Previous research has demonstrated that individuals with panic disorder (PD) report significant sleep disturbances, although the mechanism of this disturbance is not clear. Patients with PD tend to report abnormally high levels of anxiety sensitivity (AS). Because higher AS involves increases in attention and fearfulness about anxiety and associated physical sensations, which in turn may cause excessive psychological and physiologic arousal, we hypothesized that amongst individuals with PD, higher AS would be associated with sleep disruption, particularly in the form of increased sleep latency. As expected, PD was associated with poorer sleep as measured by the Global Pittsburgh Sleep Quality Index (PSQI) compared to controls and AS was significantly associated with longer sleep latency. Our data suggest that sleep disturbance, and in particular sleep latency, in PD may be partly due to high levels of AS, which can be targeted with cognitive-behavioral therapeutic strategies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., (Copyright 2010 Elsevier Ltd. All rights reserved.)

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.

Background: More data are needed to guide next-step interventions for panic disorder refractory to initial intervention., Method: This 24-week randomized clinical trial (RCT) enrolled 46 patients with DSM-IV-defined panic disorder from November 2000 to April 2005 and consisted of 3 phases. Patients who failed to meet remission criteria were eligible for randomization in the next treatment phase. Phase 1 was a 6-week lead-in with open-label sertraline flexibly dosed to 100 mg (or escitalopram equivalent) to prospectively define treatment refractoriness (lack of remission). Phase 2 was a 6-week double-blind RCT of (1) increased-dose selective serotonin reuptake inhibitor (SSRI) versus (2) continued SSRI plus placebo. Phase 3 was a 12-week RCT of added cognitive-behavioral therapy (CBT) compared to "medication optimization" with SSRI plus clonazepam. Primary endpoints were remission and change in Panic Disorder Severity Scale (PDSS) score in the intent-to-treat sample in each phase., Results: In phase 1, 20.5% (8/39) of the patients achieved remission, and only baseline severity predicted endpoint PDSS score (beta [SE] = 1.04 [0.15], t = 6.76, P < .001). In phase 2, increasing the SSRI dose did not result in greater improvement or remission rates (placebo 15% [n = 2] vs increased dose 9% [n = 1]: Fisher exact test P = NS). In phase 3, remission was minimal (medication optimization = 11% [n = 1]; CBT = 10% [n = 1]), with a lack of group difference in PDSS score reduction (t(17) = 0.51, P > .60) consistent with a small effect size (d = 0.24)., Conclusions: Although power was limited and larger studies are needed, we failed to find evidence for greater benefit of increased SSRI dose versus continuation of current dose for panic disorder symptomatic after 6 weeks at moderate dose. Further, augmentation with CBT or medication optimization with clonazepam augmentation in nonremitted panic after 12 weeks of an SSRI did not differ, suggesting that both are reasonable next-step options. However, low overall remission rates in this comorbid refractory population suggest that better predictors of response to specific treatments over time and additional interventions are needed., Trial Registration: clinicaltrials.gov Identifier: NCT00118417., (Copyright 2009 Physicians Postgraduate Press, Inc.)

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.

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.

Despite the widespread application of combined selective serotonin reuptake inhibitors (SSRI) and benzodiazepine treatment for panic disorder, there has been relatively little systematic assessment of the safety and efficacy of this therapeutic strategy. Although the limited number of studies to date suggest a more rapid onset of benefit with combined treatment, this study is the first to address the critical question of whether continued combined treatment confers superior efficacy. This study is a randomized, double-blind, three-arm study in patients with panic disorder (n = 60), comparing the efficacy and safety of paroxetine and placebo (PP), paroxetine coadministered with clonazepam followed by a tapered benzodiazepine discontinuation phase (PC-D), and ongoing combination treatment (PC-M). All treatment groups demonstrated significant improvement by endpoint. There was a significant advantage for the combined treatment groups early in treatment but, subsequently, outcome in all three groups was similar. A trend towards greater achievement of endpoint remission status for the PC-D group was attenuated when variability in baseline severity was considered. The results of this study should be interpreted in the context of a relatively moderate sample size and higher rates of early dropout. Combined treatment with paroxetine and clonazepam resulted in more rapid response than with the SSRI alone, but there was no differential benefit beyond the initial few weeks of therapy. Initiating combined treatment followed by benzodiazepine taper after a few weeks may provide early benefit while avoiding the potential adverse consequences of long-term combination therapy.

Despite anecdotal reports suggesting that bupropion may be effective for panic disorder, both clinical lore and the results of one small controlled study suggest otherwise. There remains a paucity of systematic prospective data addressing this issue. Twenty outpatients meeting criteria for panic disorder with or without agoraphobia were entered in an 8 week, two center open-label flexible dose trial of bupropion SR. Treatment with bupropion SR resulted in a clinically and statistically significant mean reduction of 1 to 2 points in the primary outcome measure, the CGI Severity score, in both the intent to treat (ITT; t=4.36, df=19, p<0.001) and completer samples (t=3.89, df=13, p<0.002). Significant improvement was also noted in both completer and ITT samples for all other panic symptom measures, which included the Panic Disorder Severity Scale (PDSS), number of panic attacks in the past two weeks, and the proportion of time anticipatory anxiety was present. Although results may be influenced by the open nature of this trial, our findings suggest that bupropion SR may be effective for the treatment of panic disorder. Further controlled study of its efficacy for this condition are warranted.

We examined the rates and correlates of a childhood history of anxiety disorders in 100 adults with a primary diagnosis of social phobia (social anxiety disorder). Adulthood and childhood disorders were assessed by experienced clinicians with structured clinical interviews. Rates of childhood anxiety disorders were evaluated to diagnostic comorbidity and a comparison group of patients with panic disorder. Onset of social phobia occurred before age 18 in 80% of the sample. Over half of the sample (54%) met criteria for one or more childhood anxiety disorders other than social phobia: 47% for overanxious disorder, 25% for avoidant disorder, 13% for separation anxiety disorder, and 1% for childhood agoraphobia. A history of childhood anxiety was associated with an early age of onset of social phobia, greater severity of fear and avoidance of social situations, greater fears of negative evaluation, and greater anxiety and depression morbidity. Rates of childhood social phobia, overanxious disorder, and avoidant disorder were significantly higher in patients with social phobia relative to our panic-disordered comparison group. We found approximately equal rates of a childhood history of separation anxiety disorder in patients with social phobia and panic disorder, providing further evidence against a unique relationship between separation anxiety disorder and panic disorder., (Copyright 2001 Wiley-Liss, Inc.)

The surface immune phenotype of peripheral blood lymphocytes (PBL) was examined in 30 patients meeting DSM-III-R criteria for panic disorder and in 10 normal controls by immunostaining and cytofluorimetry. Patients with panic disorder and controls showed comparable numbers of PBL and no differences in the percentages of blood T-cells, B-cells, or NK-cells. The PBL in panic disorder patients showed a trend toward enrichment for "naive" CD45RA+ T-lymphocytes (35.0 +/- 7.6 vs. 28.7 +/- 9.8, P = 0.09) and significant enrichment for cells expressing CD62L (L-selectin, 22.9 +/- 5.9 vs. 14.6 +/- 6.3, P = 0.002), a lymphocyte homing receptor that mediates binding to lymph node endothelium. Increased expression of CD62L correlated directly with the global severity of illness, Hamilton Anxiety (HAM-A) and Hamilton Depression (HAM-D) scores. Although in the normal range, plasma cortisol levels were significantly increased in patients with panic disorder (P = 0.003) with respect to controls and correlated with the expression of CD62L by PBL. We conclude that the peripheral blood in panic disorder shows phenotypic changes that may reflect diminished cell activation in vivo.

In this study we assessed the quality of life of patients with panic disorder, with particular attention to the influence of anxiety and depression comorbidity on quality of life. Findings were compared with established general population norms as well as norms for patients with chronic medical conditions and major depression. The Medical Outcomes Study Short-Form Health Survey (SF-36) was administered to panic disorder patients entering clinical trials or treatment in an outpatient anxiety disorders program. Subjects were 73 consecutive patients with a primary diagnosis of panic disorder without current substance abuse or contributory medical illness. Their quality of life scores were compared with population mean estimates using single-sample t-tests, and the influence of comorbidity was examined with between-group comparisons. All SF-36 mental and physical health subscale scores were worse in patients with panic disorder than in the general population. This was true regardless of the presence of comorbid anxiety or mood disorders, although the presence of the comorbid conditions worsened select areas of functioning according to subscale analyses. SF-36 scores in panic patients were at approximately the same level as patients with major depression and tended to be worse in specific areas than patients with select medical conditions. This study provides evidence of the pervasive negative effects of panic disorder on both mental and physical health.

Background: The serotonin selective reuptake inhibitors are increasingly being used for the treatment of panic disorder. We examined the efficacy and safety of the serotonin selective reuptake inhibitor sertraline hydrochloride in patients with panic disorder., Methods: One hundred seventy-six nondepressed outpatients with panic disorder, with or without agoraphobia, from 10 sites followed identical protocols that used a flexible-dose design. After 2 weeks of single-blind placebo, patients were randomly assigned to 10 weeks of double-blind, flexible-dose treatment with either sertraline hydrochloride (50-200 mg/d) or placebo., Results: Sertraline-treated patients exhibited significantly greater improvement (P=.01) at end point than did patients treated with placebo for the primary outcome variable, panic attack frequency. Significant differences between groups were also evident for clinician and patient assessments of improvement as measured by the Clinical Global Impression Improvement (P=.01) and Severity (P=.009) Scales, Panic Disorder Severity Scale ratings (P=.03), high end-state function assessment (P=.03), Patient Global Evaluation rating (P=.01), and quality of life scores (P=.003). Adverse events, generally characterized as either mild or moderate, were not significantly different in overall incidence between the sertraline and placebo groups., Conclusion: Results support the safety and efficacy of sertraline for the short-term treatment of patients with panic disorder.

This study examined the use patterns and efficacy of the high potency benzodiazepine (HPB) clonazepam in panic patients who were treated and followed naturalistically in the Massachusetts General Hospital Longitudinal Study of Panic Disorder. Of 204 patients followed over a 2-year period, 46 percent were receiving clonazepam alone or in combination with an antidepressant. Treatment was not controlled at initial evaluation or during the followup period. The main variables assessed in this analysis included global severity of the panic disorder and stability of clonazepam dose. All treatment groups tended to improve over time without significant differences in outcome between groups. Clonazepam doses remained stable over time. Results of this study suggest that treatment of panic disorder with the HPB clonazepam achieved and maintained a therapeutic benefit similar to that obtained with alternative pharmacologic treatments, without the development of tolerance as manifested by dose escalation or worsening of clinical status.

The authors examined the incidence of significant life events during the year prior to the onset of panic disorder and its relationship to childhood and family history of anxiety difficulties, comorbidity, and the course of illness in 223 panic patients followed in a naturalistic study of panic disorder. Similar to previous reports, antecedent negative life events occurred in the majority (80%) of patients. Patients with a childhood history of anxiety and comorbid adulthood major depression were more likely to report an antecedent, stressful life event. Antecedent events were not linked with comorbid, adulthood anxiety disorders or a family history of anxiety difficulties. Despite its associations with childhood anxiety pathology and adulthood major depression, the presence of an identifiable antecedent at the onset of panic disorder was not associated with the subsequent severity or course of the disorder.

Objective: This study investigated the correlates of a childhood history of anxiety disorders in adult patients participating in a longitudinal study of panic disorder. The authors hypothesized that a history of anxiety during childhood would be associated with higher rates of comorbid anxiety and depressive disorders, greater likelihood of anxiety disorders in family members, and greater chronicity, as reflected by decreased time spent in remission., Method: The presence of a childhood history of anxiety disorders was assessed by structured interview, and its association with comorbid anxiety and depressive disorders, family history, and select anxiety severity variables was examined in a replication sample of 94 patients. The influence of childhood anxiety on the prospectively ascertained course of disorder was assessed in a full group of 194 patients., Results: Over half (54%) of the patients experienced anxiety disorders during childhood. These patients experienced higher rates of comorbid anxiety and depression, family history of anxiety, and increased levels of agoraphobia, panic frequency, and global severity of illness at baseline evaluation. Childhood anxiety disorders were not independently associated with the number of months in remission or the severity of illness over time, although a modest effect for this variable was evident when degree of avoidance and anxiety sensitivity at baseline were statistically controlled., Conclusions: Adult panic patients with a history of anxiety disorders in childhood have elevated rates of comorbid anxiety and depressive disorders and a tendency toward increased avoidance, but there was not strong evidence that these patients respond differently to treatment over time.

Venlafaxine has demonstrated efficacy for depression, and recent reports and clinical experience suggest that it may be effective for the treatment of anxiety disorders as well. We present what we believe are the first data from a controlled study designed to test the efficacy of venlafaxine for the treatment of panic disorder. There were 25 patients enrolled at one site of a five-center study; 13 received venlafaxine and 12 received placebo. There were more dropouts for placebo than for venlafaxine (8/12 vs. 2/13) in this 8-week acute trial. Patients treated with venlafaxine experienced significantly greater global improvement than those on placebo and exhibited trends toward greater improvement on anxiety and depression symptoms as assessed by the Hamilton rating scales. These data encourage further evaluation of venlafaxine for the treatment of panic disorder.