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Effect of quetiapine vs. placebo on response to two virtual public speaking exposures in individuals with social phobia
Journal of Anxiety Disorders 23 (2009) 362–368
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Journal of Anxiety Disorders
Effect of quetiapine vs. placebo on response to two virtual public speaking exposures in individuals with social phobia§ Christopher B. Donahue, Matt G. Kushner *, Paul D. Thuras, Tom G. Murphy, Joani B. Van Demark, David E. Adson Department of Psychiatry, University of Minnesota, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 31 July 2008 Received in revised form 8 December 2008 Accepted 9 December 2008
Objective: Clinical practice and open-label studies suggest that quetiapine (an atypical anti-psychotic) might improve symptoms for individuals with social anxiety disorder (SAD). The purpose of this study was to provide a rigorous test of the acute impact of a single dose of quetiapine (25 mg) on SAD symptoms. Method: Individuals with SAD (N = 20) were exposed to a 4-min virtual reality (VR) public speaking challenge after having received quetiapine or placebo (double-blind) 1 h earlier. A parallel VR challenge occurred 1 week later using a counter-balanced cross-over (within subject) design for the medicationplacebo order between the two sessions. Result: There was no significant drug effect for quetiapine on the primary outcome measures. However, quetiapine was associated with significantly elevated heart rate and sleepiness compared with placebo. Conclusion: Study findings suggest that a single dose of 25 mg quetiapine is not effective in alleviating SAD symptoms in individuals with fears of public speaking. ß 2008 Elsevier Ltd. All rights reserved.
Keywords: Quetiapine Social anxiety Social phobia Virtual reality Public speaking
The DSM-IV (American Psychiatric Association, 1994) describes the core feature of social anxiety disorder (SAD; a.k.a. social phobia) as a strong and persistent fear of embarrassment in social or performance situations (e.g., while eating, writing, and speaking). SAD has been identified as the third most common psychiatric disorder in the United States behind major depression and alcohol use disorder (Hofmann et al., 2006). Lifetime prevalence rate of SAD among the general population has been estimated to be 13% in the National Comorbidity Survey (NCS) (Kessler et al., 1994). However, the more recent National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) puts this estimate at closer to 5% (Grant et al., 2005). The rate of SAD among college students may be even higher than in the general population (Tillfors & Furmark, 2007). Because the most common manifestation of SAD involves fear of public speaking (Mannuzza et al., 1995; Stein, Walker, & Forde, 1996), academic and career opportunities can be missed for many sufferers due to avoidance/intolerance of public speaking. Several pharmacological and psychological therapies have been shown to be at least partially effective in treating individuals with
§ This Investigator Sponsored Trial (IRUSQUET0422) was funded in part by a grant from AstraZeneca Pharmaceuticals LP. Clinical Trials Registration: ClinicalTrials.gov identifier NCT00407199. * Corresponding author at: F282/2A West, 2450 Riverside Avenue, Minneapolis, MN 55455, United States. Tel.: +1 612 273 9809; fax: +1 612 273 9779. E-mail address: [email protected] (M.G. Kushner).
0887-6185/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.janxdis.2008.12.004
SAD (Clark et al., 2003; Davidson et al., 2004; Fava et al., 2001; Freske & Chambless, 1995; Gelernter et al., 1991; Gould, Buckminster, Pollack, Otto, & Yap, 1977). In a 12-week, randomized controlled trial, Gelernter et al. (1991) compared group cognitive behavioral therapy (CBT) alone to pharmacotherapy (phenelzine sulfate, alprazolam or placebo) plus instructions for self-directed exposure to phobic stimuli in the treatment of individuals with SAD. Each group demonstrated comparable clinically significant improvement on the primary outcome measures, with the exception of significant group differences noted in state anxiety, with phenelzine treated patients showing more improvement. At follow-up, phenelzine (medication discontinued) and CBT were the only groups that maintained initial gains, with CBT showing further improvements. Davidson et al. (2004) studied fluoxetine and CBT treatment (both alone and combined) for SAD, reporting that while both treatments are better than placebo, neither was adequate to render a majority of participants symptom free after 14 weeks of treatment. They suggested that additional research on novel SAD treatments is warranted. Although quetiapine was developed to treat psychotic disorders, including bipolar disorder, some recent efforts aimed at anxiety treatment innovation have focused on quetiapine. Regarding the former, a mean dose of 487 mg of quetiapine was used for individuals with schizophrenia in a 3-year retrospective study with side effects that included drug-induced movement disorders and rebound psychosis upon discontinuation (Margolese, Chouinard,
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Beauclair, & Belanger, 2002). Similarly, effective treatment of bipolar disorder with quetiapine requires doses in the range of 300–600 mg daily (Calabrese, 2004). However, anti-anxiety effects might be achieved at significantly lower doses of quetiapine. For example, an open-label trial of quetiapine (flexible dosing 150–300 mg/day) resulted in significant reductions in SAD symptoms (Schutters, van Megen, & Westenberg, 2005). SAD patients who were partial or nonresponders to SSRI therapy reported significant reductions in anxiety in response to adjunctive quetiapine (55.7 31.2 mg daily) (Kinrys et al., 2007). Similarly, significant reductions in anxiety have been reported when using quetiapine (maximum daily dose of 300 mg) as adjunctive therapy with stable SSRI dosing for mixed mood and anxiety disordered patients (Adson, Kushner, Eiben, & Schulz, 2004) and as monotherapy for anxiety symptoms in both GAD and MDD (Bandelow et al., 2007; Brawman-Mintzer, 2006). However, the only placebo controlled trial of quetiapine (147 105 mg) in individuals with SAD found no significant effects (Vaishnavi, Alamy, Zhang, Connor, & Davidson, 2007). In the present study we evaluated the impact of quetiapine (25 mg) vs. placebo in response to a SAD-relevant virtual reality anxiety cue exposure. This dose, while relatively low, is within the bounds of current clinical practice (range 25–200 mg) in managing anxiety (Philip, Mello, Carpenter, Tyrka, & Price, 2008; Rowe, 2007). Further, doses in this range (25 mg and 100 mg) have been shown to result in improved sleep (Cohrs et al., 2004) and decreased cortisol (de Borja Goncalves Guerra, Castel, BeneditoSilva, & Calil, 2005), a biological indicator of stress and anxiety responding (Alpers, Abelson, Wilhelm, & Roth, 2003; Nejtek, 2002). Following the lead of several recent studies (Difede et al., 2007; Hofmann et al., 2006; Ressler et al., 2004), we utilized a virtual reality (VR) environment to accomplish potent and uniform anxiety provocations. Specifically, individuals with SAD that included public speaking fears underwent two VR exposure sessions, 1 week apart, in which they gave a speech to a virtual audience. One hour prior to the first of the two sessions, participants were randomized to take either 25 mg of quetiapine or an identical looking placebo pill. On the second of the two sessions, participants were crossed-over to the other condition. We hypothesized that individuals would react with less self-reported anxiety and physiological reactivity in the active drug condition than in the placebo condition. 1. Method
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ages ranging from 18 to 25. Seventeen of the 22 participants were female (77.3%). The University of Minnesota’s Institutional Review Board’s Human Subjects Committee approved the study protocol. All participants received referral information regarding treatment of their SAD. 1.2. Measures 1.2.1. Personal Report of Confidence as a Speaker (PRCS) The short form of the PRCS (Paul, 1966) is a 30-item questionnaire that asks respondents to endorse as true or false specific statements about their experience during their most recent experience speaking in front of an audience. One point is given for each fear-relevant response allowing for scores to range between 0 (no fear responses are endorsed) and 30 (all fear responses are endorsed) with a recommended clinical cut-off of 16 or greater (Paul, 1966). We used a more conservative clinical cutoff of 21 for study inclusion as recommended by others (Carrigan & Levis, 1999). The PRCS demonstrates adequate psychometric properties (Daly, 1978; Tarico, van Velzen, & Altmaier, 1986), has been used as a screening (Jones, Phillips, & Rieger, 1995) and treatment outcome measure for fear of public speaking (Altmaier, Ross, Leary, & Thornbrough, 1982; Schuler, Gilner, Austrin, & Davenport, 1982) and has proven sensitive to measuring reactivity to virtual audiences (Pertaub, Slater, & Barker, 2002). 1.2.2. Liebowitz Social Anxiety Scale (LSAS) The LSAS (Liebowitz, 1987) is used to evaluate the wide range of social situations that are difficult for individuals with social phobia. The LSAS has demonstrated adequate psychometric properties (Fresco et al., 2001) and has been used as an outcome measure for SAD treatments including CBT (Hofmann et al., 2006) and quetiapine (Schutters et al., 2005). Normative data for the LSAS in social anxiety samples are available. For example, in treatment seeking patients with SAD, Heimberg et al. (1999) reported LSAS total score means = 67.2 (S.D. = 27.5), total fear mean = 35.5 (S.D. = 13.6) and total avoidance mean = 31.6 (S.D. = 14.5). 1.2.3. Beck Depression Inventory (BDI) (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961) The BDI was used as a baseline measure of self-reported symptoms of depression and has demonstrated good psychometric properties (Beck, Steer, & Garbin, 1988; Marton, Churchard, Kutcher, & Korenblum, 1991).
1.1. Participants Participants recruited for this study were full-time college students in the metropolitan area of Minneapolis-St. Paul. Potential participants were identified through advertisements that we placed in campus publications and fliers seeking individuals with a strong fear of public speaking. Inclusion criteria were a current diagnosis of SAD using DSM-IV criteria and clinically significant public speaking fears (see definition below). Exclusion criteria were: (a) current contraindications or a history of sensitivity to quetiapine; (b) current regular use of benzodiazapine, tranquilizer, or antipsychotic medications; (c) an active psychotic, manic, or depressed episode; (d) unstable diabetes mellitus; (e) heart disease; (f) neurologic disorder (by history); or (g) liver disease. Of 111 individuals who responded to recruiting advertisements, 30 could not be reached, 37 were deemed not qualified and 20 were qualified but decided not to participate. Of the 24 participants who were qualified and enrolled, 20 completed the study while two were pilot participants and two were non-completers (one missed session 2 and one discontinued during session 1 due to anxiety). Participants’ mean age was 21.2 years (S.D. = 1.7), with
1.2.4. Stanford Sleepiness Scale (SSS) The SSS (Hoddes, Dement, & Zarcone, 1973) is a time-dependent self-rating of sleepiness and the tendency to fall asleep. The SSS ratings range from 1 (feeling active and vital; alert, wide awake) to 7 (almost in reverie; sleep onset soon; lost struggle to remain awake). The SSS was used to monitor sedation effects of the drug. 1.2.5. Side effects/adverse effects The research assistant (RA) asked patients about adverse effects from study medication post-VR exposure in each session. 1.2.6. Subjective Units of Distress (SUDS) Participants rated their degree of distress on a scale by making a mark along a 100 mm line anchored as 0 = ‘‘none’’ on the left to 100 = ‘‘extreme’’ on the right. A score on the SUDS was generated by measuring the distance (in mm) from the left most anchor (zero) to the patient’s mark (e.g., 75 mm = a score of 75). 1.2.7. Mini-Structured Clinical Interview (Mini-SCID) (First, Gibbon, Williams, & Spitzer, 1990) for social phobia The Mini-SCID was used to confirm diagnosis of social phobia.
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1.2.8. Heart rate (HR) and blood pressure (BP) HR and BP were measured using Omron Healthcare Automatic Blood Pressure monitor and easy wrap cuff (Model HEM-773). 1.3. Procedures 1.3.1. Phone screen A trained RA completed a 15-min telephone screen, including the social phobia module of the Mini-SCID and PRCS, with all participants. Participants who were determined to be eligible and interested were scheduled for a medical evaluation and the first VR exposure session within 1 week of the telephone screen. Individuals meeting full DSM-IV diagnostic criteria for SAD were invited to an interview with a board certified psychiatrist who reviewed and confirmed the Mini-SCID results and obtained psychiatric and medical history pertinent to the study, as described in more detail below. 1.3.2. Medical evaluation Upon arriving for the first study appointment, participants underwent a final screening step with a board certified psychiatrist (author, DA) who obtained a medical and psychiatric history with a focus on detecting mood or thought disorders. Current mania, depression and psychosis were ruled out by history combined with a current mental status exam. No other formal diagnostics were employed; however, individuals completed a number of standardized social anxiety and public speaking fear measures (PRCS, LSAS). 1.3.3. Medication AstraZeneca Pharmaceuticals provided 25 mg quetiapine capsules and matching placebo. These were randomized by our institution’s investigational pharmacy to provide evenly weighted double-blind allotments of placebo vs. quetiapine for study visits one and two. 1.3.4. VR exposure session At the conclusion of the 1-h post-medication waiting period, the subject was moved from the waiting area into the VR exposure laboratory. The procedure is overviewed here: (1) the RA fitted the subject with a head-mounted display visor (HMD; VFX-3D, Interactive Imaging Systems, Rochester, NY) and operated the computer to initiate the virtual speaking environment software (developed by Virtually Better, Decatur, Georgia); (2) through the visor, participants viewed a virtual curtain and podium and heard audience noise in the background ostensibly coming from behind the virtual curtain; (3) participants were presented with one of two speech tasks (scenario A or B described below); (4) participants were given 4 min to prepare for their speech; (5) the virtual curtain was opened and the 4-min speech period was initiated. For both scenarios A and B, the RA presented the following instructions: ‘‘Imagine that you are running for president of the University Government and you will now be speaking in front of a faculty board.’’ For Scenario A, the RA also told the subject to: ‘‘Please consider when preparing your talk the following: why you are a good candidate for this office; what changes in the university you would like to facilitate; how you deal with interpersonal conflicts; and finally, why people should vote for you.’’ For Scenario B, the RA described the same scenario, but asked the subject to focus on: ‘‘an example in which you overcame adversity; how you plan to make the university a better place to go to school; and how you work in team-oriented environments.’’ Once for each of the 4 min of the speech, the RA manipulated features of the VR audience to increase the realistic nature of the speech task. Virtual audience manipulations included a ‘‘receptive’’
audience (e.g., maintained eye contact with the presenter) and audience disruptions (virtual audience member asking a standard question, a cell phone ringing, an audience member leaving the virtual room and slamming door, and an audience member falling asleep). Subjective and physiological measures were obtained four times during the speech (each minute) and immediately after the speech. 1.3.5. Session conclusion Following each exposure session participants were required to arrange for an adult companion to meet them and escort them home due to the possible sedating effects of the study drug. Participants were compensated for transportation costs. 2. Results 2.1. Clinical status at baseline SAD assessments indicated that participants were clinically significantly impaired with mean PRCS scores of 25.7 (S.D. = 2.6), and LSAS scores of 30.4 (S.D. = 14.1) (Fear/Anxiety) and 27.3 (S.D. = 10.7) (Avoidance), which are in excess of the recommended LSAS (Heimberg et al., 1999) and PRCS (Carrigan & Levis, 1999) clinical cut-off scores. 2.2. Medication side effects To quantify the sedative effects of quetiapine, participants were given the SSS before administration of the drug or placebo and then again 1 h later, just prior to the participant’s exposure to the VR speaking task. Scores for the latter administration were significantly higher (indicating more sedation) when participants had taken quetiapine vs. placebo (F(1,38) = 21.5, p < .001, h2 = .361; M = 3.55, S.D. = 1.6 vs. M = 2.28, S.D. = .78). Similarly, the change in mean SSS sedation ratings from before to 1 h after taking medication was significantly greater for the quetiapine (M = 2.35, S.D. = .67 to M = 4.65, S.D. = 1.5) than for the placebo (F(1,18) = 20.6, p < .001, h2 = .53; M = 2.20, S.D. = .89 to M = 2.60, S.D. = .99). The study medication was generally well tolerated; one participant reported dry mouth and another dizziness after talking quetiapine. No adverse effects were reported in the placebo group. 2.3. Response to VR environment 2.3.1. PRCS We evaluated main effects within participants by comparing the post-exposure PRCS scores between the placebo and quetiapine sessions, using baseline PRCS as a covariate. As shown in Fig. 1,
Fig. 1. Group comparisons of speaking fears experienced during the speech provocation (measured by the Personal Report of Confidence as a Speaker, PRCS).
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2.3.2. SUDS ratings Using mixed regression models, we examined change in distress (i.e., SUDS) across a time series within sessions that spanned: (a) the speech preparation period; (b) immediately before the speech; (c) four times during the speech (one per minute); and (d) immediately after the VR speech. These data are depicted in Fig. 2a (session 1) and b (session 2). As can be seen, both groups began both time series with moderate to low subjective anxiety as they began their speech preparation (around 30 on the 100 point scale). In session 1 these ratings rose in both groups reaching a maximum rating of about 60 on the scale by the end of the speech. In session 2, however, the drug group remained
relatively flat in their ratings across the seven time points at around 30 while the placebo group’s ratings ranged between 40 and 50 for most of the latter ratings. Collapsing the sessions to evaluate time effect alone demonstrated a significant effect over the course of the seven time points from the preparatory period until immediately after the speech task, with scores increasing from 29.8 (S.D. = 22.1) immediately prior to task to 53.4 (S.D. = 29.1) immediately after the task (F(6,120) = 13.0, p < .001; effect size h2 = .628). However, given the appearance in the data of a differing pattern of drug effects in the two sessions (see Fig. 2a vs. b) we also statistically tested for a drug-by-session effect to determine whether session carry-over effects were potentially obscuring drug effects for the SUDS ratings. Importantly, this result was not significant (F(1,18) = .34, p < .57, Cohen’s d = .27). However, as with the PRCS, mean SUDS ratings collapsed within the sessions were significantly higher in session 1 than in session 2 (56.0, S.D. = 25.5 vs. 40.5, S.D. = 27.5; F(1,19) = 71.8, p < .001, Cohen’s d = 3.9). Finally, we specifically tested the study hypothesis by evaluating drug vs. placebo effect on SUDS collapsed across sessions. Contrary to study predictions this effect was not significant (F(1,18) = .83, p < .375, Cohen’s d = 0.32).
Fig. 2. Subjective distress (mean S.E.) during VR session comparing drug to placebo: (a) Session 1 and (b) Session 2.
Fig. 3. Systolic blood pressure (mean S.E.) during VR session comparing drug to placebo: (a) Session 1 and (b) Session 2.
both placebo and drug condition PRCS scores were highly similar (placebo M = 22.5, S.D. = 5.7 vs. drug M = 21.9, S.D. = 6.2; effect size Cohen’s d = 0.3). We did find that scores on the PRCS were significantly higher after the first session compared with scores after the second session (M = 23.7, S.D. = 6.0 vs. M = 17.9, S.D. = 6.2; F(1,17) = 29.5, p < .001; effect size Cohen’s d = 1.2). However, there was no significant interaction on the PRCS between drug condition and session, indicating that cross-over (session) effects were not confounding drug effects.
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2.3.3. HR and BP Using mixed regression models we examined change in HR and BP during: (a) the speech preparation period, (b) immediately before, and (c) immediately after the VR speech. Time effects for physiologic measures showed significant response to the VR environment with HR and diastolic BP both increasing over time in the sessions (F(2,40) = 13.0, p < .001 and F(2,40) = 4.8, p < .02, respectively). However, increases in systolic blood pressure did not meet criteria for statistical significance. Collapsing time and session showed that overall BP values were somewhat lower in the drug condition than in the placebo condition although these differences did not reach statistical significance (F(2,40) = 0.8, p = .45; Cohen’s d for systolic = .83, Cohen’s d for diastolic = .87). However, HR was significantly higher when participants were taking the drug (M = 91.4, S.D. = 15.5) compared to when they were taking the placebo (M = 84.2, S.D. = 13.4; F(1,17) = 28.0, p < .001; Cohen’s d = 2.4). Similar to findings for the PRCS and SUDS reported above, both systolic and diastolic BP means were significantly higher during the first session when compared with the second session: systolic means 115.5 (S.D. = 14.2) vs. 109.8 (S.D. = 9.6) (F(1,18) = 12.4, p < .003); diastolic means 82.4 (S.D. = 8.7) vs. 76.9 (S.D. = 8.5) (F(1,18) = 14.9, p < .001). Although HR was higher during the first session than the second (M = 88.9, S.D. = 14.8) vs. (M = 86.4, S.D. = 14.9), this difference did not quite reach significance (F(1,18) = 3.7, p < .07, Cohen’s d = .90). We also observed an interaction between session and drug for systolic BP which was higher for the placebo group as compared with the quetiapine group during the first session (M = 123.7, S.D. = 14.9 vs. 108.1, S.D. = 9.9) but lower than the drug group during the second session (105.1, S.D. = 8.3 vs. 114.7, S.D. = 9.1) (F(1,17) = 6.8, p < .02) (Fig. 3). No other significant interactions were observed. 3. Discussion We found that 25 mg of quetiapine, relative to placebo, did not affect response to a VR public speaking challenge in individuals with social phobia with specific fears of public speaking. This would appear to indicate that quetiapine at this dose does not have significant acute clinical benefits for individuals with social anxiety symptoms. However, before reaching this conclusion we considered several aspects of the methodology that could have affected the results including: (a) the effectiveness of the VR task as a potent elicitor of social anxiety symptoms; (b) the representativeness of SAD cases recruited; (c) the dose of drug; (d) the potential for cross-over effects; (e) the type of anxiety disorder studied; and (f) the possibility of the study being underpowered. Was the VR speech task a potent elicitor of social anxiety symptoms? Our data show that PRCS scores (a validated indicator of level of public speaking fear) obtained within the VR environment were above the most conservative clinical severity cutoffs recommended in the literature (see Section 1). Virtual reality studies with anxiety disorders, including social phobia and specific fear of public speaking, find a high degree of ‘‘presence’’ (i.e., similarity to real world phobic reactions) in VR environments eliciting strong phobic reactions (Cornwell, Johnson, Berardi, & Grillon, 2006; Difede et al., 2007; Hofmann et al., 2006; Ressler et al., 2004; Slater, Pertaub, Barker, & Clark, 2006). Participants in the present study rated the VR exposures as ‘‘moderately similar’’ to actual speaking experiences (10-point Likert scale; mean = 5.7, S.D. = 2.5) and of moderate intensity relative to in vivo experiences (M = 6.1; S.D. = 2.4). These data and those from past studies then support the conclusion that the VR speaking task was reasonably effective in eliciting clinical-level social anxiety symptoms that participants found more similar than not to their ‘‘typical’’ speaking fears.
Were participants representative of individuals with typical SAD symptoms? As noted, participants were young adult college students who met DSM-IV criteria for SAD that included significant public speaking fear. While we have no reason to believe that this population is atypical of other individuals with SAD found in the community, we cannot rule out the possibility that non-college or post-college individuals with SAD would have responded differently in this study. Participants in this study were found to be severely impaired according to PRCS scores relative to other samples (Carrigan & Levis, 1999) and, according to the LSAS, fear and avoidance scores were comparable to treatment seeking patients with SAD (Heimberg et al., 1999). One aspect of the study we did not adequately control, however, was non-drug related treatment status (e.g., CBT). Participants were not screened for, nor excluded if they were actively involved in non-drug therapies (e.g., psychotherapy) for the treatment of SAD. However, because subjects were symptomatic in response to the VR challenge and also served as their own controls in the cross-over design, any such influence upon responses in our study should have been nullified. Could cross-over effects from session 1 to session 2 have obscured drug effects? As noted in Section 1, all participants were in both drug and placebo conditions (within subject) with order being random and counter-balanced, in effect distributing possible contaminating effects evenly between the two drug conditions. Nonetheless, there did appear to be some habituation between sessions 1 and 2 as indicated by significant reductions in several measures across the sessions (without reference to the counterbalanced drug–placebo assignment). However, several aspects of this habituation effect leave us confident that it did not compromise the validity of the study. In the current study anxiety levels (PRCS scores) remained at or above clinical levels for both sessions, consistent with other studies showing fear extinction in individuals with SAD requiring 6–16 sessions (Freske & Chambless, 1995). In similar speech challenge studies for individuals with SAD (Turner, Beidel, & Jacob, 1994), up to 20 exposure sessions were completed in order to achieve habituation. In addition, there were no significant session-by-drug effects. That is, while the overall level of responding in the VR environment was lower in the second session than in the first session, the drug vs. placebo effect was not significantly different across the two sessions. Future research could seek to further minimize cross-over effects by extending the time interval between VR exposure sessions or by using a between subject design requiring only one exposure session. Was the study design adequately powered? This was a pilot study and therefore had power that was only sufficient to find large effects. We do report effect sizes in addition to the results of significance testing. Notably, effects sizes for drug vs. placebo in response to VR challenge were very modest suggesting that even with a larger sample we still would not have observed significant effects. Was the 25 mg dose of quetiapine an adequate dose for the purpose of reducing acute social anxiety reactions in the VR environment? As noted earlier, the dose of quetiapine used in this study is within the bounds of current clinical practice (range 25– 200 mg) in managing anxiety (Philip et al., 2008; Rowe, 2007). Regarding SAD particularly, quetiapine doses up to 300 mg/day (Schutters et al., 2005) and as low as 56 mg/day (Kinrys et al., 2007) have appeared to be therapeutic. However, consistent with our findings, the one double-blind placebo-controlled study addressing this question was negative (dose = 147 105 mg) (Vaishnavi et al., 2007). Nonetheless, because only a single relatively low dose of the drug was used, we cannot judge whether higher or chronic doses of the drug would have been more effective in reducing participants’ social anxiety symptoms in response to the VR challenge. Our study also does not address the combination of drug treatment plus a fuller course of therapeutic exposures sessions
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than the two VR sessions used in this study. Turner et al. (1994) noted therapeutic effects for individuals with SAD following 20 exposure or flooding sessions using in vivo speech challenge in comparison to 16 weeks of atenolol, a beta blocker, with increasing dosing from 25, 50, to 100 mg. The chronic administration of atenolol in this study, in the absence of exposure therapy, was insufficient to treat symptoms of SAD. Future studies that combine a fuller course of exposures with quetiapine could result in enhanced treatment outcomes for SAD. Might quetiapine exert more robust effects for anxiety symptoms stemming from anxiety conditions other than SAD? There is a growing body of literature suggesting that quetiapine is effective in reducing symptoms of generalized anxiety disorder (Adson et al., 2004; Bandelow et al., 2007; Brawman-Mintzer, 2006) and depression (Bauer, Pretorius, Earley, Lindgren, & Brecher, 2007; Montgomery, Cutler, Lazarus, Schollin, & Brecher, 2007). These findings raise the possibility that quetiapine may be more effective in treating symptoms of GAD and depression than SAD. In spite of the limitations noted, our findings are immediately clinically relevant since the use of acute low dosing of quetiapine has been reported to be common in several psychiatric populations. For example, Philip et al. (2008) noted that approximately 1335 of 1912 previously hospitalized psychiatric patients surveyed (nearly 70%) received ‘‘as needed’’ doses of quetiapine, with the most common dose at 50 mg (followed by 25 mg and 100 mg) every 1–2 h for agitation, anxiety, or insomnia. As rigorous studies into the costs and benefits of quetiapine at particular doses for particular populations become increasingly available, it will be important for frontline clinicians to factor these research findings into their off-label therapeutic decision-making. In conclusion, results from this study, in combination with the only other published placebo-controlled study examining quetiapine in SAD (Vaishnavi et al., 2007), suggest that acute, low dosing of quetiapine is not effective in the treatment of SAD symptoms. Future research may consider higher and/or chronic dosing of quetiapine in treating individuals with SAD and should also consider whether quetiapine in combination with CBT is better than either treatment alone. References Adson, D. E., Kushner, M. G., Eiben, K. M., & Schulz, S. C. (2004). Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors. Depress Anxiety, 19(2), 121–126. Alpers, G. W., Abelson, J. L., Wilhelm, F. H., & Roth, W. T. (2003). Salivary cortisol response during exposure treatment in driving phobics. Psychosomatic Medicine, 65(4), 679–687. Altmaier, E., Ross, S., Leary, M., & Thornbrough, M. (1982). Matching stress inoculation’s treatment components to clients’ anxiety mode. Journal of Counseling Psychology, 29, 331–334. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. Bandelow, B., Bobes, J., Ahohas, A., Eggens, I., Liu, S., & Brecher, M. (2007). Results from a phase ii study of once-daily extended release quitiapine fumarate (quitiapine xr) monotherapy in patients with generalized anxiety disorder. Paper presented at the international forum on mood and anxiety disorders, Budapest, Hungary. Bauer, M., Pretorius, H. W., Earley, W., Lindgren, P., & Brecher, M. (2007). Results from a phase ii study of extended release quitiapine fumarate (quetiapine xr) as add-on to antidepressants in patients with major depressive. Paper presented at the international forum on mood and anxiety disorders, Budapest, Hungary. Beck, A. T., Steer, R. A., & Garbin, M. (1988). Psychometric properties of the beck depression inventory: twenty-five years of evaluation. Clinical Psychology Review, 8, 77–100. Beck, A. T., Ward, C. H., Mendelson, M., Mock, J., & Erbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561–571. Brawman-Mintzer, O. (2006). Quetaipine monotherapy in patients with generalized anxiety disorder. Abstract 341. A flexible dose, open-label trial evaluating the efficacy and safety of quetiapine (quetiapine) as adjunctive pharmacotherapy for the treatment of generalized anxiety disorder (gad). Paper presented at the 26th annual conference of the Anxiety Disorders Association of America (ADAA), Miami, Florida. Calabrese, J. R. e. a. (2004). Quetiapine effective against anxiety in bipolar depression. Paper presented at the annual meeting of the American Psychiatric Association, New York.
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Carrigan, M. H., & Levis, D. J. (1999). The contributions of eye movements to the efficacy of brief exposure treatment for reducing fear of public speaking. Journal of Anxiety Disorders, 13(1–2), 101–118. Clark, D. M., Ehlers, A., McManus, F., Hackmann, A., Fennell, M., Campbell, H., et al. (2003). Cognitive therapy versus fluoxetine in generalized social phobia: a randomized placebo-controlled trial. Journal of Consulting and Clinical Psychology, 71(6), 1058–1067. Cohrs, S., Rodenbeck, A., Guan, Z., Pohlmann, K., Jordan, W., Meier, A., et al. (2004). Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berlin), 174(3), 421–429. Cornwell, B. R., Johnson, L., Berardi, L., & Grillon, C. (2006). Anticipation of public speaking in virtual reality reveals a relationship between trait social anxiety and startle reactivity. Biological Psychiatry, 59(7), 664–666. Daly, J. (1978). The assessment of social-communicative anxiety via self-reports: a comparison of measures. Communcation Monographs, 45, 204–218. Davidson, J. R. T., Fos, E. B., Huppert, J. D., Keefe, F., Franklin, M., Compton, J., et al. (2004). Fluoxetine, comprehensive cbt and placebo in generalized social phobia. Archives of General Psychiatry, 13, 423–428. de Borja Goncalves Guerra, A., Castel, S., Benedito-Silva, A. A., & Calil, H. M. (2005). Neuroendocrine effects of quetiapine in healthy volunteers. International Journal of Neuropsychopharmacology, 8(1), 49–57. Difede, J., Cukor, J., Jayasinghe, N., Patt, I., Jedel, S., Spielman, L., et al. (2007). Virtual reality exposure therapy for the treatment of posttraumatic stress disorder following September 11, 2001. Journal of Clinical Psychiatry, 68(11), 1639–1647. Fava, G. A., Grandi, S., Rafanelli, C., Ruini, C., Conti, S., & Belluardo, P. (2001). Longterm outcome of social phobia treated by exposure. Psychological Medicine, 31(5), 899–905. First, M. B., Gibbon, M., Williams, J. B. W., & Spitzer, R. L. (1990). Mini-skid. Multi-Health Systems Inc. Fresco, D. M., Coles, M. E., Heimberg, R. G., Liebowitz, M. R., Hami, S., Stein, M. B., et al. (2001). The Liebowitz social anxiety scale: a comparison of the psychometric properties of self-report and clinician-administered formats. Psychological Medicine, 31(6), 1025–1035. Freske, U., & Chambless, D. L. (1995). Cognitive-behavioral vs. exposure only treatments for social phobia. Behavior Therapy, 26, 695–720. Gelernter, C. S., Uhde, T. W., Cimbolic, P., Arnkoff, D. B., Vittone, B. J., Tancer, M. E., et al. (1991). Cognitive-behavioral and pharmacological treatments of social phobia. A controlled study. Archives of General Psychiatry, 48(10), 938–945. Gould, R. A., Buckminster, S., Pollack, M. H., Otto, M. W., & Yap, L. (1977). Cognitivebehavioral and pharmacological treatment of social phobia: a meta-analysis. Clinical Psychology and Scientific Practice, 4, 291–306. Grant, B. F., Hasin, D. S., Blanco, C., Stinson, F. S., Chou, S. P., Goldstein, R. B., et al. (2005). The epidemiology of social anxiety disorder in the United States: results from the national epidemiologic survey on alcohol and related conditions. Journal of Clinical Psychiatry, 66(11), 1351–1361. Heimberg, R. G., Horner, K. J., Juster, H. R., Safren, S. A., Brown, E. J., Schneier, F. R., et al. (1999). Psychometric properties of the liebowitz social anxiety scale. Psychological Medicine, 29(1), 199–212. Hoddes, E., Dement, W. C., & Zarcone, V. (1973). The development and use of the Stanford sleepiness scale (sss). Psychophysiology, 10, 431–436. Hofmann, S. G., Meuret, A. E., Smits, J. A., Simon, N. M., Pollack, M. H., Eisenmenger, K., et al. (2006). Augmentation of exposure therapy with d-cycloserine for social anxiety disorder. Archives of General Psychiatry, 63(3), 298–304. Jones, G., Phillips, G., & Rieger, E. (1995). Effects of cardiac awareness, public speaking anxiety, and physiological ‘‘priming’’ on state-trait anxiety (state) and feelings of apprehension. Psychophysiology, 32(Suppl.), S43. Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., et al. (1994). Lifetime and 12-month prevalence of dsm-iii-r psychiatric disorders in the United States. Results from the national comorbidity survey. Archives of General Psychiatry, 51(1), 8–19. Kinrys, G., Nery, F., Vasconcelos, D., Rothstein, E., Dunn, R., Bianco, R., et al. (2007). Quetiapine augmentation of ssris for treatment refractory of social anxiety disorder (sad). Paper presented at the Poster presented at the 2th European College of Neuropsychopharmacology, Vienna Austria. Liebowitz, M. R. (1987). Social phobia. Modern Problems of Pharmacopsychiatry, 22, 141–173. Mannuzza, S., Schneier, F. R., Chapman, T. F., Liebowitz, M. R., Klein, D. F., & Fyer, A. J. (1995). Generalized social phobia Reliability and validity. Archives of General Psychiatry, 52(3), 230–237. Margolese, H. C., Chouinard, G., Beauclair, L., & Belanger, M. C. (2002). Therapeutic tolerance and rebound psychosis during quetiapine maintenance monotherapy in patients with schizophrenia and schizoaffective disorder. Journal of Clinical Psychopharmacology, 22, 347–352. Marton, P., Churchard, M., Kutcher, S., & Korenblum, M. (1991). Diagnostic utility of the beck depression inventory with adolescent psychiatric outpatients and inpatients. Canadian Journal of Psychiatry, 36(6), 428–431. Montgomery, S., Cutler, A., Lazarus, A., Schollin, M., & Brecher, M. (2007). A randomized, placebo-controlled study of once-daily extended release quetiapine fumarate (quitiapine xr) monotherapy in patients with major depressive disorder (mdd). Paper presented at the international forum on mood and anxiety disorders, Budapest, Hungary. Nejtek, V. A. (2002). High and low emotion events influence emotional stress perceptions and are associated with salivary cortisol response changes in a consecutive stress paradigm. Psychoneuroendocrinology, 27(3), 337–352. Paul, G. (1966). Insights vs. desensitization in psychotherapy. Stanford: Stanford University Press.
368
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Pertaub, D., Slater, M., & Barker, C. (2002). An experiment on public speaking anxiety in response to three different types of virtual audience. Presence: Teleoperators and Virtual Environments, 11, 68–78. Philip, N. S., Mello, K., Carpenter, L. L., Tyrka, A. R., & Price, L. H. (2008). Patterns of quetiapine use in psychiatric inpatients: an examination of off-label use. Annals of Clinical Psychiatry, 20(1), 15–20. Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., et al. (2004). Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear. Archives of General Psychiatry, 61(11), 1136–1144. Rowe, D. L. (2007). Off-label prescription of quetiapine in psychiatric disorders. Expert Review of Neurotherapeuties, 7(7), 841–852. Schuler, K., Gilner, F., Austrin, H., & Davenport, D. G. (1982). Contribution of the education phase to stress-inoculation training. Psychological Reports, 51(2), 611–617. Schutters, S. I., van Megen, H. J., & Westenberg, H. G. (2005). Efficacy of quetiapine in generalized social anxiety disorder: results from an open-label study. Journal of Clinical Psychiatry, 66(4), 540–542.
Slater, M., Pertaub, D. P., Barker, C., & Clark, D. M. (2006). An experimental study on fear of public speaking using a virtual environment. Cyberpsychology and Behavior, 9(5), 627–633. Stein, M. B., Walker, J. R., & Forde, D. R. (1996). Public-speaking fears in a community sample. Prevalence, impact on functioning, and diagnostic classification. Archives of General Psychiatry, 53(2), 169–174. Tarico, V., van Velzen, D., & Altmaier, E. (1986). Comparison of thought-listing rating methods. Journal of Counseling Psychology, 31, 81–83. Tillfors, M., & Furmark, T. (2007). Social phobia in Swedish university students: prevalence, subgroups and avoidant behavior. Social Psychiatry and Psychiatric Epidemiology, 42(1), 79–86. Turner, S. M., Beidel, D. C., & Jacob, R. G. (1994). Social phobia: a comparison of behavior therapy and atenolol. Journal of Consulting and Clinical Psychology, 62(2), 350–358. Vaishnavi, S., Alamy, S., Zhang, W., Connor, K. M., & Davidson, J. R. (2007). Quetiapine as monotherapy for social anxiety disorder: a placebo-controlled study. Progress in Neuropsychopharmacology and Biological Psychiatry, 31(7), 1464–1469.
Contents lists available at ScienceDirect
Journal of Anxiety Disorders
Effect of quetiapine vs. placebo on response to two virtual public speaking exposures in individuals with social phobia§ Christopher B. Donahue, Matt G. Kushner *, Paul D. Thuras, Tom G. Murphy, Joani B. Van Demark, David E. Adson Department of Psychiatry, University of Minnesota, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 31 July 2008 Received in revised form 8 December 2008 Accepted 9 December 2008
Objective: Clinical practice and open-label studies suggest that quetiapine (an atypical anti-psychotic) might improve symptoms for individuals with social anxiety disorder (SAD). The purpose of this study was to provide a rigorous test of the acute impact of a single dose of quetiapine (25 mg) on SAD symptoms. Method: Individuals with SAD (N = 20) were exposed to a 4-min virtual reality (VR) public speaking challenge after having received quetiapine or placebo (double-blind) 1 h earlier. A parallel VR challenge occurred 1 week later using a counter-balanced cross-over (within subject) design for the medicationplacebo order between the two sessions. Result: There was no significant drug effect for quetiapine on the primary outcome measures. However, quetiapine was associated with significantly elevated heart rate and sleepiness compared with placebo. Conclusion: Study findings suggest that a single dose of 25 mg quetiapine is not effective in alleviating SAD symptoms in individuals with fears of public speaking. ß 2008 Elsevier Ltd. All rights reserved.
Keywords: Quetiapine Social anxiety Social phobia Virtual reality Public speaking
The DSM-IV (American Psychiatric Association, 1994) describes the core feature of social anxiety disorder (SAD; a.k.a. social phobia) as a strong and persistent fear of embarrassment in social or performance situations (e.g., while eating, writing, and speaking). SAD has been identified as the third most common psychiatric disorder in the United States behind major depression and alcohol use disorder (Hofmann et al., 2006). Lifetime prevalence rate of SAD among the general population has been estimated to be 13% in the National Comorbidity Survey (NCS) (Kessler et al., 1994). However, the more recent National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) puts this estimate at closer to 5% (Grant et al., 2005). The rate of SAD among college students may be even higher than in the general population (Tillfors & Furmark, 2007). Because the most common manifestation of SAD involves fear of public speaking (Mannuzza et al., 1995; Stein, Walker, & Forde, 1996), academic and career opportunities can be missed for many sufferers due to avoidance/intolerance of public speaking. Several pharmacological and psychological therapies have been shown to be at least partially effective in treating individuals with
§ This Investigator Sponsored Trial (IRUSQUET0422) was funded in part by a grant from AstraZeneca Pharmaceuticals LP. Clinical Trials Registration: ClinicalTrials.gov identifier NCT00407199. * Corresponding author at: F282/2A West, 2450 Riverside Avenue, Minneapolis, MN 55455, United States. Tel.: +1 612 273 9809; fax: +1 612 273 9779. E-mail address: [email protected] (M.G. Kushner).
0887-6185/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.janxdis.2008.12.004
SAD (Clark et al., 2003; Davidson et al., 2004; Fava et al., 2001; Freske & Chambless, 1995; Gelernter et al., 1991; Gould, Buckminster, Pollack, Otto, & Yap, 1977). In a 12-week, randomized controlled trial, Gelernter et al. (1991) compared group cognitive behavioral therapy (CBT) alone to pharmacotherapy (phenelzine sulfate, alprazolam or placebo) plus instructions for self-directed exposure to phobic stimuli in the treatment of individuals with SAD. Each group demonstrated comparable clinically significant improvement on the primary outcome measures, with the exception of significant group differences noted in state anxiety, with phenelzine treated patients showing more improvement. At follow-up, phenelzine (medication discontinued) and CBT were the only groups that maintained initial gains, with CBT showing further improvements. Davidson et al. (2004) studied fluoxetine and CBT treatment (both alone and combined) for SAD, reporting that while both treatments are better than placebo, neither was adequate to render a majority of participants symptom free after 14 weeks of treatment. They suggested that additional research on novel SAD treatments is warranted. Although quetiapine was developed to treat psychotic disorders, including bipolar disorder, some recent efforts aimed at anxiety treatment innovation have focused on quetiapine. Regarding the former, a mean dose of 487 mg of quetiapine was used for individuals with schizophrenia in a 3-year retrospective study with side effects that included drug-induced movement disorders and rebound psychosis upon discontinuation (Margolese, Chouinard,
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Beauclair, & Belanger, 2002). Similarly, effective treatment of bipolar disorder with quetiapine requires doses in the range of 300–600 mg daily (Calabrese, 2004). However, anti-anxiety effects might be achieved at significantly lower doses of quetiapine. For example, an open-label trial of quetiapine (flexible dosing 150–300 mg/day) resulted in significant reductions in SAD symptoms (Schutters, van Megen, & Westenberg, 2005). SAD patients who were partial or nonresponders to SSRI therapy reported significant reductions in anxiety in response to adjunctive quetiapine (55.7 31.2 mg daily) (Kinrys et al., 2007). Similarly, significant reductions in anxiety have been reported when using quetiapine (maximum daily dose of 300 mg) as adjunctive therapy with stable SSRI dosing for mixed mood and anxiety disordered patients (Adson, Kushner, Eiben, & Schulz, 2004) and as monotherapy for anxiety symptoms in both GAD and MDD (Bandelow et al., 2007; Brawman-Mintzer, 2006). However, the only placebo controlled trial of quetiapine (147 105 mg) in individuals with SAD found no significant effects (Vaishnavi, Alamy, Zhang, Connor, & Davidson, 2007). In the present study we evaluated the impact of quetiapine (25 mg) vs. placebo in response to a SAD-relevant virtual reality anxiety cue exposure. This dose, while relatively low, is within the bounds of current clinical practice (range 25–200 mg) in managing anxiety (Philip, Mello, Carpenter, Tyrka, & Price, 2008; Rowe, 2007). Further, doses in this range (25 mg and 100 mg) have been shown to result in improved sleep (Cohrs et al., 2004) and decreased cortisol (de Borja Goncalves Guerra, Castel, BeneditoSilva, & Calil, 2005), a biological indicator of stress and anxiety responding (Alpers, Abelson, Wilhelm, & Roth, 2003; Nejtek, 2002). Following the lead of several recent studies (Difede et al., 2007; Hofmann et al., 2006; Ressler et al., 2004), we utilized a virtual reality (VR) environment to accomplish potent and uniform anxiety provocations. Specifically, individuals with SAD that included public speaking fears underwent two VR exposure sessions, 1 week apart, in which they gave a speech to a virtual audience. One hour prior to the first of the two sessions, participants were randomized to take either 25 mg of quetiapine or an identical looking placebo pill. On the second of the two sessions, participants were crossed-over to the other condition. We hypothesized that individuals would react with less self-reported anxiety and physiological reactivity in the active drug condition than in the placebo condition. 1. Method
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ages ranging from 18 to 25. Seventeen of the 22 participants were female (77.3%). The University of Minnesota’s Institutional Review Board’s Human Subjects Committee approved the study protocol. All participants received referral information regarding treatment of their SAD. 1.2. Measures 1.2.1. Personal Report of Confidence as a Speaker (PRCS) The short form of the PRCS (Paul, 1966) is a 30-item questionnaire that asks respondents to endorse as true or false specific statements about their experience during their most recent experience speaking in front of an audience. One point is given for each fear-relevant response allowing for scores to range between 0 (no fear responses are endorsed) and 30 (all fear responses are endorsed) with a recommended clinical cut-off of 16 or greater (Paul, 1966). We used a more conservative clinical cutoff of 21 for study inclusion as recommended by others (Carrigan & Levis, 1999). The PRCS demonstrates adequate psychometric properties (Daly, 1978; Tarico, van Velzen, & Altmaier, 1986), has been used as a screening (Jones, Phillips, & Rieger, 1995) and treatment outcome measure for fear of public speaking (Altmaier, Ross, Leary, & Thornbrough, 1982; Schuler, Gilner, Austrin, & Davenport, 1982) and has proven sensitive to measuring reactivity to virtual audiences (Pertaub, Slater, & Barker, 2002). 1.2.2. Liebowitz Social Anxiety Scale (LSAS) The LSAS (Liebowitz, 1987) is used to evaluate the wide range of social situations that are difficult for individuals with social phobia. The LSAS has demonstrated adequate psychometric properties (Fresco et al., 2001) and has been used as an outcome measure for SAD treatments including CBT (Hofmann et al., 2006) and quetiapine (Schutters et al., 2005). Normative data for the LSAS in social anxiety samples are available. For example, in treatment seeking patients with SAD, Heimberg et al. (1999) reported LSAS total score means = 67.2 (S.D. = 27.5), total fear mean = 35.5 (S.D. = 13.6) and total avoidance mean = 31.6 (S.D. = 14.5). 1.2.3. Beck Depression Inventory (BDI) (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961) The BDI was used as a baseline measure of self-reported symptoms of depression and has demonstrated good psychometric properties (Beck, Steer, & Garbin, 1988; Marton, Churchard, Kutcher, & Korenblum, 1991).
1.1. Participants Participants recruited for this study were full-time college students in the metropolitan area of Minneapolis-St. Paul. Potential participants were identified through advertisements that we placed in campus publications and fliers seeking individuals with a strong fear of public speaking. Inclusion criteria were a current diagnosis of SAD using DSM-IV criteria and clinically significant public speaking fears (see definition below). Exclusion criteria were: (a) current contraindications or a history of sensitivity to quetiapine; (b) current regular use of benzodiazapine, tranquilizer, or antipsychotic medications; (c) an active psychotic, manic, or depressed episode; (d) unstable diabetes mellitus; (e) heart disease; (f) neurologic disorder (by history); or (g) liver disease. Of 111 individuals who responded to recruiting advertisements, 30 could not be reached, 37 were deemed not qualified and 20 were qualified but decided not to participate. Of the 24 participants who were qualified and enrolled, 20 completed the study while two were pilot participants and two were non-completers (one missed session 2 and one discontinued during session 1 due to anxiety). Participants’ mean age was 21.2 years (S.D. = 1.7), with
1.2.4. Stanford Sleepiness Scale (SSS) The SSS (Hoddes, Dement, & Zarcone, 1973) is a time-dependent self-rating of sleepiness and the tendency to fall asleep. The SSS ratings range from 1 (feeling active and vital; alert, wide awake) to 7 (almost in reverie; sleep onset soon; lost struggle to remain awake). The SSS was used to monitor sedation effects of the drug. 1.2.5. Side effects/adverse effects The research assistant (RA) asked patients about adverse effects from study medication post-VR exposure in each session. 1.2.6. Subjective Units of Distress (SUDS) Participants rated their degree of distress on a scale by making a mark along a 100 mm line anchored as 0 = ‘‘none’’ on the left to 100 = ‘‘extreme’’ on the right. A score on the SUDS was generated by measuring the distance (in mm) from the left most anchor (zero) to the patient’s mark (e.g., 75 mm = a score of 75). 1.2.7. Mini-Structured Clinical Interview (Mini-SCID) (First, Gibbon, Williams, & Spitzer, 1990) for social phobia The Mini-SCID was used to confirm diagnosis of social phobia.
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1.2.8. Heart rate (HR) and blood pressure (BP) HR and BP were measured using Omron Healthcare Automatic Blood Pressure monitor and easy wrap cuff (Model HEM-773). 1.3. Procedures 1.3.1. Phone screen A trained RA completed a 15-min telephone screen, including the social phobia module of the Mini-SCID and PRCS, with all participants. Participants who were determined to be eligible and interested were scheduled for a medical evaluation and the first VR exposure session within 1 week of the telephone screen. Individuals meeting full DSM-IV diagnostic criteria for SAD were invited to an interview with a board certified psychiatrist who reviewed and confirmed the Mini-SCID results and obtained psychiatric and medical history pertinent to the study, as described in more detail below. 1.3.2. Medical evaluation Upon arriving for the first study appointment, participants underwent a final screening step with a board certified psychiatrist (author, DA) who obtained a medical and psychiatric history with a focus on detecting mood or thought disorders. Current mania, depression and psychosis were ruled out by history combined with a current mental status exam. No other formal diagnostics were employed; however, individuals completed a number of standardized social anxiety and public speaking fear measures (PRCS, LSAS). 1.3.3. Medication AstraZeneca Pharmaceuticals provided 25 mg quetiapine capsules and matching placebo. These were randomized by our institution’s investigational pharmacy to provide evenly weighted double-blind allotments of placebo vs. quetiapine for study visits one and two. 1.3.4. VR exposure session At the conclusion of the 1-h post-medication waiting period, the subject was moved from the waiting area into the VR exposure laboratory. The procedure is overviewed here: (1) the RA fitted the subject with a head-mounted display visor (HMD; VFX-3D, Interactive Imaging Systems, Rochester, NY) and operated the computer to initiate the virtual speaking environment software (developed by Virtually Better, Decatur, Georgia); (2) through the visor, participants viewed a virtual curtain and podium and heard audience noise in the background ostensibly coming from behind the virtual curtain; (3) participants were presented with one of two speech tasks (scenario A or B described below); (4) participants were given 4 min to prepare for their speech; (5) the virtual curtain was opened and the 4-min speech period was initiated. For both scenarios A and B, the RA presented the following instructions: ‘‘Imagine that you are running for president of the University Government and you will now be speaking in front of a faculty board.’’ For Scenario A, the RA also told the subject to: ‘‘Please consider when preparing your talk the following: why you are a good candidate for this office; what changes in the university you would like to facilitate; how you deal with interpersonal conflicts; and finally, why people should vote for you.’’ For Scenario B, the RA described the same scenario, but asked the subject to focus on: ‘‘an example in which you overcame adversity; how you plan to make the university a better place to go to school; and how you work in team-oriented environments.’’ Once for each of the 4 min of the speech, the RA manipulated features of the VR audience to increase the realistic nature of the speech task. Virtual audience manipulations included a ‘‘receptive’’
audience (e.g., maintained eye contact with the presenter) and audience disruptions (virtual audience member asking a standard question, a cell phone ringing, an audience member leaving the virtual room and slamming door, and an audience member falling asleep). Subjective and physiological measures were obtained four times during the speech (each minute) and immediately after the speech. 1.3.5. Session conclusion Following each exposure session participants were required to arrange for an adult companion to meet them and escort them home due to the possible sedating effects of the study drug. Participants were compensated for transportation costs. 2. Results 2.1. Clinical status at baseline SAD assessments indicated that participants were clinically significantly impaired with mean PRCS scores of 25.7 (S.D. = 2.6), and LSAS scores of 30.4 (S.D. = 14.1) (Fear/Anxiety) and 27.3 (S.D. = 10.7) (Avoidance), which are in excess of the recommended LSAS (Heimberg et al., 1999) and PRCS (Carrigan & Levis, 1999) clinical cut-off scores. 2.2. Medication side effects To quantify the sedative effects of quetiapine, participants were given the SSS before administration of the drug or placebo and then again 1 h later, just prior to the participant’s exposure to the VR speaking task. Scores for the latter administration were significantly higher (indicating more sedation) when participants had taken quetiapine vs. placebo (F(1,38) = 21.5, p < .001, h2 = .361; M = 3.55, S.D. = 1.6 vs. M = 2.28, S.D. = .78). Similarly, the change in mean SSS sedation ratings from before to 1 h after taking medication was significantly greater for the quetiapine (M = 2.35, S.D. = .67 to M = 4.65, S.D. = 1.5) than for the placebo (F(1,18) = 20.6, p < .001, h2 = .53; M = 2.20, S.D. = .89 to M = 2.60, S.D. = .99). The study medication was generally well tolerated; one participant reported dry mouth and another dizziness after talking quetiapine. No adverse effects were reported in the placebo group. 2.3. Response to VR environment 2.3.1. PRCS We evaluated main effects within participants by comparing the post-exposure PRCS scores between the placebo and quetiapine sessions, using baseline PRCS as a covariate. As shown in Fig. 1,
Fig. 1. Group comparisons of speaking fears experienced during the speech provocation (measured by the Personal Report of Confidence as a Speaker, PRCS).
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2.3.2. SUDS ratings Using mixed regression models, we examined change in distress (i.e., SUDS) across a time series within sessions that spanned: (a) the speech preparation period; (b) immediately before the speech; (c) four times during the speech (one per minute); and (d) immediately after the VR speech. These data are depicted in Fig. 2a (session 1) and b (session 2). As can be seen, both groups began both time series with moderate to low subjective anxiety as they began their speech preparation (around 30 on the 100 point scale). In session 1 these ratings rose in both groups reaching a maximum rating of about 60 on the scale by the end of the speech. In session 2, however, the drug group remained
relatively flat in their ratings across the seven time points at around 30 while the placebo group’s ratings ranged between 40 and 50 for most of the latter ratings. Collapsing the sessions to evaluate time effect alone demonstrated a significant effect over the course of the seven time points from the preparatory period until immediately after the speech task, with scores increasing from 29.8 (S.D. = 22.1) immediately prior to task to 53.4 (S.D. = 29.1) immediately after the task (F(6,120) = 13.0, p < .001; effect size h2 = .628). However, given the appearance in the data of a differing pattern of drug effects in the two sessions (see Fig. 2a vs. b) we also statistically tested for a drug-by-session effect to determine whether session carry-over effects were potentially obscuring drug effects for the SUDS ratings. Importantly, this result was not significant (F(1,18) = .34, p < .57, Cohen’s d = .27). However, as with the PRCS, mean SUDS ratings collapsed within the sessions were significantly higher in session 1 than in session 2 (56.0, S.D. = 25.5 vs. 40.5, S.D. = 27.5; F(1,19) = 71.8, p < .001, Cohen’s d = 3.9). Finally, we specifically tested the study hypothesis by evaluating drug vs. placebo effect on SUDS collapsed across sessions. Contrary to study predictions this effect was not significant (F(1,18) = .83, p < .375, Cohen’s d = 0.32).
Fig. 2. Subjective distress (mean S.E.) during VR session comparing drug to placebo: (a) Session 1 and (b) Session 2.
Fig. 3. Systolic blood pressure (mean S.E.) during VR session comparing drug to placebo: (a) Session 1 and (b) Session 2.
both placebo and drug condition PRCS scores were highly similar (placebo M = 22.5, S.D. = 5.7 vs. drug M = 21.9, S.D. = 6.2; effect size Cohen’s d = 0.3). We did find that scores on the PRCS were significantly higher after the first session compared with scores after the second session (M = 23.7, S.D. = 6.0 vs. M = 17.9, S.D. = 6.2; F(1,17) = 29.5, p < .001; effect size Cohen’s d = 1.2). However, there was no significant interaction on the PRCS between drug condition and session, indicating that cross-over (session) effects were not confounding drug effects.
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2.3.3. HR and BP Using mixed regression models we examined change in HR and BP during: (a) the speech preparation period, (b) immediately before, and (c) immediately after the VR speech. Time effects for physiologic measures showed significant response to the VR environment with HR and diastolic BP both increasing over time in the sessions (F(2,40) = 13.0, p < .001 and F(2,40) = 4.8, p < .02, respectively). However, increases in systolic blood pressure did not meet criteria for statistical significance. Collapsing time and session showed that overall BP values were somewhat lower in the drug condition than in the placebo condition although these differences did not reach statistical significance (F(2,40) = 0.8, p = .45; Cohen’s d for systolic = .83, Cohen’s d for diastolic = .87). However, HR was significantly higher when participants were taking the drug (M = 91.4, S.D. = 15.5) compared to when they were taking the placebo (M = 84.2, S.D. = 13.4; F(1,17) = 28.0, p < .001; Cohen’s d = 2.4). Similar to findings for the PRCS and SUDS reported above, both systolic and diastolic BP means were significantly higher during the first session when compared with the second session: systolic means 115.5 (S.D. = 14.2) vs. 109.8 (S.D. = 9.6) (F(1,18) = 12.4, p < .003); diastolic means 82.4 (S.D. = 8.7) vs. 76.9 (S.D. = 8.5) (F(1,18) = 14.9, p < .001). Although HR was higher during the first session than the second (M = 88.9, S.D. = 14.8) vs. (M = 86.4, S.D. = 14.9), this difference did not quite reach significance (F(1,18) = 3.7, p < .07, Cohen’s d = .90). We also observed an interaction between session and drug for systolic BP which was higher for the placebo group as compared with the quetiapine group during the first session (M = 123.7, S.D. = 14.9 vs. 108.1, S.D. = 9.9) but lower than the drug group during the second session (105.1, S.D. = 8.3 vs. 114.7, S.D. = 9.1) (F(1,17) = 6.8, p < .02) (Fig. 3). No other significant interactions were observed. 3. Discussion We found that 25 mg of quetiapine, relative to placebo, did not affect response to a VR public speaking challenge in individuals with social phobia with specific fears of public speaking. This would appear to indicate that quetiapine at this dose does not have significant acute clinical benefits for individuals with social anxiety symptoms. However, before reaching this conclusion we considered several aspects of the methodology that could have affected the results including: (a) the effectiveness of the VR task as a potent elicitor of social anxiety symptoms; (b) the representativeness of SAD cases recruited; (c) the dose of drug; (d) the potential for cross-over effects; (e) the type of anxiety disorder studied; and (f) the possibility of the study being underpowered. Was the VR speech task a potent elicitor of social anxiety symptoms? Our data show that PRCS scores (a validated indicator of level of public speaking fear) obtained within the VR environment were above the most conservative clinical severity cutoffs recommended in the literature (see Section 1). Virtual reality studies with anxiety disorders, including social phobia and specific fear of public speaking, find a high degree of ‘‘presence’’ (i.e., similarity to real world phobic reactions) in VR environments eliciting strong phobic reactions (Cornwell, Johnson, Berardi, & Grillon, 2006; Difede et al., 2007; Hofmann et al., 2006; Ressler et al., 2004; Slater, Pertaub, Barker, & Clark, 2006). Participants in the present study rated the VR exposures as ‘‘moderately similar’’ to actual speaking experiences (10-point Likert scale; mean = 5.7, S.D. = 2.5) and of moderate intensity relative to in vivo experiences (M = 6.1; S.D. = 2.4). These data and those from past studies then support the conclusion that the VR speaking task was reasonably effective in eliciting clinical-level social anxiety symptoms that participants found more similar than not to their ‘‘typical’’ speaking fears.
Were participants representative of individuals with typical SAD symptoms? As noted, participants were young adult college students who met DSM-IV criteria for SAD that included significant public speaking fear. While we have no reason to believe that this population is atypical of other individuals with SAD found in the community, we cannot rule out the possibility that non-college or post-college individuals with SAD would have responded differently in this study. Participants in this study were found to be severely impaired according to PRCS scores relative to other samples (Carrigan & Levis, 1999) and, according to the LSAS, fear and avoidance scores were comparable to treatment seeking patients with SAD (Heimberg et al., 1999). One aspect of the study we did not adequately control, however, was non-drug related treatment status (e.g., CBT). Participants were not screened for, nor excluded if they were actively involved in non-drug therapies (e.g., psychotherapy) for the treatment of SAD. However, because subjects were symptomatic in response to the VR challenge and also served as their own controls in the cross-over design, any such influence upon responses in our study should have been nullified. Could cross-over effects from session 1 to session 2 have obscured drug effects? As noted in Section 1, all participants were in both drug and placebo conditions (within subject) with order being random and counter-balanced, in effect distributing possible contaminating effects evenly between the two drug conditions. Nonetheless, there did appear to be some habituation between sessions 1 and 2 as indicated by significant reductions in several measures across the sessions (without reference to the counterbalanced drug–placebo assignment). However, several aspects of this habituation effect leave us confident that it did not compromise the validity of the study. In the current study anxiety levels (PRCS scores) remained at or above clinical levels for both sessions, consistent with other studies showing fear extinction in individuals with SAD requiring 6–16 sessions (Freske & Chambless, 1995). In similar speech challenge studies for individuals with SAD (Turner, Beidel, & Jacob, 1994), up to 20 exposure sessions were completed in order to achieve habituation. In addition, there were no significant session-by-drug effects. That is, while the overall level of responding in the VR environment was lower in the second session than in the first session, the drug vs. placebo effect was not significantly different across the two sessions. Future research could seek to further minimize cross-over effects by extending the time interval between VR exposure sessions or by using a between subject design requiring only one exposure session. Was the study design adequately powered? This was a pilot study and therefore had power that was only sufficient to find large effects. We do report effect sizes in addition to the results of significance testing. Notably, effects sizes for drug vs. placebo in response to VR challenge were very modest suggesting that even with a larger sample we still would not have observed significant effects. Was the 25 mg dose of quetiapine an adequate dose for the purpose of reducing acute social anxiety reactions in the VR environment? As noted earlier, the dose of quetiapine used in this study is within the bounds of current clinical practice (range 25– 200 mg) in managing anxiety (Philip et al., 2008; Rowe, 2007). Regarding SAD particularly, quetiapine doses up to 300 mg/day (Schutters et al., 2005) and as low as 56 mg/day (Kinrys et al., 2007) have appeared to be therapeutic. However, consistent with our findings, the one double-blind placebo-controlled study addressing this question was negative (dose = 147 105 mg) (Vaishnavi et al., 2007). Nonetheless, because only a single relatively low dose of the drug was used, we cannot judge whether higher or chronic doses of the drug would have been more effective in reducing participants’ social anxiety symptoms in response to the VR challenge. Our study also does not address the combination of drug treatment plus a fuller course of therapeutic exposures sessions
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than the two VR sessions used in this study. Turner et al. (1994) noted therapeutic effects for individuals with SAD following 20 exposure or flooding sessions using in vivo speech challenge in comparison to 16 weeks of atenolol, a beta blocker, with increasing dosing from 25, 50, to 100 mg. The chronic administration of atenolol in this study, in the absence of exposure therapy, was insufficient to treat symptoms of SAD. Future studies that combine a fuller course of exposures with quetiapine could result in enhanced treatment outcomes for SAD. Might quetiapine exert more robust effects for anxiety symptoms stemming from anxiety conditions other than SAD? There is a growing body of literature suggesting that quetiapine is effective in reducing symptoms of generalized anxiety disorder (Adson et al., 2004; Bandelow et al., 2007; Brawman-Mintzer, 2006) and depression (Bauer, Pretorius, Earley, Lindgren, & Brecher, 2007; Montgomery, Cutler, Lazarus, Schollin, & Brecher, 2007). These findings raise the possibility that quetiapine may be more effective in treating symptoms of GAD and depression than SAD. In spite of the limitations noted, our findings are immediately clinically relevant since the use of acute low dosing of quetiapine has been reported to be common in several psychiatric populations. For example, Philip et al. (2008) noted that approximately 1335 of 1912 previously hospitalized psychiatric patients surveyed (nearly 70%) received ‘‘as needed’’ doses of quetiapine, with the most common dose at 50 mg (followed by 25 mg and 100 mg) every 1–2 h for agitation, anxiety, or insomnia. As rigorous studies into the costs and benefits of quetiapine at particular doses for particular populations become increasingly available, it will be important for frontline clinicians to factor these research findings into their off-label therapeutic decision-making. In conclusion, results from this study, in combination with the only other published placebo-controlled study examining quetiapine in SAD (Vaishnavi et al., 2007), suggest that acute, low dosing of quetiapine is not effective in the treatment of SAD symptoms. Future research may consider higher and/or chronic dosing of quetiapine in treating individuals with SAD and should also consider whether quetiapine in combination with CBT is better than either treatment alone. References Adson, D. E., Kushner, M. G., Eiben, K. M., & Schulz, S. C. (2004). Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors. Depress Anxiety, 19(2), 121–126. Alpers, G. W., Abelson, J. L., Wilhelm, F. H., & Roth, W. T. (2003). Salivary cortisol response during exposure treatment in driving phobics. Psychosomatic Medicine, 65(4), 679–687. Altmaier, E., Ross, S., Leary, M., & Thornbrough, M. (1982). Matching stress inoculation’s treatment components to clients’ anxiety mode. Journal of Counseling Psychology, 29, 331–334. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. Bandelow, B., Bobes, J., Ahohas, A., Eggens, I., Liu, S., & Brecher, M. (2007). Results from a phase ii study of once-daily extended release quitiapine fumarate (quitiapine xr) monotherapy in patients with generalized anxiety disorder. Paper presented at the international forum on mood and anxiety disorders, Budapest, Hungary. Bauer, M., Pretorius, H. W., Earley, W., Lindgren, P., & Brecher, M. (2007). Results from a phase ii study of extended release quitiapine fumarate (quetiapine xr) as add-on to antidepressants in patients with major depressive. Paper presented at the international forum on mood and anxiety disorders, Budapest, Hungary. Beck, A. T., Steer, R. A., & Garbin, M. (1988). Psychometric properties of the beck depression inventory: twenty-five years of evaluation. Clinical Psychology Review, 8, 77–100. Beck, A. T., Ward, C. H., Mendelson, M., Mock, J., & Erbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561–571. Brawman-Mintzer, O. (2006). Quetaipine monotherapy in patients with generalized anxiety disorder. Abstract 341. A flexible dose, open-label trial evaluating the efficacy and safety of quetiapine (quetiapine) as adjunctive pharmacotherapy for the treatment of generalized anxiety disorder (gad). Paper presented at the 26th annual conference of the Anxiety Disorders Association of America (ADAA), Miami, Florida. Calabrese, J. R. e. a. (2004). Quetiapine effective against anxiety in bipolar depression. Paper presented at the annual meeting of the American Psychiatric Association, New York.
367
Carrigan, M. H., & Levis, D. J. (1999). The contributions of eye movements to the efficacy of brief exposure treatment for reducing fear of public speaking. Journal of Anxiety Disorders, 13(1–2), 101–118. Clark, D. M., Ehlers, A., McManus, F., Hackmann, A., Fennell, M., Campbell, H., et al. (2003). Cognitive therapy versus fluoxetine in generalized social phobia: a randomized placebo-controlled trial. Journal of Consulting and Clinical Psychology, 71(6), 1058–1067. Cohrs, S., Rodenbeck, A., Guan, Z., Pohlmann, K., Jordan, W., Meier, A., et al. (2004). Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berlin), 174(3), 421–429. Cornwell, B. R., Johnson, L., Berardi, L., & Grillon, C. (2006). Anticipation of public speaking in virtual reality reveals a relationship between trait social anxiety and startle reactivity. Biological Psychiatry, 59(7), 664–666. Daly, J. (1978). The assessment of social-communicative anxiety via self-reports: a comparison of measures. Communcation Monographs, 45, 204–218. Davidson, J. R. T., Fos, E. B., Huppert, J. D., Keefe, F., Franklin, M., Compton, J., et al. (2004). Fluoxetine, comprehensive cbt and placebo in generalized social phobia. Archives of General Psychiatry, 13, 423–428. de Borja Goncalves Guerra, A., Castel, S., Benedito-Silva, A. A., & Calil, H. M. (2005). Neuroendocrine effects of quetiapine in healthy volunteers. International Journal of Neuropsychopharmacology, 8(1), 49–57. Difede, J., Cukor, J., Jayasinghe, N., Patt, I., Jedel, S., Spielman, L., et al. (2007). Virtual reality exposure therapy for the treatment of posttraumatic stress disorder following September 11, 2001. Journal of Clinical Psychiatry, 68(11), 1639–1647. Fava, G. A., Grandi, S., Rafanelli, C., Ruini, C., Conti, S., & Belluardo, P. (2001). Longterm outcome of social phobia treated by exposure. Psychological Medicine, 31(5), 899–905. First, M. B., Gibbon, M., Williams, J. B. W., & Spitzer, R. L. (1990). Mini-skid. Multi-Health Systems Inc. Fresco, D. M., Coles, M. E., Heimberg, R. G., Liebowitz, M. R., Hami, S., Stein, M. B., et al. (2001). The Liebowitz social anxiety scale: a comparison of the psychometric properties of self-report and clinician-administered formats. Psychological Medicine, 31(6), 1025–1035. Freske, U., & Chambless, D. L. (1995). Cognitive-behavioral vs. exposure only treatments for social phobia. Behavior Therapy, 26, 695–720. Gelernter, C. S., Uhde, T. W., Cimbolic, P., Arnkoff, D. B., Vittone, B. J., Tancer, M. E., et al. (1991). Cognitive-behavioral and pharmacological treatments of social phobia. A controlled study. Archives of General Psychiatry, 48(10), 938–945. Gould, R. A., Buckminster, S., Pollack, M. H., Otto, M. W., & Yap, L. (1977). Cognitivebehavioral and pharmacological treatment of social phobia: a meta-analysis. Clinical Psychology and Scientific Practice, 4, 291–306. Grant, B. F., Hasin, D. S., Blanco, C., Stinson, F. S., Chou, S. P., Goldstein, R. B., et al. (2005). The epidemiology of social anxiety disorder in the United States: results from the national epidemiologic survey on alcohol and related conditions. Journal of Clinical Psychiatry, 66(11), 1351–1361. Heimberg, R. G., Horner, K. J., Juster, H. R., Safren, S. A., Brown, E. J., Schneier, F. R., et al. (1999). Psychometric properties of the liebowitz social anxiety scale. Psychological Medicine, 29(1), 199–212. Hoddes, E., Dement, W. C., & Zarcone, V. (1973). The development and use of the Stanford sleepiness scale (sss). Psychophysiology, 10, 431–436. Hofmann, S. G., Meuret, A. E., Smits, J. A., Simon, N. M., Pollack, M. H., Eisenmenger, K., et al. (2006). Augmentation of exposure therapy with d-cycloserine for social anxiety disorder. Archives of General Psychiatry, 63(3), 298–304. Jones, G., Phillips, G., & Rieger, E. (1995). Effects of cardiac awareness, public speaking anxiety, and physiological ‘‘priming’’ on state-trait anxiety (state) and feelings of apprehension. Psychophysiology, 32(Suppl.), S43. Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., et al. (1994). Lifetime and 12-month prevalence of dsm-iii-r psychiatric disorders in the United States. Results from the national comorbidity survey. Archives of General Psychiatry, 51(1), 8–19. Kinrys, G., Nery, F., Vasconcelos, D., Rothstein, E., Dunn, R., Bianco, R., et al. (2007). Quetiapine augmentation of ssris for treatment refractory of social anxiety disorder (sad). Paper presented at the Poster presented at the 2th European College of Neuropsychopharmacology, Vienna Austria. Liebowitz, M. R. (1987). Social phobia. Modern Problems of Pharmacopsychiatry, 22, 141–173. Mannuzza, S., Schneier, F. R., Chapman, T. F., Liebowitz, M. R., Klein, D. F., & Fyer, A. J. (1995). Generalized social phobia Reliability and validity. Archives of General Psychiatry, 52(3), 230–237. Margolese, H. C., Chouinard, G., Beauclair, L., & Belanger, M. C. (2002). Therapeutic tolerance and rebound psychosis during quetiapine maintenance monotherapy in patients with schizophrenia and schizoaffective disorder. Journal of Clinical Psychopharmacology, 22, 347–352. Marton, P., Churchard, M., Kutcher, S., & Korenblum, M. (1991). Diagnostic utility of the beck depression inventory with adolescent psychiatric outpatients and inpatients. Canadian Journal of Psychiatry, 36(6), 428–431. Montgomery, S., Cutler, A., Lazarus, A., Schollin, M., & Brecher, M. (2007). A randomized, placebo-controlled study of once-daily extended release quetiapine fumarate (quitiapine xr) monotherapy in patients with major depressive disorder (mdd). Paper presented at the international forum on mood and anxiety disorders, Budapest, Hungary. Nejtek, V. A. (2002). High and low emotion events influence emotional stress perceptions and are associated with salivary cortisol response changes in a consecutive stress paradigm. Psychoneuroendocrinology, 27(3), 337–352. Paul, G. (1966). Insights vs. desensitization in psychotherapy. Stanford: Stanford University Press.
368
C.B. Donahue et al. / Journal of Anxiety Disorders 23 (2009) 362–368
Pertaub, D., Slater, M., & Barker, C. (2002). An experiment on public speaking anxiety in response to three different types of virtual audience. Presence: Teleoperators and Virtual Environments, 11, 68–78. Philip, N. S., Mello, K., Carpenter, L. L., Tyrka, A. R., & Price, L. H. (2008). Patterns of quetiapine use in psychiatric inpatients: an examination of off-label use. Annals of Clinical Psychiatry, 20(1), 15–20. Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., et al. (2004). Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear. Archives of General Psychiatry, 61(11), 1136–1144. Rowe, D. L. (2007). Off-label prescription of quetiapine in psychiatric disorders. Expert Review of Neurotherapeuties, 7(7), 841–852. Schuler, K., Gilner, F., Austrin, H., & Davenport, D. G. (1982). Contribution of the education phase to stress-inoculation training. Psychological Reports, 51(2), 611–617. Schutters, S. I., van Megen, H. J., & Westenberg, H. G. (2005). Efficacy of quetiapine in generalized social anxiety disorder: results from an open-label study. Journal of Clinical Psychiatry, 66(4), 540–542.
Slater, M., Pertaub, D. P., Barker, C., & Clark, D. M. (2006). An experimental study on fear of public speaking using a virtual environment. Cyberpsychology and Behavior, 9(5), 627–633. Stein, M. B., Walker, J. R., & Forde, D. R. (1996). Public-speaking fears in a community sample. Prevalence, impact on functioning, and diagnostic classification. Archives of General Psychiatry, 53(2), 169–174. Tarico, V., van Velzen, D., & Altmaier, E. (1986). Comparison of thought-listing rating methods. Journal of Counseling Psychology, 31, 81–83. Tillfors, M., & Furmark, T. (2007). Social phobia in Swedish university students: prevalence, subgroups and avoidant behavior. Social Psychiatry and Psychiatric Epidemiology, 42(1), 79–86. Turner, S. M., Beidel, D. C., & Jacob, R. G. (1994). Social phobia: a comparison of behavior therapy and atenolol. Journal of Consulting and Clinical Psychology, 62(2), 350–358. Vaishnavi, S., Alamy, S., Zhang, W., Connor, K. M., & Davidson, J. R. (2007). Quetiapine as monotherapy for social anxiety disorder: a placebo-controlled study. Progress in Neuropsychopharmacology and Biological Psychiatry, 31(7), 1464–1469.