Acute anxiolytic effects of quetiapine during virtual reality exposure—A double-blind placebo-controlled trial in patients with specific phobia

European Neuropsychopharmacology (2013) 23, 1551–1560

www.elsevier.com/locate/euroneuro

Acute anxiolytic effects of quetiapine during virtual reality exposure—A double-blind placebo-controlled trial in patients with specific phobia Julia Diemera, Katharina Domschkea,b, Andreas M¨ uhlbergerc, Bernward Wintera, Maxim Zavorotnyya, Swantje Notzona, Karen Sillinga, Volker Arolta, Peter Zwanzgera,n a

Department of Psychiatry, University of Muenster, Germany Department of Psychiatry, University of Wuerzburg, Germany c Department of Psychology, University of Wuerzburg, Germany b

Received 20 September 2012; received in revised form 4 December 2012; accepted 5 January 2013

KEYWORDS

Abstract

Quetiapine; Anxiety disorders; Challenge; Virtual reality; Psychophysiology; COMT

Anxiety disorders are among the most frequent psychiatric disorders. With regard to pharmacological treatment, antidepressants, the calcium modulator pregabalin and benzodiazepines are recommended according to current treatment guidelines. With regard to acute states of anxiety, so far practically only benzodiazepines provide an immediate anxiolytic effect. However, the risk of tolerance and dependency limits the use of this class of medication. Therefore, there is still a need for alternative pharmacologic strategies. Increasing evidence points towards anxiety-reducing properties of atypical antipsychotics, particularly quetiapine. Therefore, we aimed to evaluate the putative acute anxiolytic effects of this compound, choosing the induction of acute anxiety in patients with specific phobia as a model for the evaluation of ad-hoc anxiolytic properties in a proof-of-concept approach. In a randomized, double-blind, placebo-controlled study, 58 patients with arachnophobia were treated with a single dose of quetiapine XR or placebo prior to a virtual reality spider challenge procedure. Treatment effects were monitored using rating scales for acute anxiety as well as measurements of heart rate and skin conductance. Overall, quetiapine showed significant anxiolytic effects compared to placebo. However, effects were not seen on the primary outcome measure (VAS Anxiety), but were limited to somatic anxiety symptoms. Additionally, a significant reduction of skin conductance was observed. Further exploratory analyses hint towards a

n

Correspondence to: Mood and Anxiety Disorders Research Unit, Department of Psychiatry, University of Muenster, Albert-Schweitzer-Str. 11, 49149 M¨ unster, Germany. Tel.: +49 251 83 566 13; fax: +49 251 83 566 12. E-mail addresses: [email protected], [email protected] (P. Zwanzger) 0924-977X/$ - see front matter & 2013 Elsevier B.V. and ECNP. All rights reserved. http://dx.doi.org/10.1016/j.euroneuro.2013.01.001

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J. Diemer et al. mediating role of the (COMT) val158met genotype on treatment response. The present results thus suggest a possible suitability of quetiapine in the acute treatment of anxiety, particularly with regard to somatic symptoms. & 2013 Elsevier B.V. and ECNP. All rights reserved.

1.

Introduction

Anxiety disorders are among the most frequent psychiatric disorders (Kessler et al., 2005; Wittchen et al., 2011), conferring a marked economic burden due to their high prevalence and chronicity (Olesen et al., 2012). Treatment options comprise psychotherapeutical — primarily cognitive-behavioural therapy — as well as psychopharmacological interventions (Bandelow et al., 2008; Diemer et al., 2010). With regard to pharmacotherapy, antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs) and the calcium modulator pregabalin represent the first-line therapy for most anxiety disorders according to current treatment guidelines (Bandelow et al., 2008). However, although usually effective and well tolerated, up to 30% of patients do not respond to first treatment or suffer from side effects (Barlow, 2002). Delayed onset of action represents a major disadvantage of this class of medication (Bandelow et al., 2008). On the other hand, fast-acting benzodiazepines, mostly used for the treatment of acute anxiety and severe panic attacks, bear the risk of tolerance and dependency (Lader, 2011). Therefore, there is still a need for alternative pharmacological strategies. In this context, an increasing number of reports points towards anxiolytic properties of atypical neuroleptics in anxiety disorders (for reviews see Gao et al., 2006; Maher et al., 2011). For example, single or add-on therapy with olanzapine resulted in a significant reduction in anxiety symptoms in patients with GAD and social phobia (Barnett et al., 2002; Pollack et al., 2006), and ziprasidone was equally anxiolytic as diazepam in a study of healthy subjects with dental anxiety (Wilner et al., 2002). Compared to other atypical antipsychotics, quetiapine has shown particular potential as a possible anxiolytic agent (Maher et al., 2011). Quetiapine was reported to be beneficial in reducing anxiety symptoms in patients with social phobia in two small studies over the course of 12 and 8 weeks, respectively (Schutters et al., 2005; Vaishnavi et al., 2007). More recently, a double-blind placebo-controlled trial has shown that a once-daily quetiapine XR monotherapy at 50 and 150 mg/day is effective in improving anxiety symptoms in patients with GAD already after 4 days (Bandelow et al., 2010); similar results for 150 and 300 mg/day of quetiapine XR in GAD confirm these findings (Merideth et al., 2012). Quetiapine XR has also been shown to be an effective maintenance therapy for GAD (Katzman et al., 2011). A recent Cochrane review concludes that the efficacy of quetiapine may be comparable to that of antidepressants for GAD, while the rates of drop-outs and side effects, particularly weight gain and sedation, are higher (Depping et al., 2010). Beneficial effects of drugs modulating not only the serotonergic and noradrenergic, but also the dopaminergic

system might be expected. There is evidence from both a pathobiological/-physiological and a genetic perspective that — partly linked with serotonergic dysfunction — altered dopaminergic neurotransmission might play an important role in the pathogenesis of anxiety disorders (Hettema et al., 2008). In particular, a specific role for the dopamine catabolising enzyme catecholamine-Omethyltransferase (COMT), which differentially influences phasic and tonic dopaminergic firing (Bilder et al., 2004), has been suggested for phobic anxiety and panic disorder. Significantly elevated erythrocyte COMT activity has been reported in patients with anxiety states (Shulman et al., 1978), and COMT inhibitors are effective in the treatment of anxiety symptoms in Parkinson’s disease (Richard et al., 1996). Also, molecular studies have suggested association mostly of the more active val allele of the COMT val158met polymorphism with panic disorder and phobic anxiety (Domschke et al., 2007; Hamilton et al., 2002; McGrath et al., 2004). In view of the evidence pointing towards anxiolytic effects of quetiapine and advantages over antidepressants with regard to onset of action (Depping et al., 2010), we conducted a proof-of-concept study to further explore the acute anxiolytic properties of quetiapine. Experimental induction of anxiety in patients with specific phobia was used as a paradigmatic model suited for the investigation of acute anxiety states, which can be readily provoked in phobic patients by an anxiety-relevant challenge. We employed a Virtual Reality (VR) challenge, which offers maximum standardisation. VR challenges have been shown to provoke both intense subjective fear (e.g., Cornwell et al., 2011; Freire et al., 2010; M¨ uhlberger et al., 2005) and typical behavioural avoidance associated with anxiety disorders (M¨ uhlberger et al., 2008). Quetiapine XR was chosen due to its greater tolerability, enabling us to avoid confounds with undesired drug effects. Further, our study design included two challenge procedures on the same day (results of an fMRI experiment not reported here), which required a duration of medication effects of 5–7 h. We hypothesised subjective and objective anxiety symptoms to be significantly lower following quetiapine vs. placebo treatement. Additionally, a modulating effect of the COMT val158met genotype on anxiety levels and treatment outcome was expected.

2.

Experimental procedures

This is a double-blind, randomized, placebo-controlled parallelgroup study designed to test the acute anxiolytic properties of a single dose of 100 mg quetiapine XR or placebo in patients with arachnophobia. The study was approved by the local ethics ¨ rztekammer Westfalen-Lippe committee (Ethikkommission der A und der Medizinischen Fakult¨ at der WWU M¨ unster). Written informed consent was obtained from all participants.

Acute anxiolytic effects of quetiapine during virtual reality exposure Patients were recruited via local advertisements. Subjects had to be between 18 and 70 years of age and fulfill DSM-IV-TR (American Psychiatric Association, 2000) diagnostic criteria of specific phobia. Diagnosis and comorbidity were assessed with the SCID interview (First et al., 1996) and the M.I.N.I. (Sheehan et al., 1998), respectively, by a licensed psychologist. Women of childbearing potential had to be using an effective method of birth control (Pearl indexo1%). Primary outcome measure was a Visual Analogue Scale (VAS) of subjective Anxiety. We employed further VAS for Anxiety Expectancy, Avoidance, Tension, and Sedation. Further outcome measures were the Fear of Spiders Questionnaire (FSQ; Szymanski and O’Donohue, 1995); the Beck Anxiety Inventory (BAI; Beck et al., 1988); and the Acute Panic Inventory (API; Dillon et al., 1987), which consists of three subscales: physical symptoms, cognitive symptoms, and a fear subscale (Goetz et al., 1996). We also administered the Profile of Mood States (POMS; McNair et al., 1992). As for trait measures, we employed the Anxiety Sensitivity Index (ASI; Reiss et al., 1986), and the Questionnaire for the Assessment of Disgust Sensitivity (Fragebogen zur Ekelempfindlichkeit, FEE) by Schienle et al. (2002). All questionnaires were administered at baseline and immediately after the VR challenge. At the latter assessment, subjects were instructed to rate symptoms retrospectively for the most aversive moment during the VR challenge. ASI and FEE were presented at baseline only. During VR, Subjective Units of Discomfort Scale (SUDS) measurements on a scale from 0 to 10, with 10 indicating maximum fear, were taken orally 60 s into each of the four conditions. During each VR scene, a Behavioural Approach Test (BAT) was conducted (see below). Electrodes for heart rate (HR) measurement (Red Dots, 3 M) were placed on the upper third of the sternum and on the lower rib on the left. The reference electrode was positioned centrally on the forehead; the ground electrode was attached to the left mastoid process (sintered Ag/AgCl electrodes). Two electrodes for electrodermal activity (EDA) measurement (sintered Ag/AgCl electrodes) were placed on the thenar and hypothenar of the non-dominant hand. During VR, physiological measures (HR, EDA) were continuously monitored, using V-Amp 16 (BrainProducts, Gilching, Germany), and BrainVision Recorder Software (V-Amp Edition 1.10, Brain Products GmbH, Gilching, Germany). Subjects visited the study centre twice. At the screening visit, subjects underwent psychiatric examination, screening of inclusion/exclusion criteria, laboratory routine testing and electrocardiogram (ECG). A venous EDTA blood sample was taken for genetic analysis. All subjects had to refrain from alcohol or caffeine intake 24 h preceding study procedures. On the study day, subjects arrived at 8:30 am and underwent a physical and neurological examination including vital signs, a check for concomitant medication, a urinary drug screen, and a pregnancy test (women). Baseline questionnaires were filled in. Study medication was dispensed at 9:00 am. At 3:00 pm subjects underwent an fMRI scan (results not reported here). At 5:00 pm the VR exposure challenge was performed. Subjects were seated, and recording electrodes were fitted. Subjects were equipped with head-mounted display and earphones, and the experimental room was darkened for the VR challenge. The VR environment (created with Source Engine, Valve Corporation, Bellevue, Washington, USA) was presented monoscopically using a Z800 3D Visor head-mounted display (800  600 pixels, eMagin, Bellevue, Washington, USA). Head movements were assessed using the Patriot electromagnetic tracking device (Polhemus Corporation, Colchester, Vermont, USA). The simulation was controlled by the CyberSession software built at the Psychological Department of the University of Wuerzburg (www.cybersession. info). The VR challenge consisted of four scenes. A laboratory room with a white table at the far end served as a neutral practice scene. For baseline measurements, this scene was shown again, followed

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by three spider scenes of increasing aversiveness. Each scene consisted of 180 s of passive viewing, during which SUDS ratings were given after 60 s. After passive viewing, patients were requested to approach the spiders via a portable game pad (BAT). Participants were genotyped for the functional COMT val158met polymorphism (Domschke et al., 2004). Genotypes were determined by investigators blinded for outcome measures. For further analyses, genotypes were grouped according to functionality and to previous findings in anxiety-related phenotypes suggesting a recessive model for the G allele (GG=val/val vs. AG/AA=val/met and met/met; cf. Domschke et al., 2004). Physiological data were pre-analysed with BrainVision Analyser Software 2.0 (Brain Products GmbH, Gilching, Germany). Mean HR (beats per minute) and mean skin conductance levels (SCL; mS) during the initial 110 s of each challenge condition, excluding speaking time for SUDS ratings, were calculated. Statistical analyses were calculated with IBM SPSS Statistics 20 software. Pearson correlations were obtained between baseline measures and outcome variables to discover possible covariates. To assess the anxiogenic effects of the VR challenge, repeatedmeasure analysis of covariance (RM-ANCOVA) of the online measures SUDS and BAT was used with treatment (quetiapine vs. placebo) as a between-subjects factor and time (baseline, spider scenes) as a within-subjects factor. To evaluate the effects of quetiapine on outcome, we conducted a multivariate analysis of covariance (MANCOVA) of the mean change from baseline of the total scores of all questionnaire measures with treatment (quetiapine vs. placebo) as the between-subjects factor. To determine the sources of overall treatment effects, post-hoc F-Tests were conducted on group means adjusted for covariate(s). For measures with more than two time points (SUDS, BAT, and physiology), separate repeatedmeasure analyses of (co)variance (RM-AN(C)OVA) were conducted with treatment (quetiapine vs. placebo) as a between-subjects factor and time (baseline, spider scenes) as a within-subjects factor. Baseline variables were included as covariates if they differed between the treatment groups at po0.10 and correlated with the outcome measures in question. Post-hoc, exploratory ANOVAs of the effects of COMT val158met genotype were conducted.

3.

Results

We screened 112 prospective participants. Sixty patients met inclusion criteria and were included in the study. Fiftyeight subjects took part in the VR challenge. The flow of participants is shown in Figure 1. Demographic data and baseline measures are given in Table 1. Baseline scores did not differ between the groups except VAS Tension and, on a trend level, FSQ. Patients in the quetiapine group were tenser at baseline and more fearful of spiders than subjects in the placebo group. Correlations of baseline trait measures (ASI, FEE), baseline VAS Tension, baseline FSQ and outcome measures are provided in Table 2. There was no significant correlation between baseline measures and physiological responses. We found baseline FSQ, but not baseline VAS Tension, to significantly correlate with most questionnaire and BAT outcome measures. Both baseline FSQ and baseline VAS Tension correlated with SUDS. Complete SUDS ratings were available from n= 51 subjects. The VR challenge produced a marked increase in anxiety (see Table 3), as shown by a significant main effect of condition (baseline, scenes 1, 2, and 3) at po0.001 (F3,45 =7.780) in the RM-ANCOVA (covariates: baseline FSQ

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J. Diemer et al.

Figure 1

Flow of participants.

and VAS Tension). As seen in the BAT (see Table 3), the VR challenge produced behavioural avoidance (data available from n =55 subjects), as shown by a significant main effect of condition (baseline, scenes 1 and 2) at po0.001 (F2,51 =17.190) in the RM-ANCOVA (covariate: baseline FSQ). The MANCOVA of the mean changes from baseline of the questionnaire scale scores (covariate: baseline FSQ) yielded an overall significance for group differences of p=0.001 (F13,43 = 3.716). As expected, baseline FSQ was confirmed as a significant overall covariate (F13,43 =4.046; po0.001). The results of the post-hoc F-Tests are summarised in Table 4. There was no treatment effect on the primary outcome measure VAS Anxiety. Quetiapine significantly reduced mean change scores on the scales API-Physical, BAI, and VAS Tension (see Table 4). The RM-ANCOVA of SUDS returned no significant main effect of group, while the interaction group  time was statistically significant at p= 0.020 (F3,45 =3.636), indicating that fear increased significantly more in the placebo than the quetiapine group. The RM-ANCOVA of the BAT revealed no significant group differences. Full datasets for HR were available from n= 42 subjects. The RM-ANOVA of mean HR yielded a significant main effect of time (F3,38 =6.188; p= 0.002), but no further significant effects. Complete data sets of SCL were available from n=39 subjects. The RM-ANOVA revealed significant main effects of time (F3,35 =13.163; po0.001) and group (F1 =18.322; po0.001); the interaction group  time was not significant. Data from n =56 Caucasian subjects were analysed. Hardy-Weinberg criteria, assessed with the online available programme DeFinetti (Wienker and Strom, accessed on May 9th 2012 on http://ihg.gsf.de/cgi-bin/hw/hwa1.pl), were

fulfilled for COMT val158met genotype distribution in the present sample (met/met ( =AA): N=20, val/met ( =AG): N =26, val/val ( =GG): N =10; p=0.78) (see Table 1). COMT val158met genotype distribution did not differ between treatment groups (see Table 1). We discerned an effect of COMT genotype on baseline VAS Anxiety (F1,54 =10.234; p=0. 002) and baseline FSQ (F1,54 =9.447; p= 0.003), with GG (val/ val) genotype carriers displaying significantly higher anxiety levels than the carriers of at least one A allele (val/met and met/met genotype carriers). Based on these findings, we analysed the impact of COMT val158met genotype on quetiapine effects for both measures. RM-ANOVA of VAS Anxiety revealed a main effect of COMT genotype (F1 =9. 581; p=0.003) but no further effects. RM-ANOVA of FSQ indicated a significant three-way interaction (F1,52 =5.351; p =0.025) implicating the GG (val/val) genotype to confer a better response to quetiapine as compared to the AG/AA (val/met and met/met) genotypes. While FSQ increased from baseline to VR challenge in the placebo group by 15.77 points for the AG/AA (val/met and met/met) genotypes, and 23.33 points for the GG (val/val) genotype, in the quetiapine group, FSQ increased by 18.14 points for the AG/ AA (val/met and met/met) genotypes, while the average change for the GG (val/val) genotype was 1.86 points (i.e., a slight decrease). Quetiapine was well tolerated by most patients. Number and severity of AEs did not differ between the groups. The most frequent AEs were headache (quetiapine: n =4, placebo: n=5), followed by nausea (quetiapine: n =0, placebo: n=2), weakness (quetiapine: n =2, placebo: n =0), and backache (quetiapine: n =0, placebo: n=1). The side effect profile observed is in line with reports in other trials investigating quetiapine in anxiety (Stein et al., 2011).

Acute anxiolytic effects of quetiapine during virtual reality exposure

Table 1

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Demographic and baseline measures of the study sample.

Sample characteristics Gender Female Male COMT genotype val(G)158met(A) AA AG GG Baseline measures Age ASI FEE VAS Anxiety VAS Anxiety Expectancy VAS Avoidance VAS Tension VAS Sedation BAI FSQ POMS Dejection POMS Fatigue POMS Vigour POMS Hostility API Physical API Cognitive API Fear

Placebo (n= 29)

Quetiapine (n = 29)

Total (n = 58)

%

%

%

79.3 20.7

n

23 6

n

82.2 17.2

24 5

81.0 19.0

n

w2

df

p

0.112

1

0.738a

2.215

2

0.330a

df 56 56 45.3 56 56 56 56 56 56 56 56 56 56 56 56 56 56

p 0.567 0.397 0.718 0.878 0.429 0.537 0.023 0.499 0.189 0.061 0.192 0.228 0.843 0.867 0.422 0.425 0.607

47 11

35.7 53.6 10.7

10 15 3

35.7 39.3 25.0

10 11 7

35.7 46.4 17.9

20 26 10

M 25.59 12.93 77.25 13.38 28.00 66.34 24.24 21.52 2.97 58.65 4.10 7.59 17.10 1.07 0.93 0.76 0.97

SD 5.31 6.81 25.15 22.57 25.39 27.48 22.50 20.41 2.96 17.84 5.12 6.36 8.85 2.58 1.16 1.09 0.87

M 26.55 11.34 79.22 14.21 32.76 61.86 37.38 25.55 4.41 66.66 5.87 9.93 16.69 0.97 1.21 1.00 0.86

SD 7.30 7.36 14.80 18.21 19.73 27.43 20.41 24.56 5.07 13.73 5.08 8.18 6.87 2.10 1.42 1.20 0.64

M 26.07 12.14 78.23 13.79 30.38 64.10 30.81 23.53 3.69 62.65 4.99 8.76 16.90 1.02 1.07 0.88 0.91

SD 6.34 7.07 20.47 20.33 22.66 27.31 22.30 22.48 4.18 16.29 5.13 7.35 7.85 2.33 1.30 1.14 0.76

API, Acute Panic Inventory; ASI, Anxiety Sensitivity Index; BAI, Beck Anxiety Inventory; FSQ, Fear of Spiders Questionnaire; FEE, Questionnaire for the Assessment of Disgust Sensitivity; VAS, Visual Analogue Scale; POMS, Profile of Mood States. a Pearson w2.

4.

Discussion

This study aimed to investigate the putative acute anxiolytic effects of quetiapine in a proof-of-concept design using phobic anxiety as a model of pathological anxiety. In a randomised, double-blind placebo-controlled study, a single dose of 100 mg quetiapine XR was administered to patients with arachnophobia prior to a VR exposure challenge. Overall, the experimental induction of anxiety using a VR challenge had significant anxiogenic effects. This is in line with previous studies. A reliable, strong and significant anxiety response was produced by VR challenges in patients with anxiety disorders including specific phobia (e.g., M¨ uhlberger et al., 2005), social anxiety disorder (Cornwell et al., 2011), and panic disorder (Freire et al., 2010). Like M¨ uhlberger et al. (2008), we found a pronounced effect of the VR challenge on behavioural avoidance. Moreover, in our study the VR challenge was associated with a marked psychophysiological reaction. Although only few studies so far have focused on psychophysiological reactivity during VR, existing data indicate marked EDA responses to VR challenge procedures (e.g., Freire et al., 2010; M¨ uhlberger et al., 2005).

With regard to treatment effects of quetiapine, our results show that single-dose treatment led to a significant reduction in anxiety reported by the patients. However, anxiolytic effects were only found in questionnaires and scales measuring somatic anxiety, while significant effects on psychic anxiety were found in only one (SUDS) of a range of measures. As regards physiological measures, an effect on EDA was observed, while no effects were seen in HR. Nonetheless, our results point towards an anxiolytic potency of quetiapine and are consistent with previous studies suggesting that quetiapine has the potential to reduce anxiety in social phobia (Vaishnavi et al., 2007), bipolar disorder (Calabrese et al., 2005), and GAD (Bandelow et al., 2010; Merideth et al., 2012). In the latter studies, both somatic and psychic anxiety symptoms were reduced under 50 mg and 150 mg quetiapine XR. In the literature, significant anxiolytic action of quetiapine has been reported at least at day 4 in patients with GAD (Bandelow et al., 2010; Merideth et al., 2012). In our study the effects were observed within hours after single dose administration, indicating fast acting anxiolytic properties of quetiapine, which so far have not been investigated. So far, such rapid anxiolytic action can almost only be obtained with

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Table 2

Correlations between baseline and challenge measures for (a) questionnaires and (b) online measures.

(a)

Baseline

Challenge

ASI FEEa FSQ VAS Tension

VAS Anxiety

VAS Anxiety Expectancy

VAS Avoidance

VAS Tension

BAI

API Physical

API Cognitive

API Fear

FSQ

0.187 0.259 0.403 0.164

0.254 0.189 0.379 0.313

0.061 0.247 0.332 0.181

0.241 0.166 0.346 0.174

0.176 0.335 0.513 0.152

0.083 0.193 0.407 0.112

0.122 0.068 0.221 0.033

0.253 0.142 0.196 0.123

0.220 0.281 0.585 0.202

n = 58. (b)

Baseline

n = 51 (SUDS); n = 55 (BAT).

Challenge

ASI FEEb FSQ VAS Tension

SUDS neut

SUDS 1

SUDS 2

SUDS 3

BAT neut

BAT 1

BAT 2

0.026 0.223 0.089 0.386

0.192 0.429 0.491 0.488

0.073 0.357 0.551 0.322

0.096 0.327 0.456 0.236

0.255 0.251 0.152 0.018

0.178 0.157 0.394 0.223

0.238 0.061 0.269 0.054

n=51 (SUDS); n=55 (BAT). ASI, Anxiety Sensitivity Index; API, Acute Panic Inventory; BAI, Beck Anxiety Inventory; BAT, Behavioural Approach Test; FSQ, Fear of Spiders Questionnaire; FEE, Questionnaire for the Assessment of Disgust Sensitivity; neut, neutral; SUDS, Subjective Units of Discomfort Scale; VAS, Visual Analogue Scale. n po0.05. nn po0.01. a n=57. b n=50 (SUDS)/n=54 (BAT).

J. Diemer et al.

Acute anxiolytic effects of quetiapine during virtual reality exposure

Table 3 Means and standard deviations (SD) of SUDS and BAT during VR challenge. Veruma Mean SUDS (0–10)

BAT (Approach in m)

Baseline Spider scene 1 Spider scene 2 Spider scene 3

SD

Placebob Mean

SD

1.33 1.37 0.74 .98 3.13 1.65 2.85 1.99 5.98 1.97 5.63 2.40 7.44 1.99 7.56 2.17

Baseline 2.20 0.94 2.14 1.05 Spider scene 1.56 0.84 1.62 0.83 1 Spider scene 0.40 0.41 0.48 0.41 2

BAT, Behavioural Approach Test; SUDS, Subjective Units of Discomfort Scale. a SUDS: n=24; BAT: n=28. b SUDS: n=27; BAT: n=27.

Table 4 Results of ANCOVA for questionnaire change scores (challenge minus baseline). Verum (n =29)

Placebo (n = 29)

Mean D SEM Mean D SEM VAS Anxiety VAS Anxiety Expectancy VAS Avoidance VAS Tension VAS Sedation BAI API Physical API Cognitive API Fear POMS Dejection POMS Fatigue POMS Vigour POMS Hostility

51.10 4.96 21.48 5.88 22.48 31.97 0.55 7.59 1.72 2.86 0.79 21.97 5.03 9.79 4.21

FSQ

13.24 3.08

ANCOVAa

p-value

53.48 5.39 0.489 29.24 5.63 0.203

4.85 13.76 6.37 4.84 46.38 6.02 4.55 6.90 5.43 1.50 12.31 2.02 0.47 3.14 0.65 0.52 2.56 0.45 0.20 0.48 0.25 2.56 17.30 3.37 1.68 5.48 2.28 1.02 11.52 1.54 1.08 3.66 1.39

0.174 0.027 0.755 0.003 0.004 0.934 0.402 0.069 0.370 0.335 0.956

16.14 3.10 0.509b

API, Acute Panic Inventory; BAI, Beck Anxiety Inventory; FSQ, Fear of Spiders Questionnaire; VAS, Visual Analogue Scale; POMS, Profile of Mood States; SEM, standard error of the mean. a With baseline FSQ as covariate. b ANOVA.

benzodiazepines. Thus, our results argue for a potential role of quetiapine in the treatment of acute anxiety, for example in cases where benzodiazepines should be avoided.

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Our results are in contrast to findings from Donahue et al. (2009), who failed to show significant acute anxiolytic effects of quetiapine compared to placebo during a VR challenge in patients with social anxiety disorder. Donahue et al. (2009) exposed n =20 patients in a crossover design to a VR public speaking task after administration of 25 mg quetiapine or placebo, respectively. Compared to our study, differences in methodology, like smaller sample size, dosing, study design, and psychometric measures, might account for divergent findings. In our study, anxiolytic effects were not observed across all facets of the anxiety response. However, patients received just one single dose of 100 mg quetiapine XR. More marked effects might have been seen after repeated administration on several days. It might also be discussed whether a single anxiety-relevant challenge is enough to reliably evaluate changes in anxiety levels. Likewise, experiencing fewer somatic symptoms during a single exposure challenge might not be sufficient for phobic patients to perceive a subjective change in anxiety, even though they report fewer somatic symptoms. As Hofmann (2008) summarises, current theories of extinction learning postulate a range of cognitive mediators necessary for subjective changes in anxiety, including increased sense of control, decreased harm expectancy, and self-efficacy. It seems plausible that these mechanisms require time and repeated experience. As for the pharmacodynamics of quetiapine, both quetiapine and its active metabolite N-Desalkylquetiapine have affinities to a range of serotonin and dopamine receptors, to the norepinephrine reuptake transporter, and to the histamine H1 receptor (Bandelow et al., 2010; Jensen et al., 2008). Antidepressant/anxiolytic effects of quetiapine have been discussed to be primarily mediated via partial agonism at the serotonin 1A receptor and norepinephrine transporter inhibition (Jensen et al., 2008). Animal studies have shown that anxiolytic effects of atypical antipsychotics might also be mediated by D2 and/or D3 antagonism (Maciag et al., 2007). Quetiapine effects on the noradrenergic and serotonergic systems might parallel the effects of SSRIs and SNRIs (Bandelow et al., 2010; Goldstein et al., 2008). Furthermore, histamine H1 receptor blockade might lead to a certain degree of sedation. Finally, the a1 receptor antagonism of quetiapine might beneficially influence the sympathetic autonomic symptoms of anxiety and panic. With regard to genetic findings, we observed the more active COMT GG (val/val) genotype to be associated with increased baseline scores on the VAS Tension and FSQ scales. This finding is in line with previous molecular studies reporting association of the more active val allele of the COMT val158met polymorphism with panic disorder and phobic anxiety rendering the COMT gene to be one of the major and best replicated candidates in anxiety (e.g., Domschke et al., 2007; Hamilton et al., 2002; McGrath et al., 2004). Also, the more active G allele has been found to increase amygdala activity in response to anxiety-relevant emotional stimuli (Domschke et al., 2012), suggesting the COMT val158met genotype to shape limbic activity related to anxiety. Furthermore, the present pharmacogenetic results suggest the more active GG (val/val) genotype to confer a better response to quetiapine in terms of FSQ scores as compared to the less active AG/AA (val/met and met/met) genotypes. This

1558 finding is in accordance with a recent psychotherapy–genetic study in panic disorder reporting panic disorder patients carrying at least one COMT val allele to respond better to (exposure-based) cognitive behavioural treatment compared to patients carrying the met/met genotype (Lonsdorf et al., 2010). This at first sight paradoxical association of the more active COMT val allele with increased baseline scores on the VAS Tension and FSQ scales on the one hand and better response to quetiapine on the other hand could be reconciled based on the hypothesis of phasic and tonic dopaminergic firing driven by COMT gene variation (Bilder et al., 2004): the more active COMT val allele, while decreasing overall cortical dopamine activity, increases phasic dopamine transmission subcortically. Thus, persons at risk for higher anxiety due to increased phasic dopamine levels conferred by the val allele might particularly profit from a pharmacological intervention with quetiapine, which by partial serotonin receptor 1A agonism might allow for a more efficient processing of anxiety-related stimuli via an increase in tonic cortical dopamine (cf. Ichikawa et al., 2002; Silverstone et al., 2012). However, the exact mechanism of the genetically determined anxiolytic effects of quetiapine remains to be elucidated in future studies. This study has certainly to be considered in the light of some limitations. First, although we found a strong anxiogenic effect of the VR challenge, results of experimentally induced anxiety are not necessarily transferable to in vivo conditions. For example, it might be discussed whether the artificial environment would have anxiolytic effects per se, or might have increased arousal and fear. Furthermore, there is debate about the relation between the emotional effects of VR and the degree of presence experienced by the participant, which varies considerably across participants (Schubert et al., 2001). While presence and fear during VR exposure seem to be related, the direction of the effect is unclear (Robillard et al., 2003). Nonetheless, both factors — novelty and variance in participants’ degree of presence — might have contributed to obscuring a drug effect. On the other hand, the VR challenge was superior to an in vivo exposure in terms of standardisation. With regard to the genetic/pharmacogenetic results, these should be interpreted with caution in view of the uneven distribution of genotypes in our sample, which was not a-priori stratified for the COMT val158met variant. Also, based on the current knowledge of the receptor profile of quetiapine suggesting that the antidepressant and therefore potentially also anxiolytic activity of quetiapine is primarily mediated through partial serotonin receptor 1A agonism and norepinephrine transporter inhibition (Jensen et al., 2008), in the future further potentially relevant candidate genes should be analysed for their impact on the anxiolytic effect of quetiapine such as the HTR1A (e.g., McIntyre et al., 2007; Domschke et al., 2006) and NET (e.g., Bj¨ orkholm et al., in press; Lee et al., 2005) genes. Taken together, this study has investigated acute anxiolytic properties of the atypical neuroleptic quetiapine. We found a significant reduction of somatic anxiety after a single dose treatment, which points towards fast-acting anxiolytic properties of quetiapine. Future studies should investigate acute effects in larger patient samples in order to further evaluate the potential use of quetiapine in the acute and short-term treatment of anxiety.

J. Diemer et al.

Role of the funding source AstraZeneca supported this study providing a grant, study medication and randomisation (Protocol Code no. D1443L00051). This study was further supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to P.Z. (SFB-TRR-58, project C1) and K.D. (SFB-TRR-58, project C2) and from the Innovative Medical Research Foundation Muenster (IMF 220805) to P.Z. None of these funding bodies had any further role in study design, the collection, analysis and interpretation of data, the writing of this manuscript, nor in the decision to submit this paper for publication.

Contributors Peter Zwanzger, Volker Arolt and Katharina Domschke designed the study and wrote the study protocol. Julia Diemer coordinated the study, recruited the participants, undertook the statistical analysis and wrote the first draft of the manuscript. Andreas M¨ uhlberger designed the VR system used in this study. Bernward Winter conducted part of the physiological measures and analyses. Maxim Zavorotnyy, Swantje Naunin and Karen Silling screened the participants and obtained written informed consent. All authors contributed to and have approved the final manuscript.

Conflict of interest Andreas M¨ uhlberger is stakeholder and executive officer of a commercial company that develops and distributes virtual environment research systems. KD has received speaker fees from Pfizer, Lilly and Bristol-Myers Squibb, she was a consultant for Johnson & Johnson and has received funding by Astra Zeneca. PZ has received speaker fees from Pfizer, Servier, Lilly, Astra Zeneca, and BristolMyers Squibb, he is on the advisory board of Pfizer, is a consultant for Ironwood Pharmaceuticals and has received funding from AstraZeneca. VA is member of advisory boards and/or gave presentations for the following companies: Astra-Zeneca, JanssenOrganon, Lilly, Lundbeck, Servier, Pfizer, and Wyeth. He chairs the committee for the ‘‘Wyeth Research Award Depression and Anxiety’’, now the DGPPN/Pfizer ‘‘Clinical Neuroscience Award’’. All other authors declare that they have no conflicts of interest.

Acknowledgement We thank Mathias M¨ uller for the implementation of the virtual reality system and technical support.

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