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d-Cycloserine does not enhance the effects of in vivo exposure among young people with broad-based anxiety disorders
Behaviour Research and Therapy 87 (2016) 225e231
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d-Cycloserine does not enhance the effects of in vivo exposure among young people with broad-based anxiety disorders Ronald M. Rapee a, *, Michael P. Jones a, Jennifer L. Hudson a, Gin S. Malhi b, Heidi J. Lyneham a, Sophie C. Schneider a a b
Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, New South Wales, 2109, Australia CADE Clinic, Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 January 2016 Received in revised form 30 September 2016 Accepted 17 October 2016 Available online 18 October 2016
Use of the partial NMDA receptor agonist d-Cycloserine (DCS) to increase extinction to feared cues among anxious adults has shown mixed, although overall positive effects. Few studies have extended this effect to youth and none have addressed young people with broad-based anxiety such as separation anxiety, social anxiety, or generalised anxiety. In the current trial 51 children and adolescents with diagnosed anxiety disorders, aged 7e14 years received four sessions of graduated, experimenter-led, in vivo exposure to a hierarchy of feared cues relevant to their primary fear. They were randomly allocated to receive either 50 mg of DCS or a matched placebo capsule in a fully double-blind design. Both groups showed large reductions across sessions in their primary fear according to both parent and child report, but there were no significant differences between conditions at any session. The results are consistent with most studies to date of DCS-augmented exposure in young people. © 2016 Elsevier Ltd. All rights reserved.
Keywords: d-Cycloserine Anxiety Youth in vivo exposure Child anxiety Treatment
The child anxiety treatment literature has featured an extensive focus on comprehensive treatment packages to manage the broadbased and widely generalised forms of anxiety disorder that most commonly present to clinics (Rapee, Schniering, & Hudson, 2009). Exposure to feared stimuli forms the cornerstone of treatments for anxiety at all life stages, including anxiety in youth. Within the comprehensive treatment packages aimed at broad-based anxiety, in vivo exposure to feared cues remains a fundamental component and is arguably the critical element in all successful treatments for fears and anxiety among young people. Hence increasing our understanding of the mechanisms underlying exposure and improving its effects is important to produce maximally efficacious treatments. Among theories of the mechanisms underlying in vivo exposure, strong parallels have been drawn between this clinical technique and the process of extinction (Craske et al., 2008; Davey, 1992; Field, 2006). Despite the fact that the origins of broad-based anxieties are not completely understood and are likely multi-faceted (Rapee et al., 2009), the reduction of clinical fears is likely to
* Corresponding author. E-mail address: [email protected] (R.M. Rapee). http://dx.doi.org/10.1016/j.brat.2016.10.004 0005-7967/© 2016 Elsevier Ltd. All rights reserved.
involve information change in long term memory. Current concepts of extinction argue that delivery of a CS in the absence of the US leads to the learning of a new relationship - in other words, CS - no US (Bouton, Westbrook, Corcoran, & Maren, 2006; Lovibond, 2004), which must be consolidated into memory. Successful extinction therefore, relies on learning about new relationships between two stimuli. As a result, factors that maximise such learning and consolidation of the subsequent memory should increase the efficiency of extinction while processes that disrupt learning or memory consolidation should reduce extinction (Craske et al., 2008). A relatively recent and exciting development has been the identification of several chemical means to enhance consolidation of extinction memories. Of the various cognitive enhancers that have so far been identified, d-Cycloserine (DCS) has received the most extensive evaluation. DCS is a glutamatergic partial NMDA receptor agonist, which facilitates extinction learning related to cued fear (Ledgerwood, Richardson, & Cranney, 2003; Walker, Ressler, Lu, & Davis, 2002). While the precise mechanisms of its action are still not known, DCS appears to facilitate consolidation of new memories associated with the fear response (Baker, McNally, & Richardson, 2012; Vervliet, 2008). A substantial body of work with rats has shown that relative to animals given placebo, those
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administered DCS show more rapid fear extinction, stronger generalisation to related cues, and are less likely to relapse following re-exposure to the UCS (Norberg, Krystal, & Tolin, 2008; Richardson, Ledgerwood, & Cranney, 2004). Among human adults a growing number of studies has begun to demonstrate similar effects in the reduction of clinical fears (Hofmann, 2014; Vervliet, 2008). However, several exceptions have been published (Guastella, Dadds, Lovibond, Mitchell, & Richardson, 2007; Storch et al., 2007). In fact an early meta-analysis demonstrated a significant enhancement of exposure to feared cues among humans by DCS immediately following intervention, but the size of the effect was relatively small (d ¼ 0.42) and markedly smaller than found among animal samples (d ¼ 1.19) (Norberg et al., 2008). A more recent review of cognitive behavioural interventions augmented with DCS compared against augmentation with placebo, showed no significant differences between these conditions (Ori et al., 2015). The slightly different conclusions between these reviews might be due to the updated literature in the latter, but are more likely due to the inclusion of broader and more comprehensive cognitive behavioural treatment programs in the second review. DCS is hypothesised to augment a very specific component of one element of therapy. Therefore, while it is proposed to specifically enhance extinction, it is unlikely to demonstrate marked augmenting effects in the context of an overall efficacious treatment program. Although augmentation of extinction through DCS has been evaluated among adults with several types of anxiety (Guastella et al., 2008; Otto, McHugh, & Kantak, 2010; Ressler et al., 2004), there has been very little evaluation among children (Byrne, Farrell, Storch, & Rapee, 2014). Recent research with rats has suggested that extinction in preweanling rats is not under NMDA receptor control but is more likely to be controlled by an opioid system (Kim & Richardson, 2010; Langton, Kim, Nicholas, & Richardson, 2007). This would imply that DCS may not facilitate extinction in very young rats, but that this effect would only emerge later in development. Determining human age equivalence in rats is complex (Clancy, Finlay, Darlington, & Anand, 2007), however, 16-day-old rats are likely to be most similar to extremely young humans (toddler age) (Quinn, 2005). This suggests that at least from middle childhood, extinction should be mediated by NMDA functioning in the amygdala and that DCS should therefore augment its effects. However the developmental effects are sufficiently unclear that they warrant investigation. To date only a handful of studies has evaluated the use of DCS to enhance extinction among children and most have focussed on obsessive compulsive disorder (OCD). In the earliest report, 30 young people with OCD aged 8e17 years (mean 12 years), were randomly allocated to receive either DCS or placebo (Storch et al., 2010). Capsules (either 25 mg or 50 mg depending on weight) were delivered by parents one hour prior to 7 exposure sessions, couched within an overall CBT treatment program. Although there were some indications that DCS was associated with slightly larger effects than placebo, there were no significant group by time interactions on any variables. A later analysis of this sample also failed to indicate that DCS increased home practice of exposure (Park et al., 2014). A more recent study allocated 17 treatment refractory young people with OCD to either receive DCS or placebo immediately before five sessions of exposure, within a 9-session treatment program (Farrell et al., 2013). The participants were aged 8e18 years, with a mean of 13 years. Most participants showed strong improvements and there were no significant differences between conditions immediately following treatment or at 3-month follow-up. However, the degree of improvement from post-treatment to 1-month follow-up was significantly greater for children given DCS on several measures. Finally, in a minor variation to the standard procedure, Mataix-Cols et al. (2014) delivered
50 mg DCS or placebo to 27 young people with OCD immediately following each of 10 sessions of exposure, within an overarching 14-session CBT program. The two conditions did not differ significantly on outcome and there was no evidence that DCS augmented exposure over placebo at any individual session. A recent study that evaluated the effects of DCS in a sample of children not suffering from OCD failed to show differences between DCS and placebo among 57 youth suffering PTSD (Scheeringa & Weems, 2014). Finally, two studies have evaluated the effects of DCS in augmenting a single session of exposure within anxious children with specific phobias. Byrne et al. (2015) randomly allocated 35 young people (aged 6e14 years; mean 9 years) suffering dog or spider fears to either DCS (50 mg) or placebo. Medication was given one hour before a one-hour session of exposure to the feared cue. There were no significant differences between groups on a follow-up behavioural approach test (BAT) that was conducted approximately five days following treatment in the original treatment setting. However, children given DCS showed significantly greater approach and significantly less distress on a follow-up BAT that was conducted in a different context outside the treatment setting. Farrell et al. (2015) randomly allocated 35 young people aged 7e17 years to receive DCS (35 mg or 70 mg depending on weight) or placebo immediately before a single, 3.5 h session of exposure to their feared cue. There was a significantly greater reduction in clinical global severity from post-intervention to one-month follow-up among the DCS group relative to placebo. Thus to date, there have been few studies of the addition of DCS to in vivo exposure among anxious young people and most have focussed on anxiety-related disorders, OCD and PTSD. Current results do not provide strong support to indicate that DCS augments the effects of in vivo exposure among young people. However, the few positive indications and the occasional positive results among anxious adults, encourages further investigation. Among youth there are currently no studies evaluating effects of DCS with the common, broad-based clinical anxiety disorders, separation anxiety disorder (SAD), social anxiety disorder (SOC), and generalised anxiety disorder (GAD). This was the aim of the current experimental study. In short, the current study involved a short-term comparison of the effects on specific fear of in vivo exposure either supplemented with DCS or placebo among children with broad-based anxiety disorders. Based on the extant literature, we predicted that exposure supplemented with DCS would lead to greater reductions in specific fear and symptoms of anxiety across sessions than exposure plus placebo. Given the variations in effects of DCS across previous trials and the limited research with youth, we also explored the impact of several moderators (including age and diagnosis). In particular, we expected that trials in which exposure was of “good quality” would lead to greater DCS-placebo differences than “poor quality” exposures. 1. Method 1.1. Participants Participants for the study included 25 girls and 26 boys aged 6.8e13.5 years (M ¼ 9.22, s.d. ¼ 1.59 years) who met criteria for an anxiety disorder according to DSM-IV criteria (American Psychiatric Association, 2000). Principal disorders in the sample included: generalised anxiety disorder (45%); social anxiety disorder (31%), separation anxiety disorder (12%); other anxiety (12%). The participants were randomly allocated to receive either DCS or placebo (see procedure). Participants were recruited from the Centre for Emotional Health and were part of a larger cohort seeking treatment for their anxiety disorder. Families wanting
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treatment contacted the clinic following referral from a mental health professional, school personnel, or word of mouth and the current study was conducted before formal treatment commenced. Participants were included in the study if they were aged between 6 and 17 years, met criteria for an anxiety disorder other than specific phobia as their principal disorder, and agreed to participate in an experimental study involving use of a medication. They were excluded if they indicated any of a range of physical or emotional difficulties including: marked depressive symptoms; pervasive developmental disorder; psychotic symptoms; epilepsy; liver or kidney disease. Exclusion criteria were indicated by a checklist completed by a parent and then reviewed by the prescribing psychiatrist (GM). A total of 131 participants were invited to participate and 22 (17%) met one of the exclusion criteria. Of the remaining 109, 46 refused participation (primarily due to unwillingness to take medication) and an additional 12 refused to commit to all sessions, leaving a final sample of 51 (39% of original). A total of 27 participants were randomly allocated to receive DCS (48% boys; M age ¼ 9.41, s.d. ¼ 1.76 years) and 24 received placebo (54% boys; M age ¼ 9.02, s.d. ¼ 1.38 years). The two groups did not differ significantly in age, t(46) ¼ 0.85, p ¼ 0.40, gender, c2(1, N ¼ 51) ¼ 0.18, p ¼ 0.67, or principal diagnosis, c2(3, N ¼ 51) ¼ 0.22, p ¼ 0.98. 1.2. Measures 1.2.1. Diagnoses All diagnoses were assigned by graduate students in clinical psychology or qualified clinical psychologists following structured interview with the Anxiety Disorders Interview Schedule for DSMIV, Parent and Child versions (Silverman & Albano, 1996). Interviewers received training to criterion and research from our clinic has demonstrated inter-rater agreement of kappa ¼ 1.00 for an overall diagnosis of anxiety disorder, and ranging from 0.68 to 0.93 across the major anxiety disorders (Lyneham, Abbott, & Rapee, 2007). Diagnoses and clinician-rated severity of each diagnosis (CSR; on a scale of 0e8) were based on composite parent and child report. 1.2.2. Anxiety symptoms To measure symptoms of anxiety over the previous week, children completed one subscale of the Spence Children's Anxiety Scale SCAS (Spence, 1998) and their parents completed the parallel parent version SCASp (Nauta, Scholing, Rapee, Abbott, & Spence, 2004). The full versions of these measures contain 38 anxiety items that load on six correlated subscales, several of which reflect DSM-based categories including social anxiety, generalised anxiety, and separation anxiety. Internal consistencies for the total scale (alpha ¼ 0.92) and subscales (alphas ~ .6-0.8) are solid and the total and subscales have shown good validity (Nauta et al., 2004; Spence, 1998). For the current study, the parents and child completed only the SCAS subscale that was most directly relevant to the child's principal anxiety disorder at the beginning of each exposure session. 1.2.3. Fear hierarchies During the first session the experimenter, child, and parent constructed a relevant fear hierarchy. Each hierarchy contained 8 to 11 steps (M ¼ 8.35, s.d. ¼ 0.80) and was relevant to the child's principal diagnosis. A key caveat was that steps on the hierarchy had to be able to be performed within the session (ie were practical and available within the university campus). The steps were rated from easiest to hardest and were recorded on a weekly stepladder form, which was then used consistently across the four sessions of the study. In other words, hierarchies were individualised for each
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child but were consistent across the duration of the study. At both the commencement and completion of each session, the experimenter asked the child to indicate how frightened they would be if they had to do each step now. Fear was rated on a visual scale from 0 (very relaxed/no problem doing task) to 10 (extremely scared/ definitely can't do it) and a mean hierarchy score was calculated for the beginning (pre) and end (post) of each session based on the mean of the fear ratings across all steps. 1.2.4. Exposure quality Immediately before each exposure, the experimenter asked the child the following question about their state fear: “You are just about to go and face your fear. How frightened are you right now?” The child was shown a pictorial scale and rated their fear on an 11point scale from 0 (no fear) to 10 (maximum fear). The rating was repeated immediately following the exposure as follows: When you were facing your fear just now, how frightened did you get? Change scores were calculated by subtracting the post-exposure rating from the pre-exposure rating so that positive difference scores indicated more successful exposures (greater fear decrease). Where more than one exposure was conducted within a session, the difference scores were averaged. A second measure of exposure quality was made by experimenters. Immediately following each exposure the experimenter rated the quality of the exposure using three items (all scored from 0 to 3): 1) How smoothly overall did exposure go; 2) How happy/ confident/proud did the child seem immediately after exposure; 3) How well do you think the child learned that what they were afraid of wouldn't happen? Responses to these three items were averaged to create a total exposure quality score for every exposure, with higher scores indicating more positive quality. Where more than one exposure was conducted within a session, the scores were averaged. 1.3. Medications Children were administered either DCS or a placebo in identical gelatine capsules at the commencement of each treatment session. Given conflicting opinions about the optimal time to combine DCS with exposure (Hofmann, 2014; Mataix-Cols et al., 2014), this delivery allowed the medication to build during the exposure period and maintain peak blood levels during the memory consolidation window following exposure. Active capsules contained 50 mg of DCS derived from powder, while placebo capsules contained lactose powder. 1.4. Exposures Experimenters conducting exposures were graduate students in clinical psychology and each child had the same experimenter for all 4 sessions. At each session the experimenter and child selected a step from the hierarchy to attempt. Parents were not present unless the child refused to allow the parent to leave. The selected step at each session was based on a) the child's indication of which step they were prepared to attempt; b) experimenter judgement in aiming to select a step that would elicit mild to moderate anxiety; and c) the previous step that was successfully attempted. Within each session, the child typically repeated tasks up to three times, depending primarily on the duration of a given step e steps that took most of a session could only be performed once, but very brief steps could be performed more often. If a child found that a given step became easy, they could attempt higher steps within the session. As noted, immediately following each task, the experimenter asked the child to indicate how frightened they became during the task. If a step was performed easily and elicited little
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fear, the experimenter encouraged the child to attempt a higher step. If a given exposure task went badly (e.g., child withdrew, reported extreme fear, did not habituate), the experimenter encouraged the child to attempt a lower step to ensure that the session ended on a positive note. 1.5. Procedure Families contacted the Centre for Emotional Health seeking treatment for their child, were given an appointment for a diagnostic assessment and had the current experimental study explained to them. Those who were willing to consider the study were referred to a brief video in which the first author explained the nature of the study, the nature of the medication (DCS), and especially emphasised its safety. Families were then asked at their diagnostic assessment whether they were willing to participate in this pre-treatment study and were asked about exclusion criteria. Those who agreed and met inclusion criteria were given an appointment for their first session. Prior to the first session, the assessment notes and medical checklist were reviewed by the prescribing psychiatrist. A randomisation schedule was prepared via a randomisation website and provided to the dispensing pharmacist who was blind to all aspects of the study hypotheses and participants. Families, experimenters and assessors were all blind to the participant's condition until the completion of the study. Four capsules, clearly marked with the participant's number were given to the relevant experimenter. There was a total of four, weekly sessions. At the commencement of each session, the experimenter gave the child a capsule to ingest, observed the child swallow the capsule, and then proceeded to conduct the session. Each session comprised: completion of pre-session measures; decision of which step to attempt; conducting of one or more exposure tasks; completion of post-session measures. 2. Results 2.1. Group comparisons on implementation of exposure The two groups were compared on several aspects of the delivery of therapy. There was no significant difference between the DCS and placebo groups on the number of sessions attended, t(49) ¼ 0.18, p ¼ 0.86 (DCS, M ¼ 3.70, s.d. ¼ 0.72; Plac, M ¼ 3.67, s.d. ¼ 0.76), total duration of exposure (mins.), t(49) ¼ 0.22, p ¼ 0.83 (DCS, M ¼ 45.10, s.d. ¼ 33.24; Plac, M ¼ 43.27, s.d. ¼ 24.50), number of steps in the hierarchy, t(49) ¼ 1.25, p ¼ 0.22 (DCS, M ¼ 8.22, s.d. ¼ 0.58; Plac, M ¼ 8.50, s.d. ¼ 0.98), and the highest step attempted, t(49) ¼ 0.77, p ¼ 0.45 (DCS, M ¼ 6.56, s.d. ¼ 1.31; Plac, M ¼ 6.92, s.d. ¼ 2.02). 2.2. Group comparisons on reductions in fearfulness Mixed model analyses of variance (ANOVA) were conducted to compare changes over time between the children receiving DCS and those receiving placebo on four outcome measures. The use of mixed models allowed all participants to be included in analyses, even when they may have missed sessions. Based on the mean stepladder score taken at the beginning of each session, there was a significant reduction in fear across time, F(3, 189) ¼ 20.14, p < 0.001, but no significant difference between groups, F(1, 189) ¼ 2.32, p ¼ 0.13, and no significant group by time interaction, F(3, 189) ¼ 0.20, p ¼ 0.90. Similarly, according to the mean stepladder score taken at the completion of each session, there was a significant reduction in fear across time, F(3, 186) ¼ 18.99, p < 0.001, but no significant difference between
groups, F(1, 186) ¼ 1.56, p ¼ 0.21, and no significant group by time interaction, F(3, 186) ¼ 0.27, p ¼ 0.85. Data are presented in Table 1. Based on children's reported anxiety on the fear-relevant SCAS subscale, there was a significant reduction in anxiety across time, F(3, 186) ¼ 4.45, p ¼ 0.005, and a significant difference between groups with children in the placebo group reporting less anxiety than those in DCS, F(1, 186) ¼ 8.71, p ¼ 0.004, but there was no significant group by time interaction, F(3, 186) ¼ 0.22, p ¼ 0.88. Similarly, according to mothers' reports on the relevant SCAS subscale, there was a significant reduction in anxiety across time, F(3, 187) ¼ 3.87, p ¼ 0.010, but no significant difference between groups, F(1, 187) ¼ 1.18, p ¼ 0.28, and no significant group by time interaction, F(3, 187) ¼ 0.27, p ¼ 0.85. Data are presented in Table 1. 2.3. Moderation by exposure quality Some research has suggested that DCS only enhances outcomes when exposure sessions are “successful” (Smits, Rosenfield, Otto, Marques, et al., 2013, Smits, Rosenfield, Otto, Powers, et al., 2013). To evaluate this possibility, because there is no accepted method to determine exposure quality, we examined moderation of the difference between groups in three different ways. First, we re-ran the previous analyses including only data from successful sessions. Each exposure session was defined as successful if the child's experienced anxiety (fear rating during exposure) was lower than their anticipatory anxiety (fear rating before the exposure) or if there was no difference in fear ratings but the experienced anxiety (during exposure) was low (less than 5 on the 0e10 scale). In other words, if there was a disconfirmation of expected fear or if fear was simply low. Defined in this way, the total number of unsuccessful exposures across the four therapy sessions ranged from 0 to 9e39.2% of children experienced no unsuccessful exposures, 78.4% of children experienced two or fewer unsuccessful exposures. In order to determine whether the augmenting effects of DCS became apparent when restricted to successful exposures, the data were re-analysed including only children who experienced two or fewer unsuccessful exposure tasks. The pattern of results was identical with no significant group by time interactions (all interaction F's < 0.50; all interaction p's > 0.70). Second, in order to provide a more continuous measure of exposure success, we used the change in children's predicted fear scores from before each exposure to following each exposure (i.e., the degree of (dis)confirmation of fear expectancy) as a continuous measure of the success of each exposure session. The average change in a child's fear score in one exposure session was poorly predictive of their stepladder score at the beginning of the subsequent exposure (correlations 0.04, 0.02 and 0.01, all p 0.6 correlating change at exposure 1 with stepladder at exposure 2,
Table 1 Estimated marginal means and standard errors (in parentheses) on measures of within-session fearfulness between groups. Session 1
Session 2
Mean pre-session stepladder score DCS group 5.65 (0.30) 4.80 Placebo group 5.60 (0.32) 4.32 Mean post-session stepladder score DCS group 5.20 (0.33) 4.30 Placebo group 4.63 (0.35) 4.11 Fear-relevant SCAS (child) DCS group 7.59 (0.68) 6.99 Placebo group 6.00 (0.73) 5.82 Fear-relevant SCAS (parent) DCS group 8.64 (0.72) 6.89 Placebo group 8.41 (0.76) 7.66
Session 3
Session 4
(0.30) (0.32)
4.31 (0.31) 3.94 (0.32)
3.47 (0.31) 3.04 (0.32)
(0.33) (0.36)
3.46 (0.35) 3.01 (0.36)
2.51 (0.34) 2.50 (0.36)
(0.70) (0.74)
5.66 (0.71) 4.55 (0.74)
5.58 (0.76) 3.42 (0.76)
(0.72) (0.78)
6.05 (0.74) 6.96 (0.78)
5.74 (0.76) 6.62 (0.79)
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etc). Mixed model analysis of variance did not yield any evidence that the degree of correlation between change in fear and subsequent session stepladder score was moderated over the course of the program (p ¼ 0.4). In other words, the extent to which expectancy (dis)confirmation predicted later fear did not differ significantly between the two groups. A final indicator of exposure success was provided by experimenters who rated three qualitative indicators that were averaged for each exposure session. In contrast to the child's fear score, the experimenter's evaluation of the child's response to a therapy session was moderately correlated with stepladder scores at the beginning of the subsequent exposure (correlations 0.28, 0.21, 0.31, all p 0.03). In other words, experimenters' overall judgements of the quality of a given exposure significantly predicted later fear. However mixed model analysis of variance did not yield any evidence that the degree of correlation between experimenters' evaluation and subsequent stepladder score was moderated by pill condition over the course of program (p ¼ 0.3). In other words, this significant prediction did not differ between DCS and placebo, suggesting that it is a general characteristic of exposure, rather than a variable that affects the impact of DCS. 2.4. Subgroup analyses It might be argued that DCS is more likely to augment exposure for those young people with more concrete or clear cut fears. Given the broader and more generalised range of stimuli that are feared by children suffering GAD, it is possible that DCS augmentation effects will be weaker for this population. Therefore, the data were reanalysed excluding those youth who met criteria for a diagnosis of GAD as their principal disorder. Again, the pattern of results was identical with no significant group by time interactions (all interaction F's < 0.43; all interaction p's > 0.74). Finally, given evidence that extinction in preweanling rats is not under NMDA receptor control (Kim & Richardson, 2010), we examined whether the lack of significant differences might have been influenced by the youngest portion of the sample. The data were re-analysed excluding children less than 8 years of age. Again, the pattern of results was identical with no significant group by time interactions (all interaction F's < 0.65; all interaction p's > 0.58). 3. Discussion The potential to increase the effects of a psychological process (extinction) using chemical means arguably represents one of the most exciting developments in cognitive behaviour therapy, both theoretically and practically. As a specific chemical, d-Cycloserine appears to show relatively small effects and a potential for rapid tolerance that makes it unlikely to realise strong practical utility. In fact, RCTs comparing DCS to placebo to augment overall cognitive behavioural programs have failed to indicate clinically significant benefits (Ori et al., 2015). Nonetheless, because of its widespread availability, safety, and long history, DCS provides an ideal substance for “proof of concept”. Indeed, DCS has shown some promising ability to increase the specific effects and generalisation of in vivo exposure among adults suffering anxiety disorders (Norberg et al., 2008). Interestingly, among anxious youth, DCS has shown less consistent effects and has mostly failed to show an enhancement of in vivo exposure (Mataix-Cols et al., 2014; Scheeringa & Weems, 2014; Storch et al., 2010). In fact, within the extant child literature, of five published studies, three have failed to demonstrate significant DCS augmentation effects and two have shown inconsistent effects across time and measures. The only study to
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date that appears to have shown a significant augmentation of exposure by DCS (Farrell et al., 2015) is currently unpublished. Consistent with this literature, the current results also failed to demonstrate an augmentation of fear reduction through in vivo exposure following ingestion of DCS among anxious youth. This is the first trial to have used DCS with young people suffering the types of broad-based anxiety disorders seen most commonly in clinical practice, SAD, GAD, and SOC. On initial consideration, the lack of a significant DCS augmentation appears disappointing. However, the very large number of potential variables (e.g., dosage, timing of DCS delivery, extinction parameters) means that a great deal more investigation is required before concluding that the strong effects noted in carefully controlled animal laboratory studies cannot be generalised to application with young humans. It has been argued that cognitive enhancers will increase whatever learning occurs and hence have the potential to increase the negative effects of “bad” exposures as much as the positive effects of “good” exposures (Hofmann, 2014). Following this logic, Mataix-Cols et al. (2014) delivered medication at the conclusion of exposure so that they were able to only medicate “good” exposures. Theoretically, good exposures should be those that lead to new learning about the lack of CS-US association. However, the best way to operationalise such learning, especially among children who are less able to verbalise their cognitive processes, is far from clear. When we operationalised good exposures as those that resulted in a disconfirmation of expected anxiety (anxiety reduction or low anxiety) (Craske et al., 2008; Lovibond, 2004), restricting analyses to those youth who primarily reported positive disconfirmations did not affect the results. This might partly be due to the fact that our experimenters were instructed to try to ensure that all sessions ended with a positive disconfirmation of predicted anxiety. Nonetheless, more fine-grained examination of the impact of positive vs negative exposures on DCS augmentation, also failed to indicate any moderation. When the degree of change in state anxiousness during exposure according to children's reports was used as an index of exposure quality, there was no moderation of fear reduction between the two groups. A similar lack of moderation was shown when experimenters' qualitative ratings of exposure quality were used. The parameters of delivering in vivo exposure are extensive and it is possible that other ways of delivering exposure may have resulted in a greater DCS/placebo difference. However, using the current methods, which reflect common practice, we were unable to detect any major impact of DCS. Despite the fact that it did not moderate the augmentation of exposure by DCS, experimenters' ratings of exposure quality did predict subsequent fear overall. The fact that experimenters are able to provide some estimate of exposure success has both theoretical and clinical implications. Experimenters' ratings were comprised of subjective estimates of the exposure process, the child's reaction to the exposure, and the extent of apparent expectancy change that the child expressed. Any one of these items may have been critical to the prediction of subsequent fear, and more focussed research is needed to determine the precise parameters by which therapists can best predict exposure quality. Being able to determine these parameters will facilitate means of maximising the quality and efficacy of exposure-based treatments. Of theoretical interest, it is possible that extinction learning in youth is under the control of different neurological systems than it is later in development (Kim & Richardson, 2010). Hence, NMDA receptor agonists such as DCS may not augment extinction early in life. It is more likely that biological differences in fear-learning systems characterise far younger children than used in the current study, but it remains possible that such differences may have been responsible for the lack of any significant DCS augmentation. Although we also failed to show a DCS-augmentation effect when
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we excluded the youngest children, potential age differences in response to DCS deserve further evaluation with larger samples. In fact a potential limitation to the overall study was a lack of power. From a practical perspective it was difficult to recruit a large sample. Our ethics committee required us to entertain a large number of exclusion criteria and 17% of the possible sample was excluded. This issue highlights an obvious limitation to use of DCS in clinical practice. Adding to this difficulty, few families were motivated to enter the study and almost half (42%) of those who were eligible refused participation. This limitation is consistent with data showing that parents are often unwilling for anxious children to be placed on medications, especially DCS (Byrne, Rapee, & Sweller, 2015; Roberts, Farrell, Waters, Oar, & Ollendick, 2016). A further methodological issue worth discussing is the diagnostic composition of the sample. While most previous research has restricted itself to extremely narrow diagnostic selection, we included a broader range of anxiety disorders. On the one hand, this heterogeneity is a strength of the study since it allows greater generalisation of conclusions and a closer approximation to the realities of clinical practice. However, it is possible that the variety of diagnoses concealed any differences in DCS reactivity between diagnostic groups. Our exploratory analyses failed to indicate any obvious impact of a diagnosis of GAD, but the study was not properly powered to examine such moderations. From a theoretical perspective, extinction is a process that is assumed to underpin fear reduction across all CS-US relationships and there is no current theory that predicts that extinction mechanisms will differ between social threat and physical threat cues. Nonetheless, replication with a markedly larger sample that allows examination of diagnostic moderation is warranted. An additional limitation was the primary reliance on child reported fear. Data from the parent measure of anxiety symptoms was consistent with the data from children's reports. Nonetheless, including measures based on researcher reports or observational measures might produce different results in future studies. In summary, DCS failed to enhance exposure for youth with broad-based anxiety disorders. Although it is highly unlikely that DCS will prove to be the “holy grail” sought by clinical practitioners, the paradigm of using chemical means to directly enhance fear extinction is a ground-breaking innovation that deserves considerably more experimental investigation. On a positive note, the results of this study also strongly reinforce the power of in vivo exposure to reduce a wide variety of fears and avoidance. Children in both groups showed dramatic reductions in their primary fear following only a few brief sessions. It is often useful to remind ourselves of the old lessons. Funding source This research was supported by Australian Research Council grant DP1095162. Conflict of interest Nil. Acknowledgements The authors acknowledge the support of Jane Stidworthy and staff at the Macquarie Hospital pharmacy for their assistance with medication preparation, supply and concealment. References American Psychiatric Association. (2000). Diagnostic and statistical manual of mental
disorders (4th ed. TR). Washington, D.C: American Psychiatric Association. Baker, K. D., McNally, G. P., & Richardson, R. (2012). D-cycloserine does not facilitate fear extinction by reducing conditioned stimulus processing or promoting conditioned inhibition to contextual cues. Learning and Memory, 19, 461e469. Bouton, M. E., Westbrook, R. F., Corcoran, K. A., & Maren, S. (2006). Contextual and temporal modulation of extinction: Behavioral and biological mechanisms. Biological Psychiatry, 60, 352e360. Byrne, S. P., Rapee, R. M., & Sweller, N. (Producer). (2015b). Factors predicting parental consent to use D-Cycloserine in the treatment of child anxiety. Unpublished manuscript. Byrne, S. P., Farrell, L. J., Storch, E. A., & Rapee, R. M. (2014). D-cycloserine augmented treatment of anxiety disorders in children and adolescents: A review of preliminary research. Psychopathology Review, 1(1), 157e168. Byrne, S. P., Rapee, R. M., Richardson, R., Malhi, G. S., Jones, M., & Hudson, J. L. (2015a). D-cycloserine enhances generalization of fear extinction in children. Depression and Anxiety, 32(6), 408e414. Clancy, B., Finlay, B. L., Darlington, R. B., & Anand, K. J. S. (2007). Extrapolating brain development from experimental species to humans. Neurotoxicology, 28, 931e937. Craske, M. G., Kircanski, K., Zelikowsky, M., Mystkowski, J., Chowdhury, N., & Baker, A. (2008). Optimizing inhibitory learning during exposure therapy. Behaviour Research and Therapy, 46(1), 5e27. Davey, G. C. L. (1992). Classical conditioning and the acquisition of human fears and phobias: A review and synthesis of the literature. Advanced Behavior Research and Therapy, 14, 29e66. Farrell, L. J., Waters, A. M., Boschen, M. J., Hattingh, L., McConnell, H., Milliner, E. L., et al. (2013). Difficult-to-treat pediatric obsessive-compulsive-disorder: Feasibility and preliminary results of a randomized pilot trial of d-cycloserineaugmented behavior therapy. Depression and Anxiety, 30(8), 723e731. http:// dx.doi.org/10.1002/da.22132. Farrell, L. J., Waters, A. M., Tiralongo, E., Garbharren, V., McConnell, H., Oar, E. L., et al. (2015). d-Cycloserine augmented one-session treatment of pediatric specific Phobia: Moderating effects of successful within session exposure. In Paper presented at the annual meeting of the association for behavioral and cognitive therapies, Chicago, USA. Field, A. P. (2006). Is conditioning a useful framework for understanding the development and treatment of phobias? Clinical Psychology Review, 26(7), 857e875. Guastella, A. J., Dadds, M. R., Lovibond, P. F., Mitchell, P., & Richardson, R. (2007). A randomized controlled trial of the effect of D-Cycloserine on exposure therapy for spider fears. Journal of Psychiatric Research, 41, 466e471. Guastella, A. J., Richardson, R., Lovibond, P. F., Rapee, R. M., Gaston, J. E., Mitchell, P., et al. (2008). A randomised controlled trial of D-Cycloserine enhancement of exposure therapy for social phobia. Biological Psychiatry, 63, 544e549. Hofmann, S. G. (2014). D-Cycloserine for treating anxiety disorders: Making good exposures better and bad exposures worse. Depression and Anxiety, 31, 175e177. Kim, J. H., & Richardson, R. (2010). New findings on extinction of conditioned fear early in development: Theoretical and clinical Implications. Biological Psychiatry, 67, 297e303. Langton, J. M., Kim, J. H., Nicholas, J., & Richardson, R. (2007). The effect of the NMDA receptor antagonist MK-801 on the acquisition and extinction of learned fear in the developing rat. Learning and Memory, 14, 665e668. Ledgerwood, L., Richardson, R., & Cranney, J. (2003). Effects of D-cycloserine on extinction of conditioned freezing. Behavioral Neuroscience, 117(2), 341e349. Lovibond, P. F. (2004). Cognitive processes in extinction. Learning and Memory, 11(5), 495e500. Lyneham, H. J., Abbott, M. J., & Rapee, R. M. (2007). Inter-rater reliability of the anxiety disorders interview schedule for DSM-IV: Child and parent version. Journal of the American Academy of Child and Adolescent Psychiatry, 46(6), 731e736. Mataix-Cols, D., Turner, C., Monzani, B., Isomura, K., Murphy, C., Krebs, G., et al. (2014). Cognitive-behavioural therapy with post-session d-cycloserine augmentation for paediatric obsessive-compulsive disorder: Pilot randomised controlled trial. The British Journal of Psychiatry, 204, 77e78. Nauta, M. H., Scholing, A., Rapee, R. M., Abbott, M., & Spence, S. H. (2004). Development of a parent report measure of children's anxiety: Psychometric properties and comparison with child report in a clinic and normal sample. Behaviour Research and Therapy, 42, 813e839. Norberg, M. M., Krystal, J. H., & Tolin, D. F. (2008). A meta-analysis of d-cycloserine and the facilitation of fear extinction and exposure therapy. Biological Psychiatry, 63, 1118e1126. Ori, R., Amos, T., Bergman, H., Soares-Weiser, K., Ipser, J. C., & Stein, D. J. (2015). Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders. Cochrane Database of Systematic Reviews, 5, CD007803. http://dx.doi.org/10.1002/14651858.CD007803.pub2. Otto, M. W., McHugh, K., & Kantak, K. M. (2010). Combined pharmacotherapy and cognitive-behavioral therapy for anxiety disorders: Medication effects, glucocorticoids, and attenuated treatment outcomes. Clinical Psychology: Science and Practice, 17, 91e103. Park, J. M., Small, B. J., Geller, D. A., Murphy, T. K., Lewin, A. B., & Storch, E. A. (2014). Does D-cycloserine augmentation of CBT improve therapeutic homework compliance for pediatric obsessive-compulsive disorder? Journal of Child and Family Studies, 23(5), 863e871. Quinn, R. (2005). Comparing rat's to human's age: How old is my rat in people years? Nutrition, 21, 775e777.
R.M. Rapee et al. / Behaviour Research and Therapy 87 (2016) 225e231 Rapee, R. M., Schniering, C. A., & Hudson, J. L. (2009). Anxiety disorders during childhood and adolescence: Origins and treatment. Annual Review of Clinical Psychology, 5, 311e341. 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 Dcycloserine in phobics to facilitate extinction of fear. Archives of General Psychiatry, 61, 1136e1144. Richardson, R., Ledgerwood, L., & Cranney, J. (2004). Facilitation of fear extinction by D-cycloserine: Theoretical and clinical implications. Learning and Memory, 11, 510e516. Roberts, C. L., Farrell, L. J., Waters, A. M., Oar, E. L., & Ollendick, T. H. (Jun 2016). Parents' perceptions of novel treatments for child and adolescent specific phobia and anxiety disorders. Child Psychiatry and Human Development, 47(3), 459e471. Scheeringa, M. S., & Weems, C. F. (2014). Randomized placebo-controlled D-cycloserine with cognitive behavior therapy for pediatric posttraumatic stress. Journal of Child and Adolescent Psychopharmacology, 24(2), 69e77. Silverman, W. K., & Albano, A. M. (1996). The anxiety disorders interview schedule for children-IV (child and parent versions). San Antonio: Texas: Psychological Corporation. Smits, J. A. J., Rosenfield, D., Otto, M. W., Marques, L., Davis, M. L., Meuret, A. E., et al. (2013a). D-cycloserine enhancement of exposure therapy for social anxiety
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disorder depends on the success of exposure sessions. Journal of Psychiatric Research, 47, 1455e1461. Smits, J. A. J., Rosenfield, D., Otto, M. W., Powers, M. B., Hofmann, S. G., Telch, M. J., et al. (2013b). D-Cycloserine enhancement of fear extinction is specific to successful exposure sessions: Evidence from the treatment of height phobia. Biological Psychiatry, 73, 1054e1058. Spence, S. H. (1998). A measure of anxiety symptoms among children. Behaviour Research and Therapy, 36(5), 545e566. Storch, E. A., McKay, D., Reid, J. M., Geller, D. A., Goodman, W. K., Lewin, A. B., et al. (2010). D-cycloserine augmentation of cognitive-behavioral therapy: Directions for pilot research in pediatric obsessive-compulsive disorder. Child and Youth Care Forum, 39(2), 101e112. Storch, E. A., Merlo, L. J., Bengtson, M., Murphy, T. K., Lewis, M. H., Yang, M. C., et al. (2007). D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder. International Clinical Psychopharmacology, 22(4), 230e237. Vervliet, B. (2008). Learning and memory in conditioned fear extinction: Effects of D-cycloserine. Acta Psychologica, 127, 601e613. Walker, D. L., Ressler, K. J., Lu, K.-T., & Davis, M. (2002). Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of Dcycloserine as assessed with fear-potentiated startle in rats. Journal of Neuroscience, 22(6), 2343e2351.
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d-Cycloserine does not enhance the effects of in vivo exposure among young people with broad-based anxiety disorders Ronald M. Rapee a, *, Michael P. Jones a, Jennifer L. Hudson a, Gin S. Malhi b, Heidi J. Lyneham a, Sophie C. Schneider a a b
Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, New South Wales, 2109, Australia CADE Clinic, Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 January 2016 Received in revised form 30 September 2016 Accepted 17 October 2016 Available online 18 October 2016
Use of the partial NMDA receptor agonist d-Cycloserine (DCS) to increase extinction to feared cues among anxious adults has shown mixed, although overall positive effects. Few studies have extended this effect to youth and none have addressed young people with broad-based anxiety such as separation anxiety, social anxiety, or generalised anxiety. In the current trial 51 children and adolescents with diagnosed anxiety disorders, aged 7e14 years received four sessions of graduated, experimenter-led, in vivo exposure to a hierarchy of feared cues relevant to their primary fear. They were randomly allocated to receive either 50 mg of DCS or a matched placebo capsule in a fully double-blind design. Both groups showed large reductions across sessions in their primary fear according to both parent and child report, but there were no significant differences between conditions at any session. The results are consistent with most studies to date of DCS-augmented exposure in young people. © 2016 Elsevier Ltd. All rights reserved.
Keywords: d-Cycloserine Anxiety Youth in vivo exposure Child anxiety Treatment
The child anxiety treatment literature has featured an extensive focus on comprehensive treatment packages to manage the broadbased and widely generalised forms of anxiety disorder that most commonly present to clinics (Rapee, Schniering, & Hudson, 2009). Exposure to feared stimuli forms the cornerstone of treatments for anxiety at all life stages, including anxiety in youth. Within the comprehensive treatment packages aimed at broad-based anxiety, in vivo exposure to feared cues remains a fundamental component and is arguably the critical element in all successful treatments for fears and anxiety among young people. Hence increasing our understanding of the mechanisms underlying exposure and improving its effects is important to produce maximally efficacious treatments. Among theories of the mechanisms underlying in vivo exposure, strong parallels have been drawn between this clinical technique and the process of extinction (Craske et al., 2008; Davey, 1992; Field, 2006). Despite the fact that the origins of broad-based anxieties are not completely understood and are likely multi-faceted (Rapee et al., 2009), the reduction of clinical fears is likely to
* Corresponding author. E-mail address: [email protected] (R.M. Rapee). http://dx.doi.org/10.1016/j.brat.2016.10.004 0005-7967/© 2016 Elsevier Ltd. All rights reserved.
involve information change in long term memory. Current concepts of extinction argue that delivery of a CS in the absence of the US leads to the learning of a new relationship - in other words, CS - no US (Bouton, Westbrook, Corcoran, & Maren, 2006; Lovibond, 2004), which must be consolidated into memory. Successful extinction therefore, relies on learning about new relationships between two stimuli. As a result, factors that maximise such learning and consolidation of the subsequent memory should increase the efficiency of extinction while processes that disrupt learning or memory consolidation should reduce extinction (Craske et al., 2008). A relatively recent and exciting development has been the identification of several chemical means to enhance consolidation of extinction memories. Of the various cognitive enhancers that have so far been identified, d-Cycloserine (DCS) has received the most extensive evaluation. DCS is a glutamatergic partial NMDA receptor agonist, which facilitates extinction learning related to cued fear (Ledgerwood, Richardson, & Cranney, 2003; Walker, Ressler, Lu, & Davis, 2002). While the precise mechanisms of its action are still not known, DCS appears to facilitate consolidation of new memories associated with the fear response (Baker, McNally, & Richardson, 2012; Vervliet, 2008). A substantial body of work with rats has shown that relative to animals given placebo, those
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administered DCS show more rapid fear extinction, stronger generalisation to related cues, and are less likely to relapse following re-exposure to the UCS (Norberg, Krystal, & Tolin, 2008; Richardson, Ledgerwood, & Cranney, 2004). Among human adults a growing number of studies has begun to demonstrate similar effects in the reduction of clinical fears (Hofmann, 2014; Vervliet, 2008). However, several exceptions have been published (Guastella, Dadds, Lovibond, Mitchell, & Richardson, 2007; Storch et al., 2007). In fact an early meta-analysis demonstrated a significant enhancement of exposure to feared cues among humans by DCS immediately following intervention, but the size of the effect was relatively small (d ¼ 0.42) and markedly smaller than found among animal samples (d ¼ 1.19) (Norberg et al., 2008). A more recent review of cognitive behavioural interventions augmented with DCS compared against augmentation with placebo, showed no significant differences between these conditions (Ori et al., 2015). The slightly different conclusions between these reviews might be due to the updated literature in the latter, but are more likely due to the inclusion of broader and more comprehensive cognitive behavioural treatment programs in the second review. DCS is hypothesised to augment a very specific component of one element of therapy. Therefore, while it is proposed to specifically enhance extinction, it is unlikely to demonstrate marked augmenting effects in the context of an overall efficacious treatment program. Although augmentation of extinction through DCS has been evaluated among adults with several types of anxiety (Guastella et al., 2008; Otto, McHugh, & Kantak, 2010; Ressler et al., 2004), there has been very little evaluation among children (Byrne, Farrell, Storch, & Rapee, 2014). Recent research with rats has suggested that extinction in preweanling rats is not under NMDA receptor control but is more likely to be controlled by an opioid system (Kim & Richardson, 2010; Langton, Kim, Nicholas, & Richardson, 2007). This would imply that DCS may not facilitate extinction in very young rats, but that this effect would only emerge later in development. Determining human age equivalence in rats is complex (Clancy, Finlay, Darlington, & Anand, 2007), however, 16-day-old rats are likely to be most similar to extremely young humans (toddler age) (Quinn, 2005). This suggests that at least from middle childhood, extinction should be mediated by NMDA functioning in the amygdala and that DCS should therefore augment its effects. However the developmental effects are sufficiently unclear that they warrant investigation. To date only a handful of studies has evaluated the use of DCS to enhance extinction among children and most have focussed on obsessive compulsive disorder (OCD). In the earliest report, 30 young people with OCD aged 8e17 years (mean 12 years), were randomly allocated to receive either DCS or placebo (Storch et al., 2010). Capsules (either 25 mg or 50 mg depending on weight) were delivered by parents one hour prior to 7 exposure sessions, couched within an overall CBT treatment program. Although there were some indications that DCS was associated with slightly larger effects than placebo, there were no significant group by time interactions on any variables. A later analysis of this sample also failed to indicate that DCS increased home practice of exposure (Park et al., 2014). A more recent study allocated 17 treatment refractory young people with OCD to either receive DCS or placebo immediately before five sessions of exposure, within a 9-session treatment program (Farrell et al., 2013). The participants were aged 8e18 years, with a mean of 13 years. Most participants showed strong improvements and there were no significant differences between conditions immediately following treatment or at 3-month follow-up. However, the degree of improvement from post-treatment to 1-month follow-up was significantly greater for children given DCS on several measures. Finally, in a minor variation to the standard procedure, Mataix-Cols et al. (2014) delivered
50 mg DCS or placebo to 27 young people with OCD immediately following each of 10 sessions of exposure, within an overarching 14-session CBT program. The two conditions did not differ significantly on outcome and there was no evidence that DCS augmented exposure over placebo at any individual session. A recent study that evaluated the effects of DCS in a sample of children not suffering from OCD failed to show differences between DCS and placebo among 57 youth suffering PTSD (Scheeringa & Weems, 2014). Finally, two studies have evaluated the effects of DCS in augmenting a single session of exposure within anxious children with specific phobias. Byrne et al. (2015) randomly allocated 35 young people (aged 6e14 years; mean 9 years) suffering dog or spider fears to either DCS (50 mg) or placebo. Medication was given one hour before a one-hour session of exposure to the feared cue. There were no significant differences between groups on a follow-up behavioural approach test (BAT) that was conducted approximately five days following treatment in the original treatment setting. However, children given DCS showed significantly greater approach and significantly less distress on a follow-up BAT that was conducted in a different context outside the treatment setting. Farrell et al. (2015) randomly allocated 35 young people aged 7e17 years to receive DCS (35 mg or 70 mg depending on weight) or placebo immediately before a single, 3.5 h session of exposure to their feared cue. There was a significantly greater reduction in clinical global severity from post-intervention to one-month follow-up among the DCS group relative to placebo. Thus to date, there have been few studies of the addition of DCS to in vivo exposure among anxious young people and most have focussed on anxiety-related disorders, OCD and PTSD. Current results do not provide strong support to indicate that DCS augments the effects of in vivo exposure among young people. However, the few positive indications and the occasional positive results among anxious adults, encourages further investigation. Among youth there are currently no studies evaluating effects of DCS with the common, broad-based clinical anxiety disorders, separation anxiety disorder (SAD), social anxiety disorder (SOC), and generalised anxiety disorder (GAD). This was the aim of the current experimental study. In short, the current study involved a short-term comparison of the effects on specific fear of in vivo exposure either supplemented with DCS or placebo among children with broad-based anxiety disorders. Based on the extant literature, we predicted that exposure supplemented with DCS would lead to greater reductions in specific fear and symptoms of anxiety across sessions than exposure plus placebo. Given the variations in effects of DCS across previous trials and the limited research with youth, we also explored the impact of several moderators (including age and diagnosis). In particular, we expected that trials in which exposure was of “good quality” would lead to greater DCS-placebo differences than “poor quality” exposures. 1. Method 1.1. Participants Participants for the study included 25 girls and 26 boys aged 6.8e13.5 years (M ¼ 9.22, s.d. ¼ 1.59 years) who met criteria for an anxiety disorder according to DSM-IV criteria (American Psychiatric Association, 2000). Principal disorders in the sample included: generalised anxiety disorder (45%); social anxiety disorder (31%), separation anxiety disorder (12%); other anxiety (12%). The participants were randomly allocated to receive either DCS or placebo (see procedure). Participants were recruited from the Centre for Emotional Health and were part of a larger cohort seeking treatment for their anxiety disorder. Families wanting
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treatment contacted the clinic following referral from a mental health professional, school personnel, or word of mouth and the current study was conducted before formal treatment commenced. Participants were included in the study if they were aged between 6 and 17 years, met criteria for an anxiety disorder other than specific phobia as their principal disorder, and agreed to participate in an experimental study involving use of a medication. They were excluded if they indicated any of a range of physical or emotional difficulties including: marked depressive symptoms; pervasive developmental disorder; psychotic symptoms; epilepsy; liver or kidney disease. Exclusion criteria were indicated by a checklist completed by a parent and then reviewed by the prescribing psychiatrist (GM). A total of 131 participants were invited to participate and 22 (17%) met one of the exclusion criteria. Of the remaining 109, 46 refused participation (primarily due to unwillingness to take medication) and an additional 12 refused to commit to all sessions, leaving a final sample of 51 (39% of original). A total of 27 participants were randomly allocated to receive DCS (48% boys; M age ¼ 9.41, s.d. ¼ 1.76 years) and 24 received placebo (54% boys; M age ¼ 9.02, s.d. ¼ 1.38 years). The two groups did not differ significantly in age, t(46) ¼ 0.85, p ¼ 0.40, gender, c2(1, N ¼ 51) ¼ 0.18, p ¼ 0.67, or principal diagnosis, c2(3, N ¼ 51) ¼ 0.22, p ¼ 0.98. 1.2. Measures 1.2.1. Diagnoses All diagnoses were assigned by graduate students in clinical psychology or qualified clinical psychologists following structured interview with the Anxiety Disorders Interview Schedule for DSMIV, Parent and Child versions (Silverman & Albano, 1996). Interviewers received training to criterion and research from our clinic has demonstrated inter-rater agreement of kappa ¼ 1.00 for an overall diagnosis of anxiety disorder, and ranging from 0.68 to 0.93 across the major anxiety disorders (Lyneham, Abbott, & Rapee, 2007). Diagnoses and clinician-rated severity of each diagnosis (CSR; on a scale of 0e8) were based on composite parent and child report. 1.2.2. Anxiety symptoms To measure symptoms of anxiety over the previous week, children completed one subscale of the Spence Children's Anxiety Scale SCAS (Spence, 1998) and their parents completed the parallel parent version SCASp (Nauta, Scholing, Rapee, Abbott, & Spence, 2004). The full versions of these measures contain 38 anxiety items that load on six correlated subscales, several of which reflect DSM-based categories including social anxiety, generalised anxiety, and separation anxiety. Internal consistencies for the total scale (alpha ¼ 0.92) and subscales (alphas ~ .6-0.8) are solid and the total and subscales have shown good validity (Nauta et al., 2004; Spence, 1998). For the current study, the parents and child completed only the SCAS subscale that was most directly relevant to the child's principal anxiety disorder at the beginning of each exposure session. 1.2.3. Fear hierarchies During the first session the experimenter, child, and parent constructed a relevant fear hierarchy. Each hierarchy contained 8 to 11 steps (M ¼ 8.35, s.d. ¼ 0.80) and was relevant to the child's principal diagnosis. A key caveat was that steps on the hierarchy had to be able to be performed within the session (ie were practical and available within the university campus). The steps were rated from easiest to hardest and were recorded on a weekly stepladder form, which was then used consistently across the four sessions of the study. In other words, hierarchies were individualised for each
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child but were consistent across the duration of the study. At both the commencement and completion of each session, the experimenter asked the child to indicate how frightened they would be if they had to do each step now. Fear was rated on a visual scale from 0 (very relaxed/no problem doing task) to 10 (extremely scared/ definitely can't do it) and a mean hierarchy score was calculated for the beginning (pre) and end (post) of each session based on the mean of the fear ratings across all steps. 1.2.4. Exposure quality Immediately before each exposure, the experimenter asked the child the following question about their state fear: “You are just about to go and face your fear. How frightened are you right now?” The child was shown a pictorial scale and rated their fear on an 11point scale from 0 (no fear) to 10 (maximum fear). The rating was repeated immediately following the exposure as follows: When you were facing your fear just now, how frightened did you get? Change scores were calculated by subtracting the post-exposure rating from the pre-exposure rating so that positive difference scores indicated more successful exposures (greater fear decrease). Where more than one exposure was conducted within a session, the difference scores were averaged. A second measure of exposure quality was made by experimenters. Immediately following each exposure the experimenter rated the quality of the exposure using three items (all scored from 0 to 3): 1) How smoothly overall did exposure go; 2) How happy/ confident/proud did the child seem immediately after exposure; 3) How well do you think the child learned that what they were afraid of wouldn't happen? Responses to these three items were averaged to create a total exposure quality score for every exposure, with higher scores indicating more positive quality. Where more than one exposure was conducted within a session, the scores were averaged. 1.3. Medications Children were administered either DCS or a placebo in identical gelatine capsules at the commencement of each treatment session. Given conflicting opinions about the optimal time to combine DCS with exposure (Hofmann, 2014; Mataix-Cols et al., 2014), this delivery allowed the medication to build during the exposure period and maintain peak blood levels during the memory consolidation window following exposure. Active capsules contained 50 mg of DCS derived from powder, while placebo capsules contained lactose powder. 1.4. Exposures Experimenters conducting exposures were graduate students in clinical psychology and each child had the same experimenter for all 4 sessions. At each session the experimenter and child selected a step from the hierarchy to attempt. Parents were not present unless the child refused to allow the parent to leave. The selected step at each session was based on a) the child's indication of which step they were prepared to attempt; b) experimenter judgement in aiming to select a step that would elicit mild to moderate anxiety; and c) the previous step that was successfully attempted. Within each session, the child typically repeated tasks up to three times, depending primarily on the duration of a given step e steps that took most of a session could only be performed once, but very brief steps could be performed more often. If a child found that a given step became easy, they could attempt higher steps within the session. As noted, immediately following each task, the experimenter asked the child to indicate how frightened they became during the task. If a step was performed easily and elicited little
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fear, the experimenter encouraged the child to attempt a higher step. If a given exposure task went badly (e.g., child withdrew, reported extreme fear, did not habituate), the experimenter encouraged the child to attempt a lower step to ensure that the session ended on a positive note. 1.5. Procedure Families contacted the Centre for Emotional Health seeking treatment for their child, were given an appointment for a diagnostic assessment and had the current experimental study explained to them. Those who were willing to consider the study were referred to a brief video in which the first author explained the nature of the study, the nature of the medication (DCS), and especially emphasised its safety. Families were then asked at their diagnostic assessment whether they were willing to participate in this pre-treatment study and were asked about exclusion criteria. Those who agreed and met inclusion criteria were given an appointment for their first session. Prior to the first session, the assessment notes and medical checklist were reviewed by the prescribing psychiatrist. A randomisation schedule was prepared via a randomisation website and provided to the dispensing pharmacist who was blind to all aspects of the study hypotheses and participants. Families, experimenters and assessors were all blind to the participant's condition until the completion of the study. Four capsules, clearly marked with the participant's number were given to the relevant experimenter. There was a total of four, weekly sessions. At the commencement of each session, the experimenter gave the child a capsule to ingest, observed the child swallow the capsule, and then proceeded to conduct the session. Each session comprised: completion of pre-session measures; decision of which step to attempt; conducting of one or more exposure tasks; completion of post-session measures. 2. Results 2.1. Group comparisons on implementation of exposure The two groups were compared on several aspects of the delivery of therapy. There was no significant difference between the DCS and placebo groups on the number of sessions attended, t(49) ¼ 0.18, p ¼ 0.86 (DCS, M ¼ 3.70, s.d. ¼ 0.72; Plac, M ¼ 3.67, s.d. ¼ 0.76), total duration of exposure (mins.), t(49) ¼ 0.22, p ¼ 0.83 (DCS, M ¼ 45.10, s.d. ¼ 33.24; Plac, M ¼ 43.27, s.d. ¼ 24.50), number of steps in the hierarchy, t(49) ¼ 1.25, p ¼ 0.22 (DCS, M ¼ 8.22, s.d. ¼ 0.58; Plac, M ¼ 8.50, s.d. ¼ 0.98), and the highest step attempted, t(49) ¼ 0.77, p ¼ 0.45 (DCS, M ¼ 6.56, s.d. ¼ 1.31; Plac, M ¼ 6.92, s.d. ¼ 2.02). 2.2. Group comparisons on reductions in fearfulness Mixed model analyses of variance (ANOVA) were conducted to compare changes over time between the children receiving DCS and those receiving placebo on four outcome measures. The use of mixed models allowed all participants to be included in analyses, even when they may have missed sessions. Based on the mean stepladder score taken at the beginning of each session, there was a significant reduction in fear across time, F(3, 189) ¼ 20.14, p < 0.001, but no significant difference between groups, F(1, 189) ¼ 2.32, p ¼ 0.13, and no significant group by time interaction, F(3, 189) ¼ 0.20, p ¼ 0.90. Similarly, according to the mean stepladder score taken at the completion of each session, there was a significant reduction in fear across time, F(3, 186) ¼ 18.99, p < 0.001, but no significant difference between
groups, F(1, 186) ¼ 1.56, p ¼ 0.21, and no significant group by time interaction, F(3, 186) ¼ 0.27, p ¼ 0.85. Data are presented in Table 1. Based on children's reported anxiety on the fear-relevant SCAS subscale, there was a significant reduction in anxiety across time, F(3, 186) ¼ 4.45, p ¼ 0.005, and a significant difference between groups with children in the placebo group reporting less anxiety than those in DCS, F(1, 186) ¼ 8.71, p ¼ 0.004, but there was no significant group by time interaction, F(3, 186) ¼ 0.22, p ¼ 0.88. Similarly, according to mothers' reports on the relevant SCAS subscale, there was a significant reduction in anxiety across time, F(3, 187) ¼ 3.87, p ¼ 0.010, but no significant difference between groups, F(1, 187) ¼ 1.18, p ¼ 0.28, and no significant group by time interaction, F(3, 187) ¼ 0.27, p ¼ 0.85. Data are presented in Table 1. 2.3. Moderation by exposure quality Some research has suggested that DCS only enhances outcomes when exposure sessions are “successful” (Smits, Rosenfield, Otto, Marques, et al., 2013, Smits, Rosenfield, Otto, Powers, et al., 2013). To evaluate this possibility, because there is no accepted method to determine exposure quality, we examined moderation of the difference between groups in three different ways. First, we re-ran the previous analyses including only data from successful sessions. Each exposure session was defined as successful if the child's experienced anxiety (fear rating during exposure) was lower than their anticipatory anxiety (fear rating before the exposure) or if there was no difference in fear ratings but the experienced anxiety (during exposure) was low (less than 5 on the 0e10 scale). In other words, if there was a disconfirmation of expected fear or if fear was simply low. Defined in this way, the total number of unsuccessful exposures across the four therapy sessions ranged from 0 to 9e39.2% of children experienced no unsuccessful exposures, 78.4% of children experienced two or fewer unsuccessful exposures. In order to determine whether the augmenting effects of DCS became apparent when restricted to successful exposures, the data were re-analysed including only children who experienced two or fewer unsuccessful exposure tasks. The pattern of results was identical with no significant group by time interactions (all interaction F's < 0.50; all interaction p's > 0.70). Second, in order to provide a more continuous measure of exposure success, we used the change in children's predicted fear scores from before each exposure to following each exposure (i.e., the degree of (dis)confirmation of fear expectancy) as a continuous measure of the success of each exposure session. The average change in a child's fear score in one exposure session was poorly predictive of their stepladder score at the beginning of the subsequent exposure (correlations 0.04, 0.02 and 0.01, all p 0.6 correlating change at exposure 1 with stepladder at exposure 2,
Table 1 Estimated marginal means and standard errors (in parentheses) on measures of within-session fearfulness between groups. Session 1
Session 2
Mean pre-session stepladder score DCS group 5.65 (0.30) 4.80 Placebo group 5.60 (0.32) 4.32 Mean post-session stepladder score DCS group 5.20 (0.33) 4.30 Placebo group 4.63 (0.35) 4.11 Fear-relevant SCAS (child) DCS group 7.59 (0.68) 6.99 Placebo group 6.00 (0.73) 5.82 Fear-relevant SCAS (parent) DCS group 8.64 (0.72) 6.89 Placebo group 8.41 (0.76) 7.66
Session 3
Session 4
(0.30) (0.32)
4.31 (0.31) 3.94 (0.32)
3.47 (0.31) 3.04 (0.32)
(0.33) (0.36)
3.46 (0.35) 3.01 (0.36)
2.51 (0.34) 2.50 (0.36)
(0.70) (0.74)
5.66 (0.71) 4.55 (0.74)
5.58 (0.76) 3.42 (0.76)
(0.72) (0.78)
6.05 (0.74) 6.96 (0.78)
5.74 (0.76) 6.62 (0.79)
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etc). Mixed model analysis of variance did not yield any evidence that the degree of correlation between change in fear and subsequent session stepladder score was moderated over the course of the program (p ¼ 0.4). In other words, the extent to which expectancy (dis)confirmation predicted later fear did not differ significantly between the two groups. A final indicator of exposure success was provided by experimenters who rated three qualitative indicators that were averaged for each exposure session. In contrast to the child's fear score, the experimenter's evaluation of the child's response to a therapy session was moderately correlated with stepladder scores at the beginning of the subsequent exposure (correlations 0.28, 0.21, 0.31, all p 0.03). In other words, experimenters' overall judgements of the quality of a given exposure significantly predicted later fear. However mixed model analysis of variance did not yield any evidence that the degree of correlation between experimenters' evaluation and subsequent stepladder score was moderated by pill condition over the course of program (p ¼ 0.3). In other words, this significant prediction did not differ between DCS and placebo, suggesting that it is a general characteristic of exposure, rather than a variable that affects the impact of DCS. 2.4. Subgroup analyses It might be argued that DCS is more likely to augment exposure for those young people with more concrete or clear cut fears. Given the broader and more generalised range of stimuli that are feared by children suffering GAD, it is possible that DCS augmentation effects will be weaker for this population. Therefore, the data were reanalysed excluding those youth who met criteria for a diagnosis of GAD as their principal disorder. Again, the pattern of results was identical with no significant group by time interactions (all interaction F's < 0.43; all interaction p's > 0.74). Finally, given evidence that extinction in preweanling rats is not under NMDA receptor control (Kim & Richardson, 2010), we examined whether the lack of significant differences might have been influenced by the youngest portion of the sample. The data were re-analysed excluding children less than 8 years of age. Again, the pattern of results was identical with no significant group by time interactions (all interaction F's < 0.65; all interaction p's > 0.58). 3. Discussion The potential to increase the effects of a psychological process (extinction) using chemical means arguably represents one of the most exciting developments in cognitive behaviour therapy, both theoretically and practically. As a specific chemical, d-Cycloserine appears to show relatively small effects and a potential for rapid tolerance that makes it unlikely to realise strong practical utility. In fact, RCTs comparing DCS to placebo to augment overall cognitive behavioural programs have failed to indicate clinically significant benefits (Ori et al., 2015). Nonetheless, because of its widespread availability, safety, and long history, DCS provides an ideal substance for “proof of concept”. Indeed, DCS has shown some promising ability to increase the specific effects and generalisation of in vivo exposure among adults suffering anxiety disorders (Norberg et al., 2008). Interestingly, among anxious youth, DCS has shown less consistent effects and has mostly failed to show an enhancement of in vivo exposure (Mataix-Cols et al., 2014; Scheeringa & Weems, 2014; Storch et al., 2010). In fact, within the extant child literature, of five published studies, three have failed to demonstrate significant DCS augmentation effects and two have shown inconsistent effects across time and measures. The only study to
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date that appears to have shown a significant augmentation of exposure by DCS (Farrell et al., 2015) is currently unpublished. Consistent with this literature, the current results also failed to demonstrate an augmentation of fear reduction through in vivo exposure following ingestion of DCS among anxious youth. This is the first trial to have used DCS with young people suffering the types of broad-based anxiety disorders seen most commonly in clinical practice, SAD, GAD, and SOC. On initial consideration, the lack of a significant DCS augmentation appears disappointing. However, the very large number of potential variables (e.g., dosage, timing of DCS delivery, extinction parameters) means that a great deal more investigation is required before concluding that the strong effects noted in carefully controlled animal laboratory studies cannot be generalised to application with young humans. It has been argued that cognitive enhancers will increase whatever learning occurs and hence have the potential to increase the negative effects of “bad” exposures as much as the positive effects of “good” exposures (Hofmann, 2014). Following this logic, Mataix-Cols et al. (2014) delivered medication at the conclusion of exposure so that they were able to only medicate “good” exposures. Theoretically, good exposures should be those that lead to new learning about the lack of CS-US association. However, the best way to operationalise such learning, especially among children who are less able to verbalise their cognitive processes, is far from clear. When we operationalised good exposures as those that resulted in a disconfirmation of expected anxiety (anxiety reduction or low anxiety) (Craske et al., 2008; Lovibond, 2004), restricting analyses to those youth who primarily reported positive disconfirmations did not affect the results. This might partly be due to the fact that our experimenters were instructed to try to ensure that all sessions ended with a positive disconfirmation of predicted anxiety. Nonetheless, more fine-grained examination of the impact of positive vs negative exposures on DCS augmentation, also failed to indicate any moderation. When the degree of change in state anxiousness during exposure according to children's reports was used as an index of exposure quality, there was no moderation of fear reduction between the two groups. A similar lack of moderation was shown when experimenters' qualitative ratings of exposure quality were used. The parameters of delivering in vivo exposure are extensive and it is possible that other ways of delivering exposure may have resulted in a greater DCS/placebo difference. However, using the current methods, which reflect common practice, we were unable to detect any major impact of DCS. Despite the fact that it did not moderate the augmentation of exposure by DCS, experimenters' ratings of exposure quality did predict subsequent fear overall. The fact that experimenters are able to provide some estimate of exposure success has both theoretical and clinical implications. Experimenters' ratings were comprised of subjective estimates of the exposure process, the child's reaction to the exposure, and the extent of apparent expectancy change that the child expressed. Any one of these items may have been critical to the prediction of subsequent fear, and more focussed research is needed to determine the precise parameters by which therapists can best predict exposure quality. Being able to determine these parameters will facilitate means of maximising the quality and efficacy of exposure-based treatments. Of theoretical interest, it is possible that extinction learning in youth is under the control of different neurological systems than it is later in development (Kim & Richardson, 2010). Hence, NMDA receptor agonists such as DCS may not augment extinction early in life. It is more likely that biological differences in fear-learning systems characterise far younger children than used in the current study, but it remains possible that such differences may have been responsible for the lack of any significant DCS augmentation. Although we also failed to show a DCS-augmentation effect when
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we excluded the youngest children, potential age differences in response to DCS deserve further evaluation with larger samples. In fact a potential limitation to the overall study was a lack of power. From a practical perspective it was difficult to recruit a large sample. Our ethics committee required us to entertain a large number of exclusion criteria and 17% of the possible sample was excluded. This issue highlights an obvious limitation to use of DCS in clinical practice. Adding to this difficulty, few families were motivated to enter the study and almost half (42%) of those who were eligible refused participation. This limitation is consistent with data showing that parents are often unwilling for anxious children to be placed on medications, especially DCS (Byrne, Rapee, & Sweller, 2015; Roberts, Farrell, Waters, Oar, & Ollendick, 2016). A further methodological issue worth discussing is the diagnostic composition of the sample. While most previous research has restricted itself to extremely narrow diagnostic selection, we included a broader range of anxiety disorders. On the one hand, this heterogeneity is a strength of the study since it allows greater generalisation of conclusions and a closer approximation to the realities of clinical practice. However, it is possible that the variety of diagnoses concealed any differences in DCS reactivity between diagnostic groups. Our exploratory analyses failed to indicate any obvious impact of a diagnosis of GAD, but the study was not properly powered to examine such moderations. From a theoretical perspective, extinction is a process that is assumed to underpin fear reduction across all CS-US relationships and there is no current theory that predicts that extinction mechanisms will differ between social threat and physical threat cues. Nonetheless, replication with a markedly larger sample that allows examination of diagnostic moderation is warranted. An additional limitation was the primary reliance on child reported fear. Data from the parent measure of anxiety symptoms was consistent with the data from children's reports. Nonetheless, including measures based on researcher reports or observational measures might produce different results in future studies. In summary, DCS failed to enhance exposure for youth with broad-based anxiety disorders. Although it is highly unlikely that DCS will prove to be the “holy grail” sought by clinical practitioners, the paradigm of using chemical means to directly enhance fear extinction is a ground-breaking innovation that deserves considerably more experimental investigation. On a positive note, the results of this study also strongly reinforce the power of in vivo exposure to reduce a wide variety of fears and avoidance. Children in both groups showed dramatic reductions in their primary fear following only a few brief sessions. It is often useful to remind ourselves of the old lessons. Funding source This research was supported by Australian Research Council grant DP1095162. Conflict of interest Nil. Acknowledgements The authors acknowledge the support of Jane Stidworthy and staff at the Macquarie Hospital pharmacy for their assistance with medication preparation, supply and concealment. References American Psychiatric Association. (2000). Diagnostic and statistical manual of mental
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