Longterm Effects of
Noradrenergic β-blocker Propranolol HCL Based
Treatment on Spider Fear
S.N. de Waal
Name: Sascha de Waal Student number: 10002728 Date: 02-09-2016
Supervisor: Jamie Elsey University of Amsterdam
2 Table of contents
1. Abstract………...3
2. Background……….4
3. Methods and materials………....9
3.1 Participants………..………..9 3.2 Assesments………..………..9 3.3 Procedure………..………...12 4. Results………...13 4.1 BDI………..13 4.2 STAIT………..14 4.3 SPQ………..15 4.4 BAT……….19 5. Discussion……….20 6. References……….27
3 1. Abstract
Noradrenergic β-blocker propranolol HCL based treatment seems able to target original fear memory in participants with spider fear. Disrupting reconsolidation after reactivating fear memory results in lower self reported fear of spiders and more approach behavior towards spiders immediately after treatment and after one year. This study investigated these results after three years.
Thirty participants, divided over the propranolol reactivation (the active treatment group), pill placebo and propranolol only group (the non-active group), who participated in the original study filled in questionnaires and completed the baby tarantula BAT and tarantula BAT.
The drop in SPQ scores in the active treatment group was maintained at the three year follow-up. Self-reported fear was still lower than at the pretest, the average score was still below the cutoff score for spider phobia. On the BAT, the active group scored lower at the three year than at the one year follow-up, showing less approach behavior. There was no significant difference between the BAT scores at the pretest and three year follow-up in the active group, despite slightly higher average BAT scores at the three year follow-up.
However, the active group still showed more approach behavior than the non-active group. There are some clear long-term effects three years after treatment. The drop in BAT scores could be partly to do with the spider being significantly bigger. Also, part of the fear memory seems to stay intact after administering propranolol, which could result in relapse rates. Future research should focus on comparing treatment like exposure with propranolol based treatment and look at the possibilities of bolstering the effects of propranolol.
4 2. Background
Remembering fearful moments is necessary to adapt to future risks. However, remembering these moments can also cause trouble. When fear memory becomes
maladaptive, disorders such as phobias or posttraumatic stress disorder can develop. One way to establish fear memory is by Pavlovian fear conditioning. Conditioning links an initially neutral cue, the conditioned stimulus (CS) to something aversive, the unconditioned stimulus (US). This is the foundation of an associative fear memory: when CS is presented a US representation is retrieved (Soeter & Kindt, 2015).
For a long time it was believed that once such a fear memory was formed, it could not be modified. Many have tried to change undesired emotional memory, but even if treatment was effective it appeared to only eliminate the fearful responding and leave the original fear memory intact (Bouton, 2002). This was supported by high percentages of relapse, even if the treatment seemed successful at first (Craske, 1999). The ‘old’ fear memory can be activated by external factors such as a change of context, which can trigger the fear response again (Bouton & Bolles, 1979).
In current treatment for anxiety disorders, cognitive behavioral therapy is often used. Evidence suggests that this therapy can be effective (Butler, Chapman, Forman & Beck, 2006; Hofmann & Smits, 2008). With cognitive behavioral therapy, new memories are formed by teaching people to think differently about their fears, and old memories are deactivated. The old memories stay intact, but new memories can become stronger than them. When this happens, they can have more influence on behavior and mood than the old memories.
However, the old memories are still present so it is possible that in time the old memories take over the control of behavior and mood from the new memories (Brewin, 2006).
Another treatment for anxiety disorders is exposure therapy. Extinction learning provides the experimental basis for this therapy. When extinction occurs, the conditioned
5 responding following a stimulus decreases when the reinforcer is omitted. However, Pavlov observed that when enough time passes, the extinguished responding to a CS spontaneously recovers. A change in context or presenting the US can also result in the return of the
extinguished response. This suggests that extinction can be seen as new learning, forming new memories while leaving the old memories intact (Quirk & Mueller, 2008).
An alternative approach to treatment is pharmacotherapy. Typical pharmacological approaches are usually seen to be more prone to relapse, as they are seen as largely palliative in nature (Hollon, Stewart & Strunk, 2006). Pharmacological therapy usually focuses on an alleged neurochemical imbalance. By delivering the involved chemicals to the brain it tries to achieve a balance again. However, this strategy does not necessarily address the original reason the imbalance occurred. When comparing CBT, exposure, and standard
pharmacological treatment, a similarity is that they do not seem to tackle the root problem of the disorder. When a balance is restored by pharmacological treatment and the treatment ends, it is possible that the balance becomes disturbed again if the original reason of the imbalance is not resolved. A difference between CBT and pharmacological treatment is that people can take what they learned during psychotherapy with them. In psychotherapy new learning occurs and new memories are formed. When people stop taking a drug, their effects may also end. Because of this, a higher relapse rate can be expected when using pharmacological treatment (Elsey & Kindt, 2016 accepted).
Previously discussed were the current treatment methods for anxiety disorders. As these treatments do not appear to target the old fear memory, it is interesting to see if it is possible to find a treatment that does, and what the long-term effects of this treatment would be. In contrast to the idea that fear memories are immutable once formed, recent research has suggested that the original fear memory can be modified. When fear memory is retrieved, it can instigate a protein synthesis-dependent restabilization process known as reconsolidation
6 (Nader, Schafe & LeDoux, 2000). Reconsolidation of even strong fear memory can be
disrupted by drugs such as Propranolol. This can happen when drugs are administered during or shortly after retrieval of fear memory (Kindt, Soeter & Vervliet, 2009; Soeter & Kindt, 2011). The noradrenergic β-blocker Propranolol HCL can pass the blood brain barrier and is supposed to block the β-adrenergic receptors in the amygdala, where it interferes with the PLA-CREB pathway that is involved in the neuroplasticity of memory (Josselyn et al. 2001; Johansen, Cain, Ostroff & LeDoux, 2011). The basic model for this treatment sees the
presence of a maladaptive fear memory, which causes a reaction of excessive fear and anxiety in response to a particular stimulus, as a very important factor. Reconsolidation can be
triggered by using specific conditions to reactivate this memory. Following reconsolidation propranolol is used that interferes with the reconsolidation process, thereby potentially reducing the strength of the original memory.
Merel Kindt has done research with this new form of therapy for anxiety disorders, and the results seem promising. Kindt, Soeter and Vervliet (2009) found that a substantial weakening of the fear response can follow when propranolol is administered before
reactivating fear memory. In this research, the behavioral expression, a startle response, of the fear memory was completely eliminated after 24 hours in one reactivation trial combined with propranolol. A well-established retrieval technique was unable to activate any fear response. It seems that the original fear memory could have been erased, or there had been a retrieval failure that made it unavailable for retrieval. Soeter and Kindt (2011) found that these retrieval techniques could reinstate fear responses when extinction training was performed, but not when memory reconsolidation had been disrupted by propranolol. This suggests that propranolol weakened the original memory trace and spontaneous recovery is unlikely to happen. Indeed, in another study, Soeter and Kindt (2010) found that when propranolol is
7 administered before activating a fear memory, the startle response was neutralized 24 hours later. These results persisted at 1 month followup.
These findings suggest that interfering with fear memory reconsolidation could serve as an effective treatment for anxiety disorders. Soeter and Kindt (2015) assessed this
possibility in participants with high fear of spiders. Spider fearful individuals were asked to approach a terrarium and touch the tarantula that was in it, so as to reactivate their fear memory. In the room where the tarantula in the open cage was, there was a mark on the ground at 60 cm from the cage. Participants were asked to walk towards this mark and stay there to look at the spider closely. The tarantula was chosen for this research because it would mostly sit at the front of the cage. When it was sprayed with water it would usually move to the middle of the cage. While watching the spider, participants were asked what their biggest fear was about touching the spider. They were also asked, on a scale from 0 till 100, how sure they were that this would happen. After this, it was told that they had to touch the tarantula and it was asked how high their fear or anxiety was on a scale from 0 till 100. The participants were now standing in front of the open cage for approximately 2 minutes and the therapist would now close the cage. The participants did not have to touch the tarantula. After this, the participants received a (double blind) oral dose 40 mg of propranolol HCl or a pill placebo in another room.
When participants in the active treatment group were asked to touch the spider 4 days later, it appeared that the reconsolidation of fear memory was disrupted by propranolol, resulting in approach behavior instead of avoidance behavior. Participants in the active treatment group were now able to touch the large tarantula, and could also touch or even hold a smaller tarantula that they had not been exposed to during treatment. Participants whose memories had not been reactivated in combination with propranolol showed no changes in their fear of spiders. In the one year follow up the same results were found again.
8 Interestingly, the subjective fear measured by the Spider Phobia Questionnaire did not seem to drop immediately along with the change in behavior. First the avoidance behavior changed to approach behavior, and the subjective fear dropped several months later. It seems like behavioral change can influence the cognitive expression of fear. This is in line with the effect of propranolol, which seems to act specifically on the β-adrenergic receptors in the amygdala. The amygdala is essential for the emotional, not the cognitive, expression of fear memory. Propranolol seems to target the old memory by acting on the amygdala, which could result in long-lasting effects.
Using this new strategy, the old memory can be modified, by which a key component of the disorder is targeted. It appears that disrupting reconsolidation with propranolol can neutralize the original fear memory, something previous methods did not appear to achieve (Bouton, 2002). This makes it different from the usual treatment used for anxiety disorders. Because the original fear memory appears to be targeted by reconsolidation, it is expected that the results will be long-lasting, and relapse rates will stay low even after a long period of time.
The current study was an even longer-term follow-up of the research of Soeter and Kindt (2015), approximately three years after the original research. Long-term effects and low relapse rates would be promising results for usage of this therapy as a new therapeutic
intervention for anxiety disorders. Even more so because current therapies leave the old memory intact which can result in spontaneous recovery of the fear reaction and high relapse rates. In this longer term follow-up there was no comparison with any other kind of treatment, the focus was just on the long-term outcome of the original study.
It was expected that the SPQ scores would be lower than at the pretest (T0), which would indicate a lower self reported fear of spiders, in the propranolol-reactivation group. The scores would be lower in the propranolol-reactivation group than in the pill
9 behavioral approach test (BAT) scores with both spiders would be higher than at the pretest (TO), which indicates a higher level of approach behavior, in the propranolol-reactivation group. The scores would be higher in the propranolol-reactivation group than in the pill placebo-reactivation group and the propranolol only group.
3. Methods and materials
3.1 Participants
A total of 30 healthy individuals who participated in the original study approximately three years ago, took part in this study. From the 30 individuals, 26 were women. We were unable to locate the participants’ dates of birth, but in the original study the 26 women ranged in age from 18-31 years (mean ± SD age, 20.96 ± 2.71 years). Men ranged in age from 20-32 years (mean ± SD age, 24.75 ± 5.25 years). Participants had previously been randomly assigned to either the propranolol + reactivation (n= 11, 9 women) or the pill placebo + reactivation group (n= 11, 10 women). An additional propranolol no reactivation, propranolol only, group was also included (n=8, 7 women) to take any nonspecific dampening effects of the propranolol drug in account.
3.2 Assessments
Questionnaires
The Beck Depression Inventory – II (BDI-II) (Beck, Steer & Brown, 1996) measures depressed mood and symptoms of depression. It consists of 21 items/symptoms and attitudes which can be rated from 0 till 3 in terms of severity. The self-report form was administered in this study. The cutoff score for no, or minimal depression is < 10, mild to moderate
depression 10-18, moderate to severe depression 19-29 and severe depression 30-63. The BDI-II has high internal consistency, both in psychiatric and nonpsychiatric samples and the construct validity is strong. The test-retest reliability is good. The BDI-II correlates with both
10 clinical assessment of depression and other well-researched instruments that measure
depression, yielding good concurrent validity. Research suggests that the BDI-II can
differentiate between psychiatric and nonpsychiatric patients (Beck, Steer & Brown, 1996). This inventory will be used to analyze whether depression correlates with BAT scores. It could be possible that depression decreases participants’ motivation to perform the BATs at their best. Differences in depression between the groups will also be analyzed. .
The Spielberger State-Trait Anxiety Inventory (STAI) (Spielberger, 1970) is
frequently used to measure anxiety. It consists of two questionnaires which each consist of 20 questions. The first questionnaire measures state anxiety, STAIS, (how one feels at the
moment), the second trait anxiety, STAIT, (how one generally feels). The STAI is a reliable and valid questionnaire (van der Ploeg, 1982). The STAIT was used to explore whether there were any group differences in trait anxiety.
The Spider Phobia Questionnaire (SPQ) (Muris & Merckelbach, 1996) is a self-report spider fear questionnaire. It consists of 31 statements reflecting how a person might feel or think about spiders, which can be rated true or false. Scores range from 0-31. A high score correlates with strong fear of spiders, and a score of 18 or above might indicate spider phobia (though this is not a diagnostic instrument). An example of a (reverse scored) question is ‘I have no fear of non-poisonous spiders.’ The SPQ can differentiate between people with and without spider phobia, which indicates a good validity. The test-retest stability is good, which indicates a good reliability. The SPQ turns out to be sensitive for therapeutic changes: after successful treatment the SPQ scores drop. The SPQ correlates with other questionnaires and behavioral experiments assessing fear of spiders, which indicates good convergent validity (Muris & Merckelbach, 1996).
11 Behavioral Tests
Behavioral approach tests (BATs) are able to assess the level of fear when participants are exposed to a live spider. By using BATs the approach behavior towards spiders becomes visible, providing an ecologically valid measure of spider fear.
Pre- and Posttreatment Assessments with Baby Tarantula.
Participants were asked to enter a room where a baby tarantula was placed in a closed jar on a table. They were asked to sit down at the table and to complete each step of the standardized baby-tarantula BAT, with 3 minutes allowed for each step (Table 1). They were free to stop when they wanted. Scores range from 0-8, depending on the last step they completed. During the BAT participants were asked to rate their level of fear on a scale from 0-100 (Wolpe, 1973) at every completed step: 0= no fear, 25= mild fear, 50=moderate fear, 75= severe fear, and 100= very severe fear. For the present analyses, we focus only on the behavioral scores rather than subjective anxiety, as BAT scores were the primary outcome measure in the original study of Soeter and Kindt (2015).
Posttreatment Assessment With Tarantula.
Participants were asked to stand in front of an open cage with a tarantula in it. After starting at approximately a 60 cm distance from the spider, participants were asked to try to touch the spider with their bare fingertips. Scores depended on the nearest proximity to the tarantula: 0= staying at a distance of 60 cm from the tarantula, 1= standing at a distance of 30 cm from the spider, 2= standing at the front of the container, 3= touching the container, 4= dangling a hand inside the container, and 5= touching the tarantula (Rodriguez, Craske, Mineka & Hladek, 1999). When the participants reached their nearest proximity, they were asked to rate their level of fear or anxiety on a scale from 0 till 100, as in the BAT above.
12 Table 1
Steps of the Standardized Baby-Tarantula BAT
Step # Instructions for the BAT
1 Sit in front of a spider that is in a closed jar at a distance of 20 cm. 2 Hold the palm of your hand on either side of the closed jar for at least
10 seconds.
3 Open the jar with the spider.
4 Pick up the open jar with the spider for at least 10 seconds.
5 Direct the spider’s movement in the jar with a pencil for at least 10 seconds.
6 Put the spider in a tummy-tub.
7 Follow the spider with a bare finger as it crawls around the tummy tub for at least 10 seconds.
8 Let the spider walk on your bare hands.
3.3 Procedure
Researchers
The research was conducted by a research assistant, a PhD candidate (the supervisor of the project), and a master student.
Procedure
Both assessors were blind to the original treatment condition the participants were in. If participants were unable to join the research at the lab, questionnaires were sent by email. Participants were first asked to fill in the questionnaire measures. The participants were then asked to do the BAT with the baby tarantula, followed by the tarantula BAT.
The participants were also asked if they had received any other treatment since the original research, done any self-treatment or had noteworthy experiences with spiders (results are not reported here, as this data was not collected consistently and will be subject to further
13 4. Results
Although participants completed the tarantula BAT, it was not suitable for analysis. It turned out that in the previous tarantula BATs, only the top of the container was opened. In the current study, the front of the container was also opened. This caused the steps of the BAT to differ in meaning and rendered the numerical steps incomparable to the prior assessment. Before, participants were seen to first touch the container at the top, before dangling their hand in. However, this step was seen to be very different when the front door was opened, touching the container was not a logical step in the path to touching the spider anymore. Moreover, as the spider was normally at the front of the contained, it did not make sense to dangle one’s hand in unless one was on the way to touching it. The two earlier steps also became more anxiety provoking. Because the steps could not be compared, we chose not to analyze this data.
4.1 BDI
The means for the BDI were calculated for the three groups, see table 2. Correlations were calculated between the BAT baby tarantula scores and the BDI. Differences between groups on the BDI were also analyzed.
A Spearman’s rank order correlation was run, as the BAT scores are nonparametric. There was a non significant trend towards an association between BDI and BAT scores, rs(29) = -.31, p =.093, so we checked for any differences between groups in case this was a cofound. There were no differences in BDI scores between the groups. The propranolol reactivation group did not differ from the pill placebo group, t (14) = 1.67, p =.188. The pill placebo group did not differ from the propranolol only group, t (9) = -2.06, p =.344. The propranolol
reactivation group did not differ from the propranolol only group, t (9) = -.914, p = .454. Because of this, depression was not used as an exclusion criteria in this study.
14 Table 2
Mean scores and standard deviations for the BDI
Group BDI
Mean (SD) propranolol + reactivation (n=12) 4.25 (3.02)
pill placebo + reactivation (n=10) 3.20 (3.29)
propranolol only (n=9) 5.67 (9.37)
4.2 STAIT
The means for the STAIT were calculated for the three groups, see table 3. There were no differences in STAIT scores between the groups. The propranolol reactivation group did not differ from the pill placebo group, t (20) = -1.18, p = .252. The pill placebo group did not differ from the propranolol only group, t (16) = -.40, p = .697. The propranolol reactivation group did not differ from the propranolol only group, t (16) = -1.44, p = .168. Trait anxiety was not a cofound in this study.
Table 3
Mean scores and standard deviations for the STAIT
Group STAIT
Mean (SD) propranolol + reactivation (n=11) 31.64 (7.74)
pill placebo + reactivation (n=11) 35.82 (8.85)
15
4.3 SPQ
First the means were calculated for the SPQ scores. They were calculated for the three different groups; propranolol + reactivation, pill placebo + reactivation and propranolol only, at the pre-test, one year follow-up and three year follow-up. The scores are summarized in table 4.
Table 4
Mean scores and standard deviations for the SPQ scores at the pre-test, one year follow-up and three year follow-up
Group SPQ pre-test Mean (SD) SPQ 1 year Mean (SD) SPQ 3 year Mean (SD) propranolol + reactivation (n=11) 19.91 (2.70) 13.00 (3.58) 14.73 (5.41) pill placebo + reactivation (n=11) 20.64 (3.17) 20.73 (3.00) 17.64 (5.35) propranolol only (n=7) 19.86 (5.82) 19.14 (4.95) 16.00 (3.37)
By using a mixed design ANOVA (treatment group (propranolol+reactivation,
Placebo+reactivation, propranolol only) x time (pre-test, one year followup, 3 year followup)) the differences between the groups and within the groups were analyzed for the SPQ scores. This analysis could show if SPQ scores changed over time and if SPQ scores differed between groups.
Mauchly’s test indicated that the assumption of sphericity had been violated, χ² (2) = 13.34, p = .001, therefore the Greenhouse-Geisser correction was used (ɛ = .71). There was a
16 significant main effect of time on the SPQ scores, F (2, 52) = 11.68, r < .001. This indicates that SPQ scores change in time, regardless of which group you are in. There was also a significant main effect of group on the SPQ scores, F (2, 52) = 3.57, r < .05. This indicates that differences between SPQ scores depended on which group a participant was in. There was a significant interaction effect between time and group, F (4, 52) = 4.22, r = .013. This indicates that changes in time of SPQ scores differed between groups. Decrease in time of self reported fear depends on which group a participant is in, see figure 1.
Figure 1. SPQ scores of the different groups at the pretest, one year follow-up and three year
17 Because we wanted to compare the groups at different times, post hoc tests were used. By using independent samples t-tests, we assessed whether the groups differed in SPQ scores at the pretest, 1 year follow-up, and 3 year follow-up. A Bonferroni correction was
considered, but since all the tests are based on previously set hypotheses and the sample size was small, we considered such an approach too conservative. Hence, results are assessed using a significance threshold of <.05.
At the pretest, the propranolol reactivation group and the pill placebo group did not differ in SPQ scores, t(20) = -.579, p = .569. The pill placebo group and the propranolol only group did not differ in SPQ scores, t(16) = .370, p = .716. The propranolol reactivation group and the propranolol only group also did not differ in SPQ scores, t(16) = .02, p = .983. In short, the three groups did not differ in their SPQ scores at pre-test.
At the one year follow-up the propranolol reactivation group scored significantly lower (M = 13.00, SD = 3.58) than the pill placebo group (M = 20.73, SD = 3.00), t(20) = -.5.49, p < .01. This indicates a lower self reported fear of spiders in the propranolol
reactivation group. The pill placebo group and the propranolol only group did not differ at the one year follow-up, t(16) = .851, p = .407. The propranolol reactivation group scored
significantly lower (M = 13.00, SD = 3.58) than the propranolol only group (M = 19.14, SD = 4.95), t(16) = -3.07, p < .01. This indicates a lower self reported fear of spiders in the
propranolol reactivation group.
At the three year follow-up the propranolol reactivation group and the pill placebo group did not differ in SPQ scores, t(20) = -1.27, p = .110. The pill placebo and propranolol only group did not differ in SPQ scores at the three year follow-up, t (16) = .72, p = .483. The propranolol reactivation and propranolol only group also did not differ in SPQ scores at the three year follow-up, t (16) = -.56, p =.294. This indicates that self reported fear was not
18 significantly lower in the propranolol reactivation group than in the pill placebo or
propranolol only group at the three year follow-up.
By using a paired samples t-test we looked if SPQ scores differed between the pretest, one year follow-up and three year follow-up for each group.
When looking at the propranolol reactivation group, SPQ scores were higher at the pretest (M = 19.91, SD = 2.70) than at the one year follow-up (M = 13.00, SD = 3.58), t (10) = 6.33, p < .01. This indicates a lower self reported fear of spiders at the one year follow-up. SPQ scores did not differ between the one year followup and three year followup, t (10) = -1.43, p =.183. SPQ scores were higher at the pretest (M = 19.91, SD = 2.70) than at the three year follow-up (M = 14.73, SD = 5.41), t (10) = 2.92, p < .01. This indicates a lower self reported fear of spiders at the three year follow-up, and that the drop in self-reported spider fear at 1 year post-treatment had been sustained at three years.
When looking at the pill placebo group, SPQ scores did not differ between the pretest and one year follow-up, t (10) = -.12, p = .910. SPQ scores were higher at the one year follow-up (M = 20.73, SD = 3.00) than at the three year follow-up (M = 17,64, SD = 5.35), t (10) = 2.47, p <.05. SPQ scores did not differ between the pretest and three year follow-up t (10) = 1.80, p =.102.
When looking at the propranolol only group, SPQ scores did not differ between the pretest and one year follow-up, t (6) = .67, p =.526. SPQ scores did not differ between the one year follow-up and three year follow-up, t (6) = 1.74, p =.132. SPQ scores also did not differ between the pretest and three year followup, t (6) = 2.02, p =.090.
19
4.4 BAT
First the means were calculated for the baby tarantula BAT at the pre-test, one year follow-up and three year follow-up. Given their comparable scores at pretest and one year followup, the non-active groups were paired together to compare those scores with the active group. The scores are summarized in table 5. Since the BAT scores are ordinal,
non-parametric tests were used.
Table 5
Mean scores and standard deviations for the BAT baby tarantula scores at the pre-test, one year follow-up and three year follow-up
Group BAT baby
tarantula pre-test Mean (SD) BAT baby tarantula 1 year Mean (SD) BAT baby tarantula 3 year Mean (SD) Active (propranolol + reactivation) (n=10) 5.00 (1.05) 7.20 (0.79) 5.60 (1.51)
Non-active (pill placebo + propranolol only) (n=15)
4.27(1.05) 4.33 (1.29) 3.87 (1.64)
By using the Wilcoxon matched-pair signed-rank, differences between the BAT scores at the pretest, one year follow-up and three-year follow-up were analyzed for the active group (propranolol reactivation group) and non-active group (pill placebo+propranolol only). For the propranolol reactivation group, the BAT score was higher at the one year follow-up (M = 7.20, SD = .79) than at the pretest (M = 5, SD = 1.05), z = -2.83, p <.01, this indicates more approach behavior at the one year follow-up. The BAT score was lower at the three year followup (M = 5.60, SD = 1.51) than at the one year followup (M = 7.20, SD = .79), z =
-20 2.38, p <.05, this indicates less approach behavior at the three year follow-up. There was no difference between the BAT score at the pretest and three year follow-up, z = -1.24, p =.108. For the control groups, the BAT scores did not differ between the pretest and one year follow-up, z = -.33, p = .739. The scores did not differ between the one year follow-up and three year follow-up, z = -1.47, p = .141. The scores also did not differ between the pretest and three year follow-up, z = -.67, p = .501.
By using the Mann-Whitney U, differences between the BAT scores of the active group (propranolol) and non-active group (pill placebo+propranolol only) at the pretest, one year follow-up and three year follow-up were analyzed. At the pretest, the active and non-active group did not differ in BAT scores, U = 52.50, z = -1.42, p =.157. At the one year follow-up, the active group (M = 7.20, SD = .789) scored higher on the BAT that the non-active group (M = 4.33, SD = 1.29), U = 4.00, z = -4.12, p <.001, this indicates more approach behavior in the active group. At the three year follow-up the active group (M = 5.60, SD = 1.51) scored higher on the BAT than the non-active group (M = 3.87, SD = 1.64), U = 35.00,
z = -2.31, p <.05, this indicates more approach behavior in the active group than the inactive
groups at 3 year follow-up.
5. Discussion
The current findings suggest that the effects of the noradrenergic β-blocker propranolol HCL based treatment on spider fear could be long-term.
On the SPQ, an interaction effect was found between time and group. How much self reported fear of spiders decreased in time, depended on which group a participant was in. The drop in SPQ scores in the active treatment group at the three year follow-up was maintained, self-reported fear was still lower after three years than at the pretest. There were no
differences between the active group and the non-active groups, which was not expected. On the BAT, the active group scored higher at the one year follow-up than at the pretest, showing
21 more approach behavior towards the spider as was expected. Contrary to what was expected, the active group scored lower at the three year follow-up than at the one year follow-up, showing less approach behavior. Furthermore, there was no significant difference between the BAT scores at the pretest and three year follow-up in the active group, despite slightly higher average BAT scores. However, the active group did show more approach behavior than the non-active group at the three year follow-up. This was also found at the one year follow-up. Indeed, the inactive groups scored marginally lower than at pre-test, whereas the active group scored marginally higher.
Self-reported fear of spiders decreased after the β-blocker propranolol HCL based treatment. This was found at the one-year follow-up and persisted after three years. After three years the average SPQ scores were still below the cutoff score of 18 for spider phobia, while at the pretest the average SPQ scores were above the cutoff score. Since the SPQ can reflect how a person might feel or think about spiders in general, this can be seen as an important result. Participants experience a feeling of significantly less fear of spiders in their life. In the study of Soeter and Kindt (2015), it was seen that a decrease in SPQ scores did not follow directly after the treatment. The change in SPQ scores seemed to follow after the drop in BAT scores, several months later. This finding is opposite of what previously had been believed; that changes in cognitions were central to behavioral changes (Clark, 1995). We have seen that if propranolol interferes with someone’s reconsolidation their behavior can change. This change in behavior can result in a change in cognitions. Propranolol seems to act on the β-adrenergic receptors in the amygdala (McGaugh, 2004), which are essential for the emotional expression of fear and not the cognitive expression (LaBar & Cabeza, 2006). But it seems that by targeting the emotional expression, the cognitive expression can be influenced. The change in cognitive expression seems long-lasting, as in this study the self reported fear
22 of spiders was found to still be lower than before the treatment. Looking at these results, it seems promising that such a short intervention can have long-term effects.
The absence of a significant difference between the propranolol reactivation group and the pill placebo and reactivation only group seems due to a decrease in SPQ scores in the last two groups. This decrease was significant in the pill placebo group. The decrease in the propranolol only group was not significant, but showed a negative trend. Because these
participants did not receive active treatment, drops in SPQ scores were not expected. Research shows that disorders are not stable throughout time, intensity can fluctuate (Wittchen, Lieb, Pfister & Schuster, 2000). It is possible that more participants who were in the pill placebo group and reactivation only group that were experiencing less fear of spiders wanted to participate, than participants who were experiencing high fear. Since they have not received active treatment, they might not want to participate anymore because they may have the feeling they will not benefit from it. They might also be reluctant to come because they have done the BAT before and might be scared of it. These could be reasons for people who are currently experiencing high fear of spiders to choose not to participate in the study. It is also possible that when participants were first participating in the study, they wanted to do so because their fear of spiders was at a very high level at that time. It could be that their fear is now less extreme than at the pretest, due to normal fluctuations in the intensity of their symptoms. This could be a reason for lower SPQ scores than at the pretest and one year follow-up.
When looking at the procedure of this study, it could be possible that procedural errors caused the scores of the BAT to turn out differently than expected. It is notable that the dwarf tarantulas used in the present study were significantly larger than that used in the previous assessments, especially after the spider shed its skin part way through the data collection. Several participants said they believed the spiders were bigger than previously, and this was
23 also suggested by one of the lead researchers on the original study. A bigger spider could of course be scarier for the participants, resulting in lower BAT scores. Indeed, looking at the results, one can see a slight trend to a decrease from pre-test BAT scores in the inactive treatment groups, which might further suggest that this test was genuinely harder than that previously conducted. Since there was a small sample size, it is important to note that one participant who was in the propranolol reactivation group scored exceedingly low on the SPQ at the three year follow-up, but was unable to return for the BAT. It can be expected that this score would have resulted in an increase of the average BAT score.
There could also be a small relapse rate, which might suggest that part of the old memory stays intact after administering propranolol after reactivating fear memory. The theory that propranolol modifies the old memory and targets reconsolidation could still be correct, but these effects might not be as strong as they initially seemed. Ryan, Roy, Pignatelli, Arons and Tonegawa (2015) disrupted consolidation with a protein synthesis inhibitor in mice. They found that there were cells in the brain that were able to cause memory retrieval, after this protein synthesis inhibitor was administered. This suggests that there might be other cellular modifications that remain intact and can lead to retrieval. The same could be the case for reconsolidation, cells that can cause memory retrieval could remain active after reconsolidation is interrupted, possibly causing relapse. Moreover, in the previous studies it was shown that declarative memory stayed intact, participant did not forget that they were afraid of spiders. This memory could cause someone to become afraid again, as they remember they once were afraid of spiders. Participants’ fear of spiders was shown to be reduced at the one year follow-up, but since SPQ scores were not reduced to zero participants still experienced some fear of spiders. This was supported by the subjective anxiety
participants reported during the BAT’s. Because of this, it is possible that fear memory became stronger again over time. Relapse rates in current treatment like cognitive behavioral
24 therapy and exposure seem due to this process of old fear memory becoming stronger again (Brewin, 2006; Quirk & Mueller, 2008).
Another possible explanation for the decrease in approach behavior in the active group at the three year follow-up, might be the stronger presence of a ‘success memory’ at the earlier tests. At the one year follow-up, not much time has passed since the participants had done the original assessments. In these assessments, they had successes with touching a spider. It is possible that this memory was still strongly present at the one year follow-up, which might have made them more convinced that they could approach the spider again, or more comfortable with it. Perhaps this memory became weaker over the years. This could be just because of the passage of time, or because they have had negative experiences with spiders in the meantime.
Because of this, it is difficult to draw hard conclusions about the longterm effects of noradrenergic β-blocker propranolol HCL based treatment on spider fear, though the results still seem promising for a treatment that only takes approximately five minutes.
It would be interesting to see how such a treatment works for other disorders as theory
suggests that relapse rates, compared to current treatment as cognitive behavioral therapy and exposure therapy, could be significantly lower. Current treatment like cognitive behavioral therapy appears to be effective in anxiety disorders. In a meta-analysis of literature that analyzed the treatment outcomes of CBT for a wide range of psychiatric disorders, large effect sizes were found for CBT for generalized anxiety disorders, social phobia and anxiety disorder (Butler et al., 2006). Hofmann and Smits (2008) meta-analytically reviewed the efficacy of cognitive behavioral therapy versus placebo for adult anxiety disorders. They found that CBT is efficacious for adult anxiety disorders. Exposure therapy was found to be effective for people with acrophobia, fear of heights. Both virtual reality exposure and exposure in vivo reduced anxiety and avoidance (Emmelkamp, Bruynzeel, Drost & van der
25 Mast, 2001). Longterm effects of exposure therapy were found for people suffering from social phobia. One year after the treatment, participants had an even further improvement in their social phobia (Haug et al., 2003). Future research could focus on directly comparing current treatments like these to treatment with propranolol in a study with participants who suffer from anxiety disorders.
When looking at the theory behind the treatment, it would be expected that any disorder in which old memory affects a person would be suitable for this treatment. Fear memory needs to be reactivated for propranolol to be able to disrupt reconsolidation, which is very well possible in other specific phobias like fear of heights. Research even suggests that propranolol could be used to prevent disorders like posttraumatic stress disorder. In a pilot study, Pitman et al. (2002) found that a course of propranolol that began shortly following an acute traumatic event, was efficacious in reducing PTSD symptoms 1 month later. It would be interesting to see what the effects of propranolol would be in other disorders than anxiety disorders.
Looking at the results from this study, it would also be interesting to see what the results would be of a second treatment session with propranolol to bolster the effects. In the current study no psychoeducation was given to the participants. Donker, Griffiths, Cuijpers, & Christensen (2009) analyzed the effectiveness of passive psychoeducation in reducing
symptoms of depression, anxiety or psychological distress. However, in their meta-analysis of 9010 studies, no randomized controlled trials were found for anxiety. They found that passive psychoeducational interventions reduced symptoms of depression and psychological distress. Research also shows that psychoeducation can cause lower relapse rates in people with
psychotic disorders (Lincoln, Wilhelm & Nestoriuc, 2007) and bipolar disorder (Gastó, 2003). Looking at the effect of psychoeducation on other disorders, it is possible that
26 Giving psychoeducation is recommended for future research. The results of noradrenergic β-blocker propranolol HCL based treatment seem promising, even on the longer-term and this treatment could have a big impact on the clinical world and people’s lives.
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