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Bachelor-project
Assessing a preventative pharmacological intervention for
traumatic memories using the Trauma Film Paradigm
Preventing the development of Post-Traumatic Stress Disorder
Alice de Bree
Student number: 10542523 Accompanist: Jamie Elsey University of Amsterdam Date: 31-05-2017
Total words abstract: 154 Total words article: 5903
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Index
Front page p.1 Index p.2 Abstract p.3 Introduction p.4 Method p.11 Results p.16 Discussion p.22 References p.263
Abstract
The amount of people suffering from Post-Traumatic Stress Disorder (PTSD) that do not benefit from the existing interventions, led to investigations into a possible
pharmacological intervention for PTSD. This study aimed to investigate if the intake of 40 mg of propranolol may have an effect on memory. Twenty three subjects (part of a larger ongoing study) received before or after watching a traumatic movie a propranolol pill, or not at all. In the week following the traumatic movie participants reported if they had experienced any intrusive memories and one week later they performed a declarative recognition memory test about the content of the film. At this stage, the results show a significant effect of propranolol on declarative memory, meaning that participants who received propranolol before had poorer declarative memory than those who received propranolol after or who only received placebo. No significant effect of propranolol on the number of intrusions people had was found.
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Assessing a preventative pharmacological intervention for
traumatic memories
Car crashes, armed conflicts and natural disasters are only some of the many examples of traumatic events and stressors that can lead to the development of Post-Traumatic Stress Disorder (PTSD), (Javidi & Yadollahie, 2012). PTSD belongs, according to the DSM-V, to the Trauma-and Stressor- Related Disorders and is characterized by recurrent,
involuntary, and intrusive distressing memories or dreams of the traumatic event(s), (Diagnostic and Statistical Manual Of Mental Disorders, 5th ed. [DSM-V]; American
Psychiatric Association, 2013). Besides the intrusive memories and experiencing a traumatic event, avoidance of stimuli related to the traumatic event and negative cognitions about it are important aspects of PTSD. When diagnosing somebody with PTSD, the symptoms need to persist for at least one month and cause clinically significant distress.
A trauma is a shocking or dangerous event that you have experienced, witnessed or heard of (PTSD: National Center for PTSD, 2016). Being exposed to trauma at some point in your life is common, 60.7% of men and 51.2% of women will experience a traumatic event during their lifetime (Breslau, 1998; Javidi & Yadollahie, 2012). Yet not everybody who experiences a traumatic event develops PTSD. According to de Vries and Olff (2009), seven or eight out of every 100 people living in the Netherlands (7.4% of the population) will develop Post Traumatic Stress Disorder (PTSD) at some point in their lives (lifetime prevalence of PTSD).
Individuals with PTSD are often experiencing high levels of psychological distress, such as feelings of shame, despair and loneliness and have 80% more chance than those without PTSD to have symptoms that meet diagnostic criteria for at least one other mental disorder (e.g., depressive, bipolar, anxiety, or substance use disorders), (Kessler et al. 2005). Besides the psychological distress PTSD also accounts for a real societal and economical cost.
5 People with PTSD have among the highest rates of healthcare services use in the United States (PTSD United, 2013).
Many secondary intervention options exist for PTSD. Examples are (Trauma-Focused) Cognitive Behavioral Therapy, Exposure Therapy, Eye Movement Desensitization and
Reprocessing (EMDR), debriefing and pharmacological interventions, (Linares, Corchs, Chagas, Zuardi, Martin-Santos & Crippa, 2016). Even though several different secondary interventions exist for the treatment of PTSD the results of those interventions are not always that promising. Many individuals are not properly responding to the interventions mentioned earlier and are still developing PTSD.
Emotional memory
Most of the interventions focus on the intrusive memories about the traumatic event. Intrusive memories can be described as involuntary, and most of the time highly emotional, thoughts or mental images of an experienced or witnessed traumatic event that appear spontaneously in consciousness (Brewin, 1998). These intrusive memories have other
characteristics than ‘normal’ memories have. Intrusive memories from individuals with PTSD are characterized by being very persistent with greater clarity, high levels of emotional
arousal and with strong perceptual and sensory aspects. Besides that, an individual suffering from PTSD often only has intrusive memories about some parts of the traumatic event, called ‘flashbacks’, and relive those over and over again (Brewin, 1998). Intrusions are not the same as repeated rumination over the traumatic event (Holmes & Bourne, 2008).
On the one hand intrusive memories are seen as an important part of the emotional processing of the traumatic event, as re-experiencing is seen as a sign of normal adaptation (Ehlers & Steil, 1995). On the other hand, when persisting for a long time, intrusive memories are linked to the development of PTSD. Research shows that the development of PTSD is less related to the level of exposure to the traumatic event or the amount of loss people
6 experienced than to the amount of intrusive memories people had after the traumatic event (McFarlane, 1992; Brewin, 1998). The experienced (un)predictability and (un)controllability of the traumatic event, perceived threat and actual danger, the impact of the traumatic event play next to the intrusive memories an important role in the development of PTSD after experiencing a traumatic event (Ehlers, Steil, 1995).
Memory consolidation
To understand how intrusive memories can play such an important role in the development of PTSD, explaining the mechanism of memory consolidation is essential. According to Abel and Lattal (2001) memory can be divided into several stages, acquisition (processing and encoding), consolidation, retrieval and later on into reconsolidation and extinction. For this study the interest lays mainly in the acquisition, consolidation and retrieval phases.
In the acquisition phase, a context is linked to a sensation, feeling, or thought. Walker, Brakefield, Hobson & Stickgold (2003) describe the process of memory consolidation as a process whereby a memory becomes more and more resistant to interference. The process of memory consolidation requires Ribonucleic Acid (RNA) and a crucial phase of protein synthesis (Alberini, 2005). In the consolidation phase the memory is moved from a labile to a more concrete state. During this labile phase, memories can be disrupted, impaired or
enhanced. Research shows that there is a six-hours window, starting from the moment an event or experience has taken place, wherein a memory is labile and therefore malleable (Walker, Brakefield, Hobson and Stickgold, 2003; Holmes, James, Coode-Bate & Deeprose
2009). The hormone epinephrine, released endogenously after an emotional event, strengthens the memory consolidation process and fear conditioning. The increased release of epinephrine enhances the significance of the experience or event and for that reason, later on the
7 passes freely through the blood-brain barrier but it activates β-adrenergic receptors in the brainstem. The brain area that plays an important role in this process is the basolateral nucleus of the amygdala (BLA). Activation of the BLA is critical for the mediation of epinephrine and activation of the β-adrenergic receptors. The BLA is not itself responsible for the long-term memory storage, it influences memory processes in other brain areas. β-adrenergic receptor agonists act on the BLA by enhancing the effects of epinephrine and memory (Packward &Teather, 1998; McCleery & Harvey, 2004). In turn, β-adrenergic receptors antagonists block the effects of epinephrine and causes a decrease of emotional arousal (McGaugh, 2012). Physiological arousal enhances the memory consolidation process. In conclusion, the
increased amounts of epinephrine that is being released at the time of a psychologically traumatic event activates the β-adrenergic receptors, that enhances the emotional memory of that specific event and can turn into or be the cause of PTSD symptoms (and intrusive memories).
A hypothesis of Eysenck and Kelly (1987; Pitman, 1989) suggests that recalling an emotional of traumatic event (intrusive memories) leads to the re-release (long after the traumatic event took place) of stress hormones, such as epinephrine. The re-release of the stress hormones enhance the strength of the (traumatic) memory, leading to a greater likelihood of intruding again and therefor releasing more stress hormones and so on. Every time a person has an intrusive memory about the traumatic event, the memory of the traumatic events becomes more enhanced. This hypothesis sheds a light on the important role of
intrusive memories in the development of PTSD.
The medication propranolol is an example of a β-adrenergic receptor blocker that can block the effects of epinephrine by blocking the reuptake of (nor)epinephrine (Fletcher, Creamer, & Forbes, 2010). Quite some research has been done with propranolol and the effect on the development of PTSD, but the results are conflicting. A meta-analysis from Lonergan,
8 Olivera-Figueroa, Pitman and Brunet (2012) shows that giving propranolol before the
memory consolidation took place reduces recall for negative stories and emotional words, pictures and the expression of cue-elicited fear responses. In another study PTSD scores were higher in the group that refused propranolol when compared to the group that received
propranolol shortly after a traumatic event (Vaiva et al., 2003; Linares et al., 2016). On the other hand, a systematic literature review of Linares et al. (2016) shows that in a study of Stein et al. (2007), no differences in scores were found on the Clinician Administered PTSD Scale (CAPS) in groups who had received propranolol or placebo after a traumatic event. Also in the study of Pitman et al. (2002) scores on the Clinician Administered PTSD Scale (CAPS) of patients that just had experienced a traumatic event (and met the DSM-IV criteria for PTSD) did not differ between the group of people that had received 40 mg of propranolol for 10 days, four times a day, and the group of people that had received placebo pills for 10 days.
The systematic literature review of Linares et al. (2016) also shows that most research that used propranolol post-trauma for the treatment of PTSD administered propranolol
between several day and weeks after the traumatic event had taken place. The positive findings of the study of Vaiva et al. (2003) could be explained by the fact that it is the only study that initiated the pharmacological intervention with propranolol within the six-hour window of memory consolidation. As mentioned before, memory consolidation takes place within the six hours after the (traumatic) event took place, so giving propranolol after these six hours should, according to this theory, not be very useful.
Unfortunately, as can be seen in the systematic review of Linares et al. (2016), in very few studies propranolol (post-trauma) was administered within the six-hour window of memory consolidation. This study, on the other hand, will administer 40 mg of propranolol, once, within the six-hour window of memory consolidation.
9 However, propranolol can also be administered pre-trauma and effect how the
traumatic event is processed and encoded. Earlier research shows that a critical function of the amygdala is the processing and perception of emotional information (van Stegeren et al., 2005). Not only the amygdala, but also the hippocampus plays a role in successful processing and encoding emotional stimuli and events. The neurotransmitter norepinephrine is important in the processing and encoding phase of emotional events. Epinephrine is made from
norepinephrine and the synthesis of epinephrine increases during times of stress. Retention of emotionally arousing stimuli is related to the degree of emotional arousal (Bradley,
Greenwald, Petry, & Lang, 1992; McCleery, & Harvey 2004). If somebody experiences high levels of general bodily arousal (feeling stressed) more epinephrine is released. As mentioned before, epinephrine activates β-adrenergic receptors in the amygdala. Enhanced amygdala activation facilitates the processing and encoding of emotional stimuli. Taking propranolol before experiencing a traumatic event might lead to lower levels of general bodily arousal (by lowering the heart rate and blood pressure) and experienced stress. If somebody experiences less emotional distress and arousal during the traumatic event (due to the use of propranolol), because less epinephrine is being released, and less noradrenergic receptors are being
activated, it is plausible that he or she will have less intrusive memories about the traumatic (because the memory consolidation was not that enhanced) event and therefore a smaller chance in developing PTSD.
Non-emotional memory
Yet when using propranolol, it is necessary to keep in mind that propranolol might not only act upon the ‘emotional memory’ (i.e. unpleasant emotional intrusions). Besides the important role of stress hormones, such as epinephrine, in the development of emotional memories, stress hormones can also enhance the declarative memory. Whereas, for this study, the emotional memory can be affected by the propranolol, it is important that the declarative
10 memory for facts about a traumatic event is maintained. Victims of a traumatic event for example, need to be able to recall the traumatic event so that they can give testimonies in court or to the police about how the perpetrator looked like or what he was wearing or what exactly happened. Ideally the declarative memory should not be affected by propranolol, whereas the emotional impact of the traumatic event can be affected. Figure 1 shows a visual representation of the experimental model used in this study, based on the experimental model of James, Lau-Zhu, Clark, Visser, Hagenaars and Holmes, (2016). On the left two time points of the administration of propranolol (before or after the traumatic movie) are seen, and on the right the three outcome variables (amount of intrusive memories and scores on declarative- and visual memory recognition tests).
Figure 1: ‘Visual representation of the experimental model used in this study’.
In this study both earlier mentioned ideas will be tested. Propranolol will only be administered once (pre- or post- experimental trauma), in the first session. All three groups will receive at two time points a pill. One group of participants will take 40 mg of propranolol one hour before the traumatic event, so that the propranolol can have his effect whilst
experiencing the traumatic event (to test the idea if general arousal during a traumatic event plays an important role in the development of intrusive memories). The second pill that they receive will be placebo. To the other group 40 mg of propranolol will be given immediately
11 after the traumatic event, falling perfectly in the six-hour window of consolidation. The first pill that they will receive will be placebo. The third group of participants will receive placebo on both time points. The amount of intrusive memories and the scores on a declarative- and visual memory test will be measured in the second session. The results will tell us if the process of memory consolidation, the experience of extreme body sensations or a combination of both is important in the development of intrusive memories. If propranolol can disrupt emotional memory consolidation, we would expect fewer intrusions in both groups who received propranolol. If arousal during the trauma is key, then we would expect reduced intrusions only in the pre- experimental trauma propranolol group. Finally, if propranolol has no effect on emotional memory consolidation, we would expect all groups to have the same number of intrusions. Likewise, we will test whether propranolol affects declarative memory for facts about the trauma film (the scores on both memory recognition tests will tell us more about that).
Methods
Participants
The full study will include a total of 75 participants. Due to the fact that the study is still running we have for the current results a preliminary sample of 23 mentally and
physically healthy students (Dutch). Fifteen of them were female and 8 of them were male, all with an age between 18-35 years old (M = 21.91, SD = 3.66). The participants were randomly assigned to one of the three groups (propranolol-placebo [N=5], placebo-placebo [N=7] and placebo-propranolol [N=11]). The students were recruited from a subject-pool of the
University from Amsterdam. Participants were excluded from participation in this study if they were older than 35 years old, younger than 18 years old, colorblind, with a low blood pressure (lower than 90/60) or low heart rate (lower than 60), diagnosed with PTSD or having
12 experienced a trauma that still had an important impact on their lives. Heart, liver or thyroid problems and psychological problems such as depression and psychotic episodes were also an exclusion criteria. Finally, participants that had participated in other studies where the Trauma Film Paradigm was used were also excluded from participation. All participants came to the laboratory for two sessions. The first session took 2.5 hours and the second one approximately half an hour. The interval between the two sessions was exactly one week. Each participant received a reward of 40 euros or four research participation credits.
Materials
This study examined the difference in the amount of intrusive memories people had in the week after seeing a traumatic movie and their score on two memory recognition tasks and the Impact of Event Scale. At the beginning of the first session all participants filled in the State and Trait Anxiety Inventory (STAI; Spielberger, Gorsuch, & Lushene, 1970), a Life Event checklist, Beck Depression Inventory- II (BDI-II; Beck, Rush, Shaw, & Emery, 1979) and the Reiss- Epstein- Gursky Anxiety Sensitivity Index (A.S.I.), (Reiss, Peterson, Gursky, & McNally, 1986). The STAI consists of 40-item inventory that assesses not only the state-anxiety but also the trait-state-anxiety. Spielberger, Gorsuch, & Lushene (1970) found an alpha coefficient for the STAI State-Anxiety scale of .90 and .92 for the STAI Trait-Anxiety scale. The Life Event Checklist (LEC) is a 19-item checklist that consists of questions such as, ‘have you ever experienced a natural disaster’. Participants had to indicate if they had experienced the traumatic event themselves, witnessed it, if it happened to a loved one or not at all. The mean kappa for all items of the LEC was .61, and the retest correlation was r = .82, p < .001 (Gray, Litz, Hsu, & Lombardo, 2004). The Beck Depression Inventory- II is a 21-item inventory that assesses the severity of depressive symptomatology. Each 21-item is rated on a 0-3 scale with summary scores ranging between 0 and 63. The BDI-II has a high internal
13 consistency with an alpha coefficient of 0.91 (Dozois, Dobson & Ahnberg, 1998). The A.S.I. is a 16-item questionnaire developed to assess a person’s beliefs about the social and somatic consequences of anxiety symptoms. Items such as ‘it makes me scared when I feel dizzy’ could be answered by choosing from answers ranging from ‘barely’ to ‘a lot’. The A.S.I has a high internal consistency reliability (alpha = .88), (Reiss et al., 1986).
Based on the research of Holmes, James, Coode-Bate and Deeprose (2009), in the first session, the Trauma Film Paradigm was used. The 12-min traumatic movie contained 11 scenes with traumatic or stressful content including drowning, human surgery, car accidents and death. Before and after seeing the movie the participants filled in a mood assessment with questions such as; ‘right at this moment I am feeling sad’ and ‘right at this moment I am feeling depressive’ (Davies & Clark, 1998; Holmes, Brewin & Hennessy, 2004). Participants had to make a line at the appropriate point along an eleven-point scale, going from ‘not at all’ (0) to ‘extremely’ (10). After the mood assessment participants had to indicate how
distressing the movie was for them and how much attention they had paid to the movie, using a rating scale anchored with 0 (not at all) to 10 (extremely). During both waiting periods (before and after seeing the traumatic video) participants had to listen to several episodes of BBC Radio 4: Inside Science. This was chosen to keep what participants did in the
intervening time periods consistent across participants, but to minimize task demands and exposure to visual information, which has previously been shown to interfere with the development of intrusive images (Iyadurai, Blackwell, Meiser-Stedman, Watson, Bonsall, Geddes, & Holmes, 2017).
Between both sessions participants had to fill in an intrusive memory diary. An edited version of the diary that Holmes, James, Coode-Bate and Deeprose (2009) used in their study, was used. In the edited intrusive memories diary used in this study, participants had to report three times a day (at morning, during the day and at night), if they had any intrusive memories
14 (a thought, an image or combined or dreams/nightmares in their sleep). Also quality of sleep was measured. The diary was used to analyze differences in the amount of intrusive memories participants from all three groups had and to see if the quality of sleep stayed the same or had changed after seeing the traumatic movie. For the purposes of the current analysis, we only looked at the number of intrusive memories.
In the second session participants had to fill in two short questionnaires. First the ‘state part’ of the State and Trait Anxiety Inventory and then the Impact of Event Scale - Revised (Creamer, Bell & Failla, 2003). The impact of event scale has a high internal consistency with a Cronbach’s alpha of 0.96 (Creamer, Bell & Failla, 2003). Subsequently, they had to
complete a visual and declarative recognition memory test on the computer, to test the extent of the memory consolidation impairment. Both tests were based on the ones Holmes, James, Coode-Bate and Deeprose (2009) used but slightly changed. The declarative memory recognition test consisted of 44 true/false statements (four statements per scene) about the movie: e.g. ‘the girl has blood coming from one of her nostrils’. After the four questions of every scene participants had to indicate how confident they felt about their answer (going from ‘not confident at all’ to ‘extremely confident’). In the visual memory recognition test, 22 images were shown to the participants where after they had to say if the images were (true) or were not (false) from the trauma movie they had seen the week before. Reaction time and reaction correctness were measured for both tests, though only the general accuracy was assessed.
Procedures
All participants received a medical screening over the phone. If no contra-indications were found, an appointment was made for the first session and an information brochure was
15 sent. A schematic representation of the basic procedure for the Trauma film paradigm is shown in Figure 2.
Figure 2: Basic procedure for trauma film paradigm.
The first session started with another small medical screening. Heart rate and blood pressure were measured and a saliva sample was taken. If heart rate and blood pressure were acceptable, the first pill was administered (placebo or propranolol, double blind). Then the first waiting period of one hour began and the participants could start filling in the
questionnaires and when finished, listen to the ‘BBC Radio 4: Inside Science’ episodes. ‘Inside Science’ was chosen to standardize what participants were exposed to pre and post experimental trauma during the waiting periods, while not involving visuospatial elements that might affect intrusive memory development (Holmes et al., 2009). Just before the waiting period of an hour ended (10 minutes before), participants were guided to the lab space where the trauma film was seen. Participants were asked to place their chin in a chin holder, which was placed 60 cm from the screen, and to lay their arms on the table whilst watching the whole traumatic movie. After seeing the movie the participants were allowed to leave the room where they just had watched the movie and go back to the main area where they had listen to the BBC Radio 4 episodes earlier on. Another saliva sample was taken and the second pill was administered (placebo or propranolol). Then, the second waiting period began (60 minutes). In this waiting period the intrusion diary was explained and participants had to listen to some more episodes of ‘BBC Radio 4: Inside Science’. When the waiting period was over, heart rate and blood pressure were measured for the last time and another saliva sample
16 was taken. Then participants were allowed to go home.
In the second session, exactly one week after the first session had taken place,
participants had to come back to the lab to hand in their diary. They were asked how accurate they had filled in the diary, answer two short questionnaires and subsequently do the visual and declarative recognition memory test. When finished with both memory tests, the researcher asked if they had any idea which of the pills they had taken was propranolol and which was not. Finally, there was time to answer some questions, if the participants had any, and if not, the participants received their reward and were allowed to go home.
Results
The aim of this study was to find out if there is an effect of propranolol on emotional memory (the amount of intrusions people had after watching a traumatic movie), and
declarative memory (scores on a declarative and visual recognition memory task). Based on a study of James, Bonsall, Hoppitt, Turnbridge, Geddes, Milton and Holmes (2015), that also used the Trauma Film Paradigm, an effect size of 0.4 was chosen. In a study of James, Lau-Zhu, Clark, Visser, Hagenaars and Holmes (2016) it is said that films typically generate a higher number of intrusions than picture stimuli do and this finding can be an advantage in terms of sample size and power. Entering the effect size, the number of groups (3) and the power (0.8) an a priori sample size calculator for a One-Way ANOVA (G*Power) calculated that the required sample size was 66. This study started with only 24 participants, but one participant was excluded from this study, due to the fact that she did not show up for the second session. The data of the remaining 23 participants was used in the analyses. As mentioned before, the results are very preliminary at this stage, as we are awaiting the remaining results.
17 In this double blind study, One-way ANOVA analysis were used because participants were randomly assigned to three different groups. Six One-way ANOVA’s revealed that no significant differences were found between groups in age (F (2.22) = 1.90, p = 0.18), STAI-S, STAI-T, Life Event Checklist, BDI-II and A.S.I. scores (all p- values >.1). Table 1 shows the means and standard deviations of all three groups on five questionnaires mentioned earlier.
Table 1: Means and standard deviations for all three groups
Group STAI-S STAI-T Trauma Checklist BDI-II A.S.I Placebo-Placebo 43.00 (4.58) 45.71 (2.75) 70.14 (6.99) 3.71 (5.38) 7.43 (3.87) Propranolol- Placebo 41.40 (1.52) 50.80 (4.97) 72.20 (3.03) 3.40 (2.30) 9.60 (3.51) Placebo- Propranolol 42.78 (4.08) 47.55 (5.96) 69.91 (5.19) 7.09 (9.50) 8.36 (3.98)
Note. STAI-S = State and Trait Anxiety Inventory- State, STAI-S = State and Trait Anxiety Inventory- Trait, BDI-II = Beck Depression Inventory- II and A.S.I = Reiss- Epstein- Gursky Anxiety Sensitivity Index.
Next, to assure that the Trauma Film Paradigm had worked, a manipulation check was executed. A Paired Sample t-test indicated that VAS scores, indicating a negative mood, were significantly higher after (M = 124.17, SE = 19.92) watching the traumatic film than before (M = 51.91, SE = 15.46). This difference, -72.26, was significant t (22) = -5.93, p < .001. A significance level of 5% was used in this study (Field, 2013), and therefore, the manipulation check succeeded. Participants had a significant lower mood after watching the traumatic movie than before watching it. The assumption of normality was checked with a p-plot and met. The average from the VAS mood questionnaires before and after seeing the traumatic movie was calculated with the accompanying standard deviation, see Table 2.
18 Table 2: Average VAS mood scores and Standard Deviations of the Pre- and Post-mood VAS
Pre-test Post-test Effect
Total participants (N = 23)
51.91 (74.12) 124.17 (95.55) 72.26
Note. Effect = Post mood VAS – Pre mood VAS.
Four other One-way ANOVA’s will be used for the main analysis. In all the ANOVA’s of the main analysis the condition (placebo-placebo, propranolol-placebo or placebo-propranolol) will be the independent variable. The first two ANOVA’s are used to test the effect of propranolol on the emotional memory, the second two on the declarative memory. In all these nine ANOVA’s the independent variable was the group participants were in.
The first ANOVA of the main analysis was executed with the score on the impact on event scale as a dependent variable. The assumptions of independence, homogeneity of variance, normality and interval data were met. The means and standard errors for the groups were as follows: for the placebo-placebo group (M = 6.86, SE = 1.28), for the propranolol-placebo group (M = 8.20, SE = 1.99) and for the propranolol-placebo- propranolol group (M = 10.36, SE = 2.15). There was no significant effect of condition on the score on the impact of event scale, F (2,22) = 0.84, p = 0.447, indicating that it did not matter in which condition participants were for their score on the impact of event scale. Figure 1 shows the average score per group on the Impact of Event Scale, filled in by all participants in the second session.
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Figure 3: Average scores per group on the Impact of Event Scale
The second ANOVA used as dependent variable the number of intrusions people had reported in their intrusion diary. The assumptions of independence, homogeneity of variance, normality and interval data were met. The means and standard errors for the groups were as follows: for the placebo-placebo group (M = 2.57, SE = 2.51), for the propranolol-placebo group (M = 2.40, SE = 1.63) and for the placebo- propranolol group (M = 3.00, SE = 2.30). There was no significant effect of condition on the number of intrusions, F (2,22) = 0.111, p = 0.895, indicating that it did not matter in which condition participants were for the amount of intrusions they had after watching the traumatic movie. Figure 2 shows the average amount
0,00 2,00 4,00 6,00 8,00 10,00 12,00
Placebo- Placebo Propranolol- Placebo Placebo- Propranolol
Im p ac t o f Ev en t S ca le S co re
Average scores on the Impact of Event Scale per group
20 of intrusions each group reported in the intrusion dairy, between the first and second session.
Figure 4: Average number of intrusions per group.
In the third ANOVA the dependent variable was the score on the declarative recognition memory test. The assumptions of independence, homogeneity of variance, normality and interval data were met. The means and standard errors for the groups were as follows: for the placebo-placebo group (M = 25.57, SE = 1.33), for the propranolol-placebo group (M = 19.20, SE = 1.34) and for the placebo- propranolol group (M = 24.82, SE = 1.19). There was a significant effect of condition on the score on the declarative recognition memory test, F (2,22) = 5.23, p = 0.015, indicating that it did matter in which condition participants were for the score on the declarative recognition memory test. The placebo-placebo group scored the highest, then the placebo-propranolol group and finally the propranolol– placebo group. An Independent t-test indicated that the scores on the declarative recognition memory test of the placebo-placebo group were significantly higher (M = 25.57, SD = 3.51) than of the propranolol-placebo group (M = 19.20, SE = 3.03). This difference, -6.37, was significant t (10) = -3.27, p =.008, meaning that people that received propranolol before the experimental trauma had lower scores on the declarative recognition memory test than people that did not receive propranolol. No significant differences on the declarative recognition memory were
0,00 0,50 1,00 1,50 2,00 2,50 3,00 3,50
Placebo- Placebo Propranolol- Placebo Placebo- Propranolol
Nu m b er o f in tru sio n s
Average number of intrusions per group
21 found between the placebo-placebo group and placebo-propranolol group, t (16) = 0.75, p =.686.
The dependent variable of the last ANOVA was the score on the visual recognition memory test. The assumptions of independence, normality and interval data were met. The assumption of homogeneity of variance was not met, the variances of the scores on the test were significantly different in the three groups, F (2,22) = 6.19, p < 0.01. The means and standard errors for the groups were as follows: for the placebo-placebo group (M = 16.14, SE = 0.459), for the propranolol-placebo group (M = 15.00, SE = 2.55), and for the placebo- propranolol group (M = 14.64, SE = 0.789).There was no significant effect of condition on the score on the visual recognition memory test, F (2,22) = 0.477, p = 0.672, indicating that it did not matter in which condition participants were for the score on the visual recognition
memory test.
Figure 3 shows the average scores per group on both memory recognition tests.
Figure 5: Average scores for each group separate on both declarative and visual recognition memory tests.
Results from a Paired t-test show that participants scored significantly higher on the VAS mood questionnaire after watching the traumatic movie, which means that their mood
0,00 5,00 10,00 15,00 20,00 25,00 30,00
Placebo- Placebo Propranolol- Placebo Placebo- Propranolol
M em o ry Re co g n it io n tes ts sc o re s
Average scores on Declarative and Visual Recognition Memory Test
22 was worsened after watching the traumatic movie. Three out of four ANOVA’s were not significant even though differences between groups can been seen. Therefore, at this moment, it is not possible to make strong conclusions because we are still awaiting more results. At present, we do not find support for the idea that pre- or post-experimental trauma propranolol is affecting the development of intrusions. However, consistent with previous research, we do find an effect of pre-trauma propranolol on later declarative memory.
Discussion
Earlier research shows that experiencing a traumatic event at some point in your life is very common (Breslau, 1998; Javidi & Yadollahie, 2012). However, not everybody that experiences a traumatic event develops PTSD. The development of PTSD is more related to the (amount and intensity of) intrusive memories people have after the traumatic event than to the level of exposure to the traumatic event (McFarlane, 1992; Brewin, 1998). As mentioned earlier, intrusive memories can be described as recurrent, involuntary, and most of the time highly emotional, thoughts or mental images of an experienced or witnessed traumatic event (Brewin, 1998). The strength of the (intrusive) memory, as well as its emotional content, is related to the release of endogenous stress hormones such as epinephrine (Henry, Fishman, & Younger, 2007). If the stimulus (the traumatic event) is very strong, a high doses of
epinephrine is being released, which in turn causes elevated levels of norepinephrine. In turn, norepinephrine can activate the β-adrenergic receptors in the amygdala and this results in over-consolidation of the memory.
Propranolol is a medication that is thought to block the effects of epinephrine by blocking the reuptake of (nor) epinephrine (Fletcher, Creamer, & Forbes, 2010). Propranolol can be administered before or after the traumatic event. When administered before,
23 subsequently on the amount of epinephrine that is being released. When administered after the traumatic event, within the six-hour window, propranolol might directly have an effect on the process of memory consolidation. However, earlier research that used propranolol show contradicting results. In the study of Vaiva et al. (2003) for example, a significant effect of propranolol on the development of PTSD symptoms was found. On the other hand, in the systematic review of Linares et al. (2016) many studies appear with no significant effects. The evidence for the effectiveness of propranolol in the prevention of PTSD and the working mechanism behind propranolol are not clear. Therefore this study was conducted. As
mentioned earlier, the findings are preliminary due to the fact that the study is still running, so no strong conclusions can be made at this point yet.
At this early stage, we have not found evidence to support the idea that taking propranolol before or after an experimental trauma affects the development of intrusive memories. As for the declarative memory, a significant effect was found on the declarative recognition memory test. The scores on the declarative recognition memory test of the placebo-placebo group were significantly higher than of the propranolol-placebo group. No significant differences on the declarative recognition memory were found between the
placebo-placebo group and placebo-propranolol group. For the visual recognition memory test no significant results were found. Participants that had received placebo twice scored the highest on both memory recognition tests. Finally, as for the Impact of Event Scale, no significant scores were found between all three groups.
The preliminary results show that there is not a significant relation between
propranolol and the amount of intrusions people had. There is a trend towards the placebo group having the least intrusions, which is clearly against the idea that pre- or post-trauma propranolol effects the noradrenergic system and later on prevents the buildup of intrusive memories. Other studies on the other hand found that people that had taken propranolol
post-24 trauma were significantly less likely to demonstrate physiological arousal patterns consistent with those seen in PTSD and have lower scores on the Clinical Administered PTSD Scale, PTSD Symptom Scale-I or PTSD Diagnostic Scale (Linares et al., 2016). These contradicting results can be explained by the heterogeneity of PTSD symptoms. It is plausible that some of the PTSD symptoms, such as intrusive memories, are less responsive to interventions that focus on norepinephrine re-uptake, than that symptoms of physiological arousal are (Fletcher, Creamer, & Forbes, 2010). The results of more participants are needed to be able to make a strong conclusion about the effect of propranolol on intrusive memories. To see if there is a consolidation effect it is necessary to look at the intrusions occurring after the first day – as that is when it is expected that a consolidation effect occurs. Unfortunately at this stage, not enough people are having multiple day intrusions to test this.
The significant effect of propranolol found on the declarative recognition memory test is in line with earlier research. The results show that the group that did not receive propranolol had the highest score on the declarative recognition memory test, while the group that
received propranolol pre-trauma had the lowest scores. This suggests that propranolol has an effect on the consolidation of declarative memories. The adrenergic system and the
amygdaloid complex (AC) are known to play an important role in emotionally arousing learning experiences. However, the AC is also involved in the formation of declarative or explicit memories of emotionally arousing event (Cahill, & McGaugh, 1998). Since
propranolol influences the adrenergic system and therefor the AC, it is comprehensible that the group that only received placebo has the highest scores on the declarative recognition memory test. Concluding, when investigating the effect of a drug, such as propranolol, it is important to keep in mind that one brain area or a system is not specialized in a domain specific function, but that it can play an important role in several parallel processes.
25 preliminary due to the amount of people tested so far so it is not possible to make strong conclusions. Second, earlier research (Pitman et al., 2002) used propranolol with people who had really been traumatized. Even though the Trauma Film Paradigm is proven to be efficient (also in this study), it can never be compared to experiencing a traumatic event in real life. Therefore it is difficult to compare the findings for this study, based on mentally healthy psychology students, with earlier research that used people that had recently experienced a real traumatizing event. Although it would be hard to generalize the results of this study, the promising of this study is that it created an almost ideal environment to test the effect of propranolol. Propranolol was administered before the experimental trauma and after (within the six hour window of memory consolidation), participants experienced the same
experimental trauma and all participants did the same during the waiting periods. By creating this environment and controlling for as many confound variables as possible, the effect of propranolol on the amount of intrusions and declarative memory could be investigated.
Finally, differences in scores on the declarative and visual recognition memory test are found. This suggests that propranolol might affect those two memory processes in a different way so further research should take this into account and investigate this more extensively.
Concluding, even though the results of this study are preliminary some promising results were found. Unfortunately no significant effect of propranolol on the amount of intrusions was found, although there is a trend towards the propranolol-placebo group. The group that received placebo twice had the highest scores on the declarative recognition memory test. The results would favor the idea that the degree of general arousal that an individual experiences before and during the traumatic event, and not so much the process of memory consolidation after the traumatic event, accounts for the enhancement of (emotional) memory.
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