Improving outcomes from exposure therapy for post-traumatic stress disorder (PTSD) with acute exercise: Augmenting Brain Derived Neurotrophic Factor (BDNF) as a mechanism of change?

This Randomised Controlled Trial (RCT) investigates whether combining acute moderate intensity (aerobic) exercise with gold-standard Prolonged Exposure (PE) (Foa et al., 2007) would increase treatment efficacy of PE in PTSD and examines whether this effect is related to increased levels of Brain Derived Neurotrophic Factor (BDNF), which are elevated by acute moderate intensity exercise and have been shown to facilitate fear extinction. PE is a cognitive behavioural intervention that involves helping the person address their trauma memories and avoided situations in a supportive, controlled and safe environment, and confront them in a graduated way in order to promote gradual extinction of the fear response and to modify interpretations of the traumatic event that are impeding recovery. In this trial all participants will receive 10-weekly sessions of 90-minute face-to-face manualised PE treatment. The treatment elements and delivery will be identical to the gold-standard manualized PE intervention which is the best researched therapy with the strongest evidence-base of efficacy for PTSD. The first session of the PE treatment consists of psycho-education and overall introduction of rationale for the therapy. In the second session, common reactions to trauma will be discussed, the rationale for in vivo PE will be presented and a hierarchical list of avoided situations will be developed. From session three to ten imaginal PE will be conducted. In these sessions, participants will be encouraged to imagine/describe the trauma in detail while focusing progressively more in the most distressing aspects of the trauma and discussing thoughts and feelings evoked during exposure. Additionally, in the last session (session 10) changes in the experience of PE, trauma memory over the course of therapy and overall progress will be reviewed and relapse prevention strategies will be discussed. During all sessions participants distress will be monitored using Subjective Units of Discomfort/Distress Scale (SUD). Acute moderate intensity exercise in this RCT is proposed as an augmentation intervention to improve the treatment response to PE. Previous research suggested that BDNF (a neuropeptide) facilitates fear extinction learning which is the core mechanism underlying PE. Therefore, increasing BDNF levels during the PE treatment may enhance underlying fear extinction processes to improve response to PE. Research shows that a well-validated way to increase BDNF is via a bout of moderate intensity exercise. In this trial acute moderate intensity exercise will be combined with the PE treatment to increase BDNF levels during PE to enhance underlying fear extinction learning and facilitate response to PE in PTSD patients. The exercise intervention will be delivered prior to each PE session one to one via cycling on a stationary bicycle. These sessions will last for 20 minutes which will be an additional 20 minutes to the each 90 minutes PE session (110 minutes together). The intensity of the exercise will be based on participants’ individual cardio-respiratory fitness levels (Maximal Oxygen Uptake; VO2max) determined at a prior physical assessment session by the trial exercise physiologists. The intensity of the exercise will set to 55-70% of VO2max level of the participants. Having the flexibility in the range of exercise intensity aims to ensure participant capacity and comfort. The exercise intervention will be administered by the trial exercise physiologists until the 3rd PE session. From PE session 3 to 10, exercise intervention will be administered by a trained research assistant or the participant's trained therapist as per the exercise protocol by trial exercise physiologists. Both PE sessions and exercise sessions will be delivered at the Phoenix Traumatic Stress Research Clinic (Royal Park). The output from all exercise sessions (data regarding participants’ heart rate, workload used in the exercise, rate of perceived exertion, signs and symptoms etc.) will be recorded in hard-copy and in a computer and the fidelity of the exercise sessions will be assessed by trial exercise physiologists via regular fortnightly review of these outputs. All PE sessions will be audio recorded (with patient consent) and reviewed in fortnightly supervision sessions with the principle investigator Professor Felmingham. Fidelity checks of a random 10% of client cases will be conducted by a clinical psychologist with expertise in PE to ensure that specific sessions pertain to the specific therapy components required by the manual. UPDATE to the protocol: Due to pandemic related restrictions and cessation of face-to-face treatment, existing participants' remaining sessions were converted into online telehealth sessions using the zoom platform if they agreed and were able to self-direct the aerobic exercise component while being monitored by the trial research assistant trained on the exercise protocol. Furthermore, the same change in the treatment and intervention modality has also been applied to the new participants enrolled in the trial during the cessation of research activities in the Phoenix Traumatic Stress Research Clinic (n=5). During this time all psychological assessments were completed online or over the phone. Participants' respective clinicians checked and ensured that participants had a safe and private space, and reliable internet connection and devices for sessions. In the initial session, clinicians developed a Telehealth management plan (TMP) with the participant which documented agreed steps for managing any risk-related situations or disruptions in connection that may arise during the course of telehealth sessions. TMP included contact details (name, email, phone, and address) of participants' (at least) two nominated support persons who were close to them both personally and physically (i.e. approximately 5-10 minutes from the session location), and able to assist in emergencies. Furthermore, TMP included the location and address where participants joined the telehealth sessions from, and a backup phone number as an alternative contact. TMPs were updated at the beginning of each session. Also, clinicians reviewed the appropriateness of telehealth for participants in each session. A telehealth risk management protocol was put in place to assess risk and respond accordingly. Risk management was disclosed to the participants in the first telehealth session. Exercise sessions were conducted via telehealth right before each therapy session with the participants. Before exercise sessions, each participant's access to exercise equipment at home (e.g., exercise bike, heart rate monitor, blood pressure monitor etc.) was assessed. For participants who did not have an exercise bike, aerobic exercise was completed using an aerobic stepper. Stepping was deemed both feasible and appropriate since it has been shown to be an effective way of conducting aerobic exercise and creating an exercise-induced BDNF response (Kneapen et al., 2010). Prior to exercise sessions, participants were sent home aerobic exercise guides to get prepared for these sessions along with rate of perceived breathing (RPB) and rate of perceived exertion (RPE) scales to bring to the session. All exercise sessions have been monitored online by the trained research assistant on the exercise protocol while each participant was completing the exercise. At the beginning of each session, the participant’s location, address and personal contact details were collected as detailed above. In the very first session, participants’ were trained on how the exercise sessions will be conducted by the research assistant. Also, they were informed of signs and symptoms where they should stop exercising (e.g., chest pain, dizziness, nausea etc.). During exercise, all participants were asked to report their RPE and RPB each minute. If participants had access to heart rate monitors, they were asked to measure and report their heart rate and blood pressure at the beginning and at the end of the session. Also, they were asked to report their heart rate on the heart rate monitor each minute during the exercise. Heart rate was used to ensure that participants were exercising at exercise intensity corresponding to participants' pre-determined VO2max levels for the existing participants. For existing participants this VO2max level and corresponding heart rate were estimated at the clinic at the very beginning of the trial by the exercise physiologists. To ensure the administration of exercise at the adequate intensity for the new participants, their heart rate were aimed to be kept around 70-80% of their age-predicted maximum heart rate (HRmax) during the sessions which was expected to approximately correspond to their heart rate at 50-70% VO2max. These participants age-predicted HRmax were calculated using the formula 208 – (0.7 x participant’s age). For participants (both existing and new) who did not own a heart rate monitor, RPE levels were used to ensure that they are exercising in the aerobic exercise zone (RPE of 12 to 14). Participants owning a exercise bike at home were asked to report their speed (revolutions per minute; kept at 60) and were asked to increase/decrease intensity (watts) on the bike depending on their heart rate and/or RPE and RPB (kept below 5 - strong or hard breathing) values to ensure correct exercise intensity and to prevent any possible adverse events. Participants using an aerobic stepper were instructed to step on the stepper following a metronome set by the research assistant. The number of steps decreased or increased depending on the RPE and RPB levels and/or heart rate of the participants. The average number of steps required to get participants exercise in the aerobic zone ranged from 20-28 depending on the participants exercise tolerance and fitness. All exercise data collected during sessions was recorded on soft-copy exercise datasheets and saved in the trial database. Each exercise session lasted for 20 mins as per trial protocol. Participants in the aerobic exercise group who had remaining sessions when the pandemic related restrictions were in place and agreed to complete their treatment via telehealth (n=3) completed their remaining therapy and exercise sessions without any complications. Furthermore, no complications have been recorded for new participants enrolled in the trial who were allocated to the aerobic exercise condition. Upon resumption of research activities in the Phoenix clinic, the original trial protocol will be resumed.