German Clinical Trials Register

Acronym/abbreviation of the study

DoxAv

URL of the study

No Entry

Brief summary in lay language

Trauma and adverse life events are relevant risk factors that can lead to psychiatric disorders like anxiety disorders and post-traumatic stress disorder. In Switzerland the probability to suffer from post-traumatic stress disorder at least once in a lifetime is roughly 2%. The treatment of this disorder is mostly carried out by psychotherapy, however, only half of the affected individuals reach full recovery with this treatment. In order to improve and complement the current type of therapy, the goal of this study is to influence the memory of adverse events by using medicaments. In the planned 6 experiments healthy adults (18-40 years) will be administered with antibiotics and its influence on the memory of adverse events will be investigated. Our assumption is that the memory of adverse events can be influenced when they are still manifesting or being recalled. By interfering with this process the memory should not be erased but a novel recall of the memory should be associated with less feelings of anxiety. The visits take place on 3-4 days. The total duration for each participant is approx. 6 h. Inclusion of 560 subjects is planned. The first visit of all experiment is a screening visit (duration: 30 min). After Informed Consent, a screening with medical history, physical examination, blood samples and urine samples is performed to check for inclusion criteria. In some experiments (type A), visit 2 (duration: 4 h) includes questionnaires of mental and physical well-being. Administration of a single dose 200 mg doxycycline or placebo (neither subject nor investigator know about the ingredient), after a waiting period, a learning task is performed, and learning success is measured with physiological readouts like respiration, skin conductance, ECG and EMG are recorded. During visit 3 (duration: 1 h) the memory retention is tested by recording physiological readouts. For other experiments (type B), visit 2 (duration: 1 h) includes a learning task, while learning success is measured with physiological readouts like respiration, skin conductance, ECG and EMG are recorded. In visit 3 (duration: 4 h), after questionnaires of mental and physical well-being, the study medication is ingested. After a waiting period, memory retention is tested by recording physiological readouts. During visit 4 (duration: 1 h) memory retention is again tested by recording physiological readouts. Detailed description of the experiments are updated prior to the start of a new experiment. Experiment 1 of type A starts recruitment in October 2019. This experiment uses a trace fear conditioning paradigm as the learning task. During the experiment participants will be presented with two geometrical figures on a computer screen and indicate their color with a key press. One of the figures will be associated with an unpleasant electrical stimulation to the dominant forearm. Between stimuli, participants will detect numbers on the screen. During the task, we measure skin conductance response, ECG, respiration response and track pupil size and eye movements. At the second visit, participants will be presented with loud white noise bursts after the figures, in order to elicit a startle reflex. Those white noise bursts are unpleasant but not harmful to the health of the participants. In addition to the other measurements, we will assess eye-blink EMG. Experiment 2 of type A starts recruitment in March 2021. This experiment uses a configural fear conditioning paradigm as the learning task. During the experiment participants will be presented with five pictures of furnished rooms on a computer screen. The rooms differ in the configuration of the furniture and/or the context (rooms). Participants should indicate picture presentation with a button press. One of the room pictures will be associated with an unpleasant electrical stimulation to the dominant forearm. During the task, we measure skin conductance response, ECG, respiration response and track pupil size and eye movements. At the second visit, participants will be presented with loud white noise bursts during the presentation of the rooms, in order to elicit a startle reflex. Those white noise bursts are unpleasant but not harmful to the health of the participants. In addition to the other measurements, we will assess eye-blink EMG. Experiment 5 of type A starts recruitment in October 2019. During the experiment participants will watch an aversive film depicting interpersonal violence (trauma film), while physiological measures will be assessed (EDA, ECG, Respiration, pupil size). Before and after the movie participants fill in questionnaires. One week following the aversive film they will write intrusions related to the movie as well as the perceived distress of the intrusions in an intrusion diary. After one week they will fill again in some questionnaires and will participate in an intrusion provocation task with blurred pictures of the aversive film that can trigger intrusions for a short time. The remaining experiments (2-4 and 6) of type A and B, will build on the findings of experiments 1 and 5. Therefore the results of the current experiments 1 and 5 will influence the planning and implementation of the subsequent experiments 2, 3, 4 and 6.

Brief summary in scientific language

Psychological trauma and early-life adversity are major risk factors for various psychiatric disorder. Across the entire spectrum of trauma-related disorders, the recommended treatment currently is cognitive-behavioral psychotherapy. However, in clinical practice the majority of patients remain symptomatic. This has led to attempts for developing adjunct pharmacological therapies. At the same time, our understanding of synaptic biology has increased exponentially, yielding a wide range of compounds that modify synapses themselves, the surrounding extracellular matrix that shapes their properties. In this project we aim to connect these disparate strands and deliver a novel approach to alter aversive memories with pharmacological agents. The conceptual idea is to activate synapses through interventions and then modifying them pharmacologically. The aim is to influence synapses directly by targeting molecular pathways involved in degrading old, and shaping new, synaptic connections. By this we intend to provide evidence for the potential of synaptic plasticity inhibitors to impair aversive learning and reduce trauma memory.