Posttraumatic Stress DisorderPhase 4NCT01631682
Pilot Study of Pharmaceutical and Behavioral Interventions to Treat Anxiety Disorders
A Phase 4 study testing Propranolol, Reactivation and Mifepristone in people with Posttraumatic Stress Disorder and Anxiety Disorder, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
The aim of this project is to create fear conditioning paradigm within which the relative strengths of various novel pharmacological and behavioral interventions can be tested. These interventions are intended to reduce the fearfulness associated with fear conditioning by blocking a memory process known as… Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Posttraumatic Stress Disorder, Anxiety Disorder
- What is being tested?
- Propranolol, Reactivation and Mifepristone
- Type of treatment
- Pill or oral medicine, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 186 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2010to Jan 2015
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age 18-35
- Top half of the normal human distribution of the Spider Phobia Questionnaire-15
Who cannot join
- Any criteria for diagnosable spider phobia
- Any current Axis I mental disorder on the Structured Clinical Interview for DSM-IV (SCID)
- Presence of drugs of abuse (e.g. opiates, marijuana, cocaine, or amphetamines) per urine screen
- Non-English speaking (due to lack of validated questionnaires/instruments in other languages)
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Charlestown, Massachusetts, 02129
About this study
Official title: Psychophysiology of Delayed Extinction and Reconsolidation in Humans
The aim of this project is to create fear conditioning paradigm within which the relative strengths of various novel pharmacological and behavioral interventions can be tested. These interventions are intended to reduce the fearfulness associated with fear conditioning by blocking a memory process known as reconsolidation. In fear conditioning, a "conditioned" stimulus (CS) is paired with an aversive "unconditioned" stimulus (US) such as an electric shock, until presentation of the CS alone comes to elicit a fear conditioned response (CR). The investigators hypothesize that by using a more highly prepared CS (i.e. video of spiders); more sensitive subjects (individuals with stronger acquired CRs); and additional experimental probes for the presence of the latent CR, the investigators may develop a normal human paradigm that is not plagued by previously observed floor effects (i.e. intervention is 100% effective), within which both the established techniques of propranolol and delayed extinction will produce significant, but only partial, CR reduction. This would leave room to test and compare potentially more powerful candidate reconsolidation-blocking or memory-updating interventions. To achieve these aims, subjects will undergo a four-day fear conditioning and delayed extinction protocol. Skin conductance response data will be gathered across the different phases of the experiment.
Read the detailed description
- BACKGROUND AND SIGNIFICANCE 1.1. Reconsolidation and its modification. Recent animal research suggests that reactivation (retrieval) of a consolidated memory can return it to a labile state from which it must be restabilized in order to persist. This stabilization process has been termed "reconsolidation," and various behavioral and pharmacologic interventions have been found to modify or block it. Although extinction can reduce or even apparently eliminate conditioned fear, it typically does so by inhibiting the expression of the fear memory, not by erasing it. In contrast, blockade of reconsolidation is believed to erase, or at least diminish, the fear memory trace. It is not uncommon for reconsolidation articles to conclude with a statement that this offers novel therapeutic possibilities for PTSD, which may in part be characterized as a disorder of over-consolidated, persistently disturbing memories that do not go away.1
- SPECIFIC AIM The aim of this project is to create an experimental assay in the form of an optimal Pavlovian differential fear conditioning paradigm, within which the relative strengths of various novel pharmacological and behavioral, reconsolidation-blocking interventions can be tested. As impressive as the Kindt8 and Schiller10 studies are for demonstrating pharmacological and behavioral fear reconsolidation-blocking interventions in normal humans, the results produced by these interventions make them nearly useless as potential assays for reconsolidation blockade. Specifically, both interventions produced an apparent total abolition of the fear memory, i.e., they both contain a floor effect. The aim in this work is to develop a normal human paradigm within which both propranolol and delayed extinction produce significant, but only partial reduction of the CR, which might then be improved upon by more powerful reconsolidation-blocking interventions. This study will not be used to support a label, advertising, or indication change of propanolol, and will not be prescribed in a patient population, route of administration, or dosage that significantly increases risk. 2.1. Elements of a new design to eliminate the floor effect 2.1.1. A stronger US. One way to produce a CR that is more resistant to reconsolidation blockade, i.e., to reduce the floor effect, would be to use a stronger US. However, because in our ongoing human conditioning studies, we are already using an electric shock selected in advance by subjects to be "highly annoying but not painful," we believe that to use a level of shock above this would be ethically impermissible, and hence we will not pursue this possibility. 2.1.2. A more highly "prepared" CS. It has long been shown that certain classes of CSs, when paired with a US, produce a stronger fear CR, i.e., they are more "prepared" to enter into an association with the US.13 The Schiller design10 did not use a prepared CS, but the Kindt study8 did, viz., still pictures of spiders. In our design, we will enhance the preparedness of the CS by using 12-sec.14 high-definition video clips of three different crawling tarantulas, each conspicuously different in appearance. Importantly, however, the present project will not be a study of spider fear or phobia; we will only use high-definition videoto enhance CS preparedness. 2.1.3. More sensitive subjects. We will limit recruitment to subject candidates who fall within the upper half of the distribution of normal humans on the Spider Phobia Questionnaire-1515 (SPQ-15) and for whom the CSs are likely to be especially salient. However in order to avoid potential adverse clinical consequences of participation, we will exclude subjects with features of diagnosable spider phobia (or the presence of any other Axis I mental disorder). 2.1.4. Selecting subjects with stronger CRs. In order for a subject who has completed the Day 1 Acquisition phase of the experiment to proceed to the remaining phases, we will require that they show strong evidence of conditioning, as manifest in CRs greater than 0.25 µSiemens to at least two CS+s. The Schiller study10 employed a differential conditioning cut-off of 0.10 µSiemens, but based upon our own experience, we favor the raw score cut-off. The Kindt study8 employed no such cut-off. 2.1.5. Employing additional probes for the presence of the latent CR. The Kindt8 and Schiller10 studies employed two of the four available techniques for revealing the presence of the latent CR: spontaneous recovery and reinstatement. In the present experiments, we will also examine renewal and savings. These will require that the CSs be presented in different contexts, which will be achieved in the following manner. Each of the three different tarantulas will appear within three different backgrounds, or contexts, resulting in a 3 x 3 design, and a total of nine different video clips. The use of high-definition video on a large-screen television will help to reduce the context-with-a-context problem. The sequence of presentation of the nine clips will be pseudorandomly varied across subjects within a group, and identical across groups.
- SUBJECT SELECTION 3.1. Inclusion/Exclusion Criteria 3.1.1. Inclusion criteria. 1) Age 18-35 2) Top half of the normal human distribution of the Spider Phobia Questionnaire-15. 3.2. Exclusion criteria 3.2.1. Exclusion criteria prior to undergoing first experimental session. 1) Any of the following criteria for diagnosable spider phobia: a) marked or persistent fear of spiders that is excessive or unreasonable; b) intense anxiety or panic upon exposure to a spider; c) avoidance of spiders, anxious anticipation of exposure to spiders, or distress in the presence of spiders, any of which interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships; or d) marked distress about having fear of spiders; 2) Any current Axis I mental disorder on the Structured Clinical Interview for DSM-IV (SCID); or 3) presence of drugs of abuse, e.g., opiates, marijuana, cocaine, or amphetamines, as determined by urine testing. Additionally (4) non-English-speaking subject candidates will be excluded because validated versions of some of the instruments and questionnaires to be administered are not available in other languages. 3.3. Recruitment methods. Healthy subject candidates will be drawn from advertisements in the media. Most subject volunteers are expected to be drawn from the pool of 250,000 students in the Boston area. No employees or students supervised by the Investigators will be enrolled in this study, nor will Harvard Medical School students. Candidates who express an interest in participating will be scheduled to make a visit to our laboratory for an evaluation as to whether they satisfy the inclusion and exclusion criteria.
- SUBJECT ENROLLMENT Prior to the initiation of the study procedures, an investigator will obtain the written informed consent using the form approved by the Partners Human Research Committee. If drugs are potentially involved, this will be a licensed physician investigator.
- STUDY PROCEDURES 5.1. Design. We will use SCR as the measure of the CR. We have chosen SCR because we have 25 years' experience with this dependent measure in human conditioning studies.20 Intertrial intervals will vary within 15 and 25 sec. with a mean of 20 sec. Two active reconsolidation-blocking interventions will be employed: 1) Propranolol reactivation as in Kindt,8 and 2) Reactivation-delayed extinction as in Schiller.10 Subjects will be randomized to one of three conditions: propranolol (40mg; single dose); placebo (single dose); behavioral (no pill). The research pharmacy will create and manage the randomization list. The study will be single blind. The experimental phases will comprise three consecutive days and a fourth day one month later. Prior to beginning the experiment, the subject will set their own level of electric stimulation (shock). They will be instructed to choose a level that is highly annoying but not painful. The experimenter will start the stimulation at a very low, nearly imperceptible level and gradually increase the level until the subject says "stop." That level will then be used throughout the experimental sessions. 5.1.1 Day 1 5.1.1.1 Interview and Questionnaire. Candidates for this project will undergo a comprehensive evaluation to assess psychiatric and medical history and a structured clinical interview to confirm lack of psychiatric diagnoses (SCID). Subjects will also complete the SPQ-15.15 Eligible candidates will proceed to Habituation and Acquisition. 5.1.1.2 Habituation and Acquisition. Subjects will view video of three rooms (contexts), different in color and content, presented on a 42" high definition television. The conditioned stimuli (CSs) will be three different videos of tarantulas, one presented in each room. Two of the three tarantulas will serve as the two CS+s and the third as the CS-. Each CS+ presentation will sometimes be followed by shock (i.e., reinforced); the CS- will never be followed by shock. Day 1 will consist of two sequential components: a) 2 unreinforced presentations of each CS (habituation), followed by b) 8 presentations of each CS, with 5 of each CS+ presentations followed by shock (i.e., 63% reinforcement, acquisition). All Day 1 CS presentations will occur within Context A. 5.1.2. Day 2 (Intervention) will consist of either 1) propranolol (40 mg oral) or placebo (oral) followed 90 min. later by a single, unreinforced presentation of one of the two CS+s, designated the reactivated CS+ (CS+R) (after Kindt8); or 2) a single, unreinforced presentation of the CS+R without receiving a pill, followed 10 min. later by a) 10 further unreinforced CS+R presentations; b) 11 unreinforced presentations of the remaining CS+, designated the CS+ with no intervention (CS+N); and c) 11 CS- presentations (after Schiller10). Subjects will be randomized to one of these three interventions (propranolol, placebo, or behavioral) following Day 1. All Day 2 CS presentations will take place within Context B. 5.1.3. Day 3 (Renewal, Reinstatement) will consist of three sequential components: a) 2 unreinforced presentations each of the CS+R, CS+N, and CS- (renewal test trials); b) 3 presentations of the US alone, and c) 8 further unreinforced presentations each the CS+R, CS+N, and CS- (reinstatement test trials, also re-extinction). All Day 3 CS presentations will occur within Context A. 5.1.4. Day 30 (Spontaneous Recovery/Renewal, Savings) will consist of two sequential components: a) 8 unreinforced presentations each of the CS+R, CS+N, and CS- (spontaneous recovery test trials, also re-extinction); and b) 8 presentations each of the two CS+s with 63% reinforcement, and the CS- (savings test trials during re-acquisition). All Day 30 CS presentations will occur within Context C. The following numbers of shocks will be delivered to each subject: Day 1: 10 shocks, Day 2: 0 shocks, Day 3: 3 shocks, Day 30: 10 shocks.
- BIOSTATISTICAL ANALYSIS 6.1. Statistical approach. Data from the above experiments will be subjected to analysis of variance techniques similar to those fully described in the Kindt article8 and supplement, Schiller article10 and supplement, as well as in our published human differential conditioning studies.14,16-19
- Conditions
- Posttraumatic Stress Disorder, Anxiety Disorder
- Being tested
- Propranolol, Reactivation, Mifepristone, Intranasal oxytocin
- Keywords
- Posttraumatic Stress Disorder, PTSD, Anxiety, Fear of spiders, Reconsolidation, Reconsolidation blockade
- Medical subject headings
- Stress Disorders, Post-Traumatic, Anxiety Disorders, Arachnophobia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PropranololDrug
Also called Inderal
40mg single pill
ReactivationBehavioural
subject is re-exposed to CS+R on day 2 (code for CS that is both paired with shock and reactivated on day 2)
MifepristoneDrug
Also called Mifeprex, Korlym
1800mg, 9 tablets
Intranasal oxytocinDrug
Also called Syntocinon
32 IU, 8 self-administered intranasal sprays, 4 in each nostril
| Study group | Role | What they receive |
|---|---|---|
| Propranolol | Active comparator | a single dose of 40mg propranolol may be given to begin visit 2, followed by 90min wait and subsequently CS reactivation Receives: Drug: Propranolol |
| Reactivation with time delay | Active comparator | For those not receiving propranolol on visit 2, one experimental CS will be reactivated, followed by a 10 minute break and subsequently extinction Receives: Behavioral: Reactivation |
| Mifepristone | Experimental | a single dose of 1800mg (200mg tablets) mifepristone may be given to begin visit 2, followed by 90min wait and subsequently CS reactivation Receives: Drug: Mifepristone |
| Intranasal oxytocin | Experimental | A single 32IU dose of Syntocinon (intranasal oxytocin) is given to begin visit 2, followed by a 10 minute wait and subsequent CS reactivation. Receives: Drug: Intranasal oxytocin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline Skin Conductance Response
Skin conductance response (SCR) is the change in skin conductance level in response to a stimulus. We compared the SCR to a non-treated conditioned stimulus (CS+N) with the SCR to a treated conditioned stimulus (CS+R) by creating a difference score (CS+R - CS+N) for the day 3 data. Day 3 is 48 hours after the fear-conditioning procedure and serves as the primary measure of whether the treatment had an effect. SCR was measured in microSiemens; the SCR difference score reflects a change in microSiemens.
Measured: 48hrs
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2012 (estimated)
- Study startNov 2010
- Primary completionJan 2015
- Study completionJan 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Posttraumatic Stress DisorderStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 186 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Scott Orr, Massachusetts General Hospital
- Investigators
- Scott P. Orr, Ph.D., Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01631682
- Sponsor's protocol ID
- W81XWH-11-2-0092
- Status last verified
- Jan 2017
- First submitted
- 25 Jun 2012
- Last updated
- 23 Feb 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Fricchione J, Greenberg MS, Spring J, Wood N, Mueller-Pfeiffer C, Milad MR, Pitman RK, Orr SP. Delayed extinction fails to reduce skin conductance reactivity to fear-conditioned stimuli. Psychophysiology. 2016 Sep;53(9):1343-51. doi: 10.1111/psyp.12687. Epub 2016 Jun 17.
PubMed 27314560Spring JD, Wood NE, Mueller-Pfeiffer C, Milad MR, Pitman RK, Orr SP. Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear-conditioned stimuli. Psychophysiology. 2015 Mar;52(3):407-15. doi: 10.1111/psyp.12326. Epub 2014 Sep 16.
PubMed 25224026
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Psychophysiology of Delayed Extinction and Reconsolidation in Humans
- ClinicalTrials.gov ID
- NCT01631682
- Acronym / sponsor ID
- W81XWH-11-2-0092
- Conditions
- Posttraumatic Stress Disorder, Anxiety Disorder
- Keywords
- Posttraumatic Stress Disorder, PTSD, Anxiety, Fear of spiders, Reconsolidation, Reconsolidation blockade
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 186 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Study start
- Nov 2010
- Primary completion
- Jan 2015 (actual)
- Study completion
- Jan 2015 (actual)
- First posted
- 29 Jun 2012 (estimated)
- Results
- Posted 23 Feb 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of this project is to create fear conditioning paradigm within which the relative strengths of various novel pharmacological and behavioral interventions can be tested. These interventions are intended to reduce the fearfulness associated with fear conditioning by blocking a memory process known as reconsolidation. In fear conditioning, a "conditioned" stimulus (CS) is paired with an aversive "unconditioned" stimulus (US) such as an electric shock, until presentation of the CS alone comes to elicit a fear conditioned response (CR). The investigators hypothesize that by using a more highly prepared CS (i.e. video of spiders); more sensitive subjects (individuals with stronger acquired CRs); and additional experimental probes for the presence of the latent CR, the investigators may develop a normal human paradigm that is not plagued by previously observed floor effects (i.e. intervention is 100% effective), within which both the established techniques of propranolol and delayed extinction will produce significant, but only partial, CR reduction. This would leave room to test and compare potentially more powerful candidate reconsolidation-blocking or memory-updating interventions. To achieve these aims, subjects will undergo a four-day fear conditioning and delayed extinction protocol. Skin conductance response data will be gathered across the different phases of the experiment.
Detailed description
- BACKGROUND AND SIGNIFICANCE 1.1. Reconsolidation and its modification. Recent animal research suggests that reactivation (retrieval) of a consolidated memory can return it to a labile state from which it must be restabilized in order to persist. This stabilization process has been termed "reconsolidation," and various behavioral and pharmacologic interventions have been found to modify or block it. Although extinction can reduce or even apparently eliminate conditioned fear, it typically does so by inhibiting the expression of the fear memory, not by erasing it. In contrast, blockade of reconsolidation is believed to erase, or at least diminish, the fear memory trace. It is not uncommon for reconsolidation articles to conclude with a statement that this offers novel therapeutic possibilities for PTSD, which may in part be characterized as a disorder of over-consolidated, persistently disturbing memories that do not go away.1
- SPECIFIC AIM The aim of this project is to create an experimental assay in the form of an optimal Pavlovian differential fear conditioning paradigm, within which the relative strengths of various novel pharmacological and behavioral, reconsolidation-blocking interventions can be tested. As impressive as the Kindt8 and Schiller10 studies are for demonstrating pharmacological and behavioral fear reconsolidation-blocking interventions in normal humans, the results produced by these interventions make them nearly useless as potential assays for reconsolidation blockade. Specifically, both interventions produced an apparent total abolition of the fear memory, i.e., they both contain a floor effect. The aim in this work is to develop a normal human paradigm within which both propranolol and delayed extinction produce significant, but only partial reduction of the CR, which might then be improved upon by more powerful reconsolidation-blocking interventions. This study will not be used to support a label, advertising, or indication change of propanolol, and will not be prescribed in a patient population, route of administration, or dosage that significantly increases risk. 2.1. Elements of a new design to eliminate the floor effect 2.1.1. A stronger US. One way to produce a CR that is more resistant to reconsolidation blockade, i.e., to reduce the floor effect, would be to use a stronger US. However, because in our ongoing human conditioning studies, we are already using an electric shock selected in advance by subjects to be "highly annoying but not painful," we believe that to use a level of shock above this would be ethically impermissible, and hence we will not pursue this possibility. 2.1.2. A more highly "prepared" CS. It has long been shown that certain classes of CSs, when paired with a US, produce a stronger fear CR, i.e., they are more "prepared" to enter into an association with the US.13 The Schiller design10 did not use a prepared CS, but the Kindt study8 did, viz., still pictures of spiders. In our design, we will enhance the preparedness of the CS by using 12-sec.14 high-definition video clips of three different crawling tarantulas, each conspicuously different in appearance. Importantly, however, the present project will not be a study of spider fear or phobia; we will only use high-definition videoto enhance CS preparedness. 2.1.3. More sensitive subjects. We will limit recruitment to subject candidates who fall within the upper half of the distribution of normal humans on the Spider Phobia Questionnaire-1515 (SPQ-15) and for whom the CSs are likely to be especially salient. However in order to avoid potential adverse clinical consequences of participation, we will exclude subjects with features of diagnosable spider phobia (or the presence of any other Axis I mental disorder). 2.1.4. Selecting subjects with stronger CRs. In order for a subject who has completed the Day 1 Acquisition phase of the experiment to proceed to the remaining phases, we will require that they show strong evidence of conditioning, as manifest in CRs greater than 0.25 µSiemens to at least two CS+s. The Schiller study10 employed a differential conditioning cut-off of 0.10 µSiemens, but based upon our own experience, we favor the raw score cut-off. The Kindt study8 employed no such cut-off. 2.1.5. Employing additional probes for the presence of the latent CR. The Kindt8 and Schiller10 studies employed two of the four available techniques for revealing the presence of the latent CR: spontaneous recovery and reinstatement. In the present experiments, we will also examine renewal and savings. These will require that the CSs be presented in different contexts, which will be achieved in the following manner. Each of the three different tarantulas will appear within three different backgrounds, or contexts, resulting in a 3 x 3 design, and a total of nine different video clips. The use of high-definition video on a large-screen television will help to reduce the context-with-a-context problem. The sequence of presentation of the nine clips will be pseudorandomly varied across subjects within a group, and identical across groups.
- SUBJECT SELECTION 3.1. Inclusion/Exclusion Criteria 3.1.1. Inclusion criteria. 1) Age 18-35 2) Top half of the normal human distribution of the Spider Phobia Questionnaire-15. 3.2. Exclusion criteria 3.2.1. Exclusion criteria prior to undergoing first experimental session. 1) Any of the following criteria for diagnosable spider phobia: a) marked or persistent fear of spiders that is excessive or unreasonable; b) intense anxiety or panic upon exposure to a spider; c) avoidance of spiders, anxious anticipation of exposure to spiders, or distress in the presence of spiders, any of which interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships; or d) marked distress about having fear of spiders; 2) Any current Axis I mental disorder on the Structured Clinical Interview for DSM-IV (SCID); or 3) presence of drugs of abuse, e.g., opiates, marijuana, cocaine, or amphetamines, as determined by urine testing. Additionally (4) non-English-speaking subject candidates will be excluded because validated versions of some of the instruments and questionnaires to be administered are not available in other languages. 3.3. Recruitment methods. Healthy subject candidates will be drawn from advertisements in the media. Most subject volunteers are expected to be drawn from the pool of 250,000 students in the Boston area. No employees or students supervised by the Investigators will be enrolled in this study, nor will Harvard Medical School students. Candidates who express an interest in participating will be scheduled to make a visit to our laboratory for an evaluation as to whether they satisfy the inclusion and exclusion criteria.
- SUBJECT ENROLLMENT Prior to the initiation of the study procedures, an investigator will obtain the written informed consent using the form approved by the Partners Human Research Committee. If drugs are potentially involved, this will be a licensed physician investigator.
- STUDY PROCEDURES 5.1. Design. We will use SCR as the measure of the CR. We have chosen SCR because we have 25 years' experience with this dependent measure in human conditioning studies.20 Intertrial intervals will vary within 15 and 25 sec. with a mean of 20 sec. Two active reconsolidation-blocking interventions will be employed: 1) Propranolol reactivation as in Kindt,8 and 2) Reactivation-delayed extinction as in Schiller.10 Subjects will be randomized to one of three conditions: propranolol (40mg; single dose); placebo (single dose); behavioral (no pill). The research pharmacy will create and manage the randomization list. The study will be single blind. The experimental phases will comprise three consecutive days and a fourth day one month later. Prior to beginning the experiment, the subject will set their own level of electric stimulation (shock). They will be instructed to choose a level that is highly annoying but not painful. The experimenter will start the stimulation at a very low, nearly imperceptible level and gradually increase the level until the subject says "stop." That level will then be used throughout the experimental sessions. 5.1.1 Day 1 5.1.1.1 Interview and Questionnaire. Candidates for this project will undergo a comprehensive evaluation to assess psychiatric and medical history and a structured clinical interview to confirm lack of psychiatric diagnoses (SCID). Subjects will also complete the SPQ-15.15 Eligible candidates will proceed to Habituation and Acquisition. 5.1.1.2 Habituation and Acquisition. Subjects will view video of three rooms (contexts), different in color and content, presented on a 42" high definition television. The conditioned stimuli (CSs) will be three different videos of tarantulas, one presented in each room. Two of the three tarantulas will serve as the two CS+s and the third as the CS-. Each CS+ presentation will sometimes be followed by shock (i.e., reinforced); the CS- will never be followed by shock. Day 1 will consist of two sequential components: a) 2 unreinforced presentations of each CS (habituation), followed by b) 8 presentations of each CS, with 5 of each CS+ presentations followed by shock (i.e., 63% reinforcement, acquisition). All Day 1 CS presentations will occur within Context A. 5.1.2. Day 2 (Intervention) will consist of either 1) propranolol (40 mg oral) or placebo (oral) followed 90 min. later by a single, unreinforced presentation of one of the two CS+s, designated the reactivated CS+ (CS+R) (after Kindt8); or 2) a single, unreinforced presentation of the CS+R without receiving a pill, followed 10 min. later by a) 10 further unreinforced CS+R presentations; b) 11 unreinforced presentations of the remaining CS+, designated the CS+ with no intervention (CS+N); and c) 11 CS- presentations (after Schiller10). Subjects will be randomized to one of these three interventions (propranolol, placebo, or behavioral) following Day 1. All Day 2 CS presentations will take place within Context B. 5.1.3. Day 3 (Renewal, Reinstatement) will consist of three sequential components: a) 2 unreinforced presentations each of the CS+R, CS+N, and CS- (renewal test trials); b) 3 presentations of the US alone, and c) 8 further unreinforced presentations each the CS+R, CS+N, and CS- (reinstatement test trials, also re-extinction). All Day 3 CS presentations will occur within Context A. 5.1.4. Day 30 (Spontaneous Recovery/Renewal, Savings) will consist of two sequential components: a) 8 unreinforced presentations each of the CS+R, CS+N, and CS- (spontaneous recovery test trials, also re-extinction); and b) 8 presentations each of the two CS+s with 63% reinforcement, and the CS- (savings test trials during re-acquisition). All Day 30 CS presentations will occur within Context C. The following numbers of shocks will be delivered to each subject: Day 1: 10 shocks, Day 2: 0 shocks, Day 3: 3 shocks, Day 30: 10 shocks.
- BIOSTATISTICAL ANALYSIS 6.1. Statistical approach. Data from the above experiments will be subjected to analysis of variance techniques similar to those fully described in the Kindt article8 and supplement, Schiller article10 and supplement, as well as in our published human differential conditioning studies.14,16-19
Study design
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Propranolol | Active comparator | Drug: Propranolola single dose of 40mg propranolol may be given to begin visit 2, followed by 90min wait and subsequently CS reactivation |
| Reactivation with time delay | Active comparator | Behavioral: ReactivationFor those not receiving propranolol on visit 2, one experimental CS will be reactivated, followed by a 10 minute break and subsequently extinction |
| Mifepristone | Experimental | Drug: Mifepristonea single dose of 1800mg (200mg tablets) mifepristone may be given to begin visit 2, followed by 90min wait and subsequently CS reactivation |
| Intranasal oxytocin | Experimental | Drug: Intranasal oxytocinA single 32IU dose of Syntocinon (intranasal oxytocin) is given to begin visit 2, followed by a 10 minute wait and subsequent CS reactivation. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Age 18-35
- Top half of the normal human distribution of the Spider Phobia Questionnaire-15
Key exclusion criteria (4 listed)
- Any criteria for diagnosable spider phobia
- Any current Axis I mental disorder on the Structured Clinical Interview for DSM-IV (SCID)
- Presence of drugs of abuse (e.g. opiates, marijuana, cocaine, or amphetamines) per urine screen
- Non-English speaking (due to lack of validated questionnaires/instruments in other languages)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PropranololAlso: Inderal40mg single pill | Drug | Propranolol |
| Reactivationsubject is re-exposed to CS+R on day 2 (code for CS that is both paired with shock and reactivated on day 2) | Behavioural | Reactivation with time delay |
| MifepristoneAlso: Mifeprex, Korlym1800mg, 9 tablets | Drug | Mifepristone |
| Intranasal oxytocinAlso: Syntocinon32 IU, 8 self-administered intranasal sprays, 4 in each nostril | Drug | Intranasal oxytocin |
Primary outcome
Change From Baseline Skin Conductance Response
Time frame: 48hrs
Skin conductance response (SCR) is the change in skin conductance level in response to a stimulus. We compared the SCR to a non-treated conditioned stimulus (CS+N) with the SCR to a treated conditioned stimulus (CS+R) by creating a difference score (CS+R - CS+N) for the day 3 data. Day 3 is 48 hours after the fear-conditioning procedure and serves as the primary measure of whether the treatment had an effect. SCR was measured in microSiemens; the SCR difference score reflects a change in microSiemens.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 27314560Fricchione J, Greenberg MS, Spring J, Wood N, Mueller-Pfeiffer C, Milad MR, Pitman RK, Orr SP. Delayed extinction fails to reduce skin conductance reactivity to fear-conditioned stimuli. Psychophysiology. 2016 Sep;53(9):1343-51. doi: 10.1111/psyp.12687. Epub 2016 Jun 17.
- Results publication: PubMed 25224026Spring JD, Wood NE, Mueller-Pfeiffer C, Milad MR, Pitman RK, Orr SP. Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear-conditioned stimuli. Psychophysiology. 2015 Mar;52(3):407-15. doi: 10.1111/psyp.12326. Epub 2014 Sep 16.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Scott P. Orr, Ph.D. principal investigator
Massachusetts General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Propranolol, Reactivation and Mifepristone in people with Posttraumatic Stress Disorder and Anxiety Disorder, run by Massachusetts General Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Feb 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline Skin Conductance Response (time frame: 48hrs). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01631682, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2017.