Pilot Study of Pharmaceutical and Behavioral Interventions to Treat Anxiety Disorders
Condition: Posttraumatic Stress Disorder; Anxiety Disorder
MeSH terms: Anxiety Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Interventional
Phase: Phase 4

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 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: 
      1. 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

        2. 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.

        3. 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.

        4. 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.

        5. 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.

        6. 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
    

Intervention name(s): Propranolol; Reactivation; Mifepristone; Intranasal oxytocin
Intervention type(s): Drug; Behavioral; Drug; Drug
Intervention description(s): 40mg single pill; subject is re-exposed to CS+R on day 2 (code for CS that is both paired with shock and reactivated on day 2); 1800mg, 9 tablets; 32 IU, 8 self-administered intranasal sprays, 4 in each nostril
Other intervention name(s): Inderal; Mifeprex; Korlym; Syntocinon
Intervention MeSH terms: Propranolol; Oxytocin; Mifepristone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: Posttraumatic Stress Disorder; PTSD; Anxiety; Fear of spiders; Reconsolidation; Reconsolidation blockade