Generalization of Extinction Learning

Cholinergic Decontextualization of Exposure Therapy for Anxiety

Fear, whether it occurs in humans suffering from an anxiety disorder or in experimental models with rodents, is reduced by exposing the frightened organism to the fearful stimulus in the absence of any negative consequences (i.e., extinction, or exposure therapy). However, fear often renews when the feared stimulus is encountered in a context different from the exposure context. In rats, the investigators found that interfering with the animal's ability to process contexts during extinction by administering an anticholinergic drug prevented fear renewal. This proposal will determine if the beneficial effect of this drug translates to exposure therapy in socially anxious humans. To this end, 100 individuals with Social Phobia who fear public speaking will undergo repeated sessions of exposure to public speaking, within a virtual reality context. Participants will be randomized to either drug placebo, .4mg/.01 mL Scopolamine, .5mg/.01 mL Scopolamine or .6mg/.01 mL Scopolamine, administered via nasal drops, prior to each session of exposure therapy. One month after completion of exposure therapy, context renewal will be tested by comparing physiological and subjective responses to public speaking in the same virtual context as used during exposure therapy versus a context different than the one used during exposure therapy. The goal is to identify the dose of Scopolamine associated with the greatest reduction in context renewal. In addition, a secondary analysis will attempt to identify those individuals who benefit most from Scopolamine-augmentation of exposure therapy.

Study Overview

• Status: Completed
• Conditions: Social Anxiety Disorder
• Intervention / Treatment: Drug: Scopolamine; Drug: intranasal placebo

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 51 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. between the ages of 18 and 55,
2. fluent in English,
3. within normal body weight (BMI=18.5 to 24.9)
4. meet DSM-IV diagnostic criteria for Social Phobia and report a fear of public speaking.

Exclusion Criteria:

1. participant report of a diagnosed medical or neurological disorder
2. prescription or over the counter medications that can interact with Scopolamine, such as anticholinergic medications (e.g. belladonna alkaloids, antihistamines, meclizine, tricyclic antidepressants, and muscle relaxants), cold medicines, cough suppressants. Other drugs that will be reasons for exclusion include: antimuscarinics, nifedipine, parasympathomimetics, amantadine, amoxapine, antacids, antidiarrheals, anxiolytics, hypnotics, atomexetine, bupropion, cisapride, clozapine, cyclobenzaprine, digoxin, disopyramide, dronabinol (THC), ethanol, maprotilline, memantine, metoclopramide, nabilone, olanzapine, opiate agonists, orphenadrine, phenothiazines, potassium salts, quinidine, sedating H1-blockers, topiramate, tricyclic antidepressants, erthyromycin, ketoconazole, and tegaserod.
3. over the counter drugs or substances that may have a sedative effect (e.g. herbal sedatives: ashwagandha, Duboisia hopwoodii, Prostanthera striatiflora, kava, mandrake, valerian, cannabis, passiflora incarnate; Antihistamines: Diphenhydramine, Dimenhydrinate, Doxylamine, Promethazine; Alcohol; Dextromethorphan)
4. individuals with urinary problems (e.g., BPH)
5. pregnant or nursing females (as the effect of Scop on fetuses is not known)
6. suicidality
7. delusions or hallucinations
8. history of substance dependence in last five years or substance abuse within the past 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Scopolamine .4mg; Participants will be randomized to either .4mg/.01 mL Scopolamine, .5mg/.01 mL Scopolamine or .6mg/.01 mL Scopolamine, administered via nasal drops, prior to each session of exposure therapy	Drug: Scopolamine; Participants will be randomized to either, .4mg/.01 mL Scopolamine, .5mg/.01 mL Scopolamine or .6mg/.01 mL Scopolamine, administered via nasal drops, prior to each session of exposure therapy
Placebo Comparator: Intranasal placebo; Participants will be randomized to a placebo, administered via nasal drops, prior to each session of exposure therapy	Drug: intranasal placebo; Participants will be randomized to a drug placebo, administered via nasal drops, prior to each session of exposure therapy
Experimental: Scopolamine .5mg; Participants will be randomized to either .4mg/.01 mL Scopolamine, .5mg/.01 mL Scopolamine or .6mg/.01 mL Scopolamine, administered via nasal drops, prior to each session of exposure therapy	Drug: Scopolamine; Participants will be randomized to either, .4mg/.01 mL Scopolamine, .5mg/.01 mL Scopolamine or .6mg/.01 mL Scopolamine, administered via nasal drops, prior to each session of exposure therapy
Experimental: Scopolamine .6mg; Participants will be randomized to either .4mg/.01 mL Scopolamine, .5mg/.01 mL Scopolamine or .6mg/.01 mL Scopolamine, administered via nasal drops, prior to each session of exposure therapy	Drug: Scopolamine; Participants will be randomized to either, .4mg/.01 mL Scopolamine, .5mg/.01 mL Scopolamine or .6mg/.01 mL Scopolamine, administered via nasal drops, prior to each session of exposure therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Eye blink startle reflex	change from final exposure session to follow-up (8 weeks following baseline)
Skin conductance responses and heart rate	change from final exposure session to follow-up (8 weeks following baseline)
Subjective Units of Distress	change from final exposure session to follow-up (8 weeks following baseline)

Secondary Outcome Measures

Outcome Measure	Time Frame
Self Statements During Public Speaking Scale	change from baseline to follow-up (8 weeks following baseline)
Personal Report of Confidence as a Speaker Scale	change from baseline to follow-up (8 weeks following baseline)
Subjective units of distress during in vivo speech	change from baseline to follow-up (8 weeks following baseline)

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Investigators: Principal Investigator: Michelle G. Craske, Ph.D., Department of Psychology, UCLA; Principal Investigator: Michael Fanselow, Ph.D., Department of Psychology, UCLA

Publications and helpful links

General Publications

• Craske MG, Fanselow M, Treanor M, Bystritksy A. Cholinergic Modulation of Exposure Disrupts Hippocampal Processes and Augments Extinction: Proof-of-Concept Study With Social Anxiety Disorder. Biol Psychiatry. 2019 Nov 1;86(9):703-711. doi: 10.1016/j.biopsych.2019.04.012. Epub 2019 Apr 19.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: July 8, 2013
• First Submitted That Met QC Criteria: July 11, 2013
• First Posted (Estimate): July 16, 2013

Study Record Updates

• Last Update Posted (Actual): October 7, 2019
• Last Update Submitted That Met QC Criteria: October 3, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: social anxiety; exposure; scopolamine; extinction learning
• Additional Relevant MeSH Terms: Mental Disorders; Phobic Disorders; Anxiety Disorders; Phobia, Social; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Antiemetics; Gastrointestinal Agents; Adjuvants, Anesthesia; Mydriatics; Scopolamine; Butylscopolammonium Bromide
• Other Study ID Numbers: MH101359-01