Fear Conditioning
Conditions
Brief summary
The purpose of the study is to learn how differences in learning under mildly-stressful circumstances may be changed by taking an antidepressant medication. This medication is called Lexapro (Escitalopram). The investigators will also examine the impact of any anxiety, depression, and stress related symptoms on learning processes. The investigators will also look at the response of these symptoms to Lexapro.
Interventions
DRUGEscitalopram
Escitalopram 10mg/day or matched pill placebo
Sponsors
Forest Laboratories
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female outpatients 18 to 75 years of age 2. Must have no current DSM-IV Axis I diagnosis as measured by the SCID (Structured Clinical Interview for DSM-IV-TR axis 1 disorders) with a trained study investigator. Past history of anxiety disorders, major depressive episodes or substance abuse disorders at least six months prior to baseline are not exclusionary.
Exclusion criteria
1. Patients will be excluded from entry into the study for current serious medical conditions or other conditions deemed likely to result in surgery or hospitalization. 2. Patients with a history of trauma resulting in head injury related seizures, or with epilepsy (except a prior history of febrile seizures of infancy which are not exclusionary). 3. Pregnant or lactating women or those of childbearing potential not using medically accepted forms of contraception will be excluded. 4. Concurrent use of other antidepressants, benzodiazepines or antipsychotic medications. 5. Patients with a history of hypersensitivity to escitalopram are excluded. 6. Individuals must have discontinued MAO inhibitors more than 14 days before starting study drug. 7. Additional contraindicated drugs during the study are pimozide, furazolidine, isocarboxazid, lazabemide, and St. John's Wort. 8. Participants meeting DSM-IV or SCID criteria for a substance use disorder in the last six months other than nicotine dependence and those with a positive toxicology screen at baseline consistent with evidence of current substance abuse or dependence as determined by clinical interview. 9. A lifetime history of Bipolar or any psychotic disorder is excluded. 10. Current claustrophobia is exclusionary. 11. Patients currently taking any narcotic will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Day 2 of Fear Conditioning Paradigm (15 to 18 days post medication initiation) | Three-way interaction between group (active vs. placebo), CS (+ vs. -), and trials (1 - 4). CS+ refers to the conditioned stimulus associated with the unconditioned stimulus (electric shock). Higher numbers reflect higher skin conductance response to the CS+ (conditioned stimulus). CS- refers to the stimulus not associated with the unconditioned stimulus. Higher numbers reflect higher skin conductance response to a CS-. Square-root transformed skin conductance conditioned response are reported for trials 1 to 4 of the Early Extinction Phase. |
| Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Baseline on Day 1 of Fear Conditioning Paradigm (14 to 17 days post medication initiation) | Three-way interaction between group (active vs. placebo), CS (+ vs. -), and trials (1 - 5). CS+ refers to the conditioned stimulus associated with the unconditioned stimulus (electric shock). Higher numbers reflect higher skin conductance response to the CS+ (conditioned stimulus). CS- refers to the stimulus not associated with the unconditioned stimulus. Higher numbers reflect higher skin conductance response to a CS-. Square-root transformed skin conductance conditioned response are reported for trials 1 to 5 of the Acquisition Phase. |
Participant flow
Recruitment details
Participants free of DSM-IV Axis I disorders with varying levels of subsyndromal anxiety were recruited by advertisements (e.g., postings on Craigslist, postings on Massachusetts General Hospital research participation registry) from March 2009 through April 2011.
Pre-assignment details
65 participants signed consent and were screened for enrollment. 10 participants did not meet study entry criteria due to exclusionary psychiatric conditions. Of the 55 eligible participants, 3 withdrew and 1 was lost to follow up. 52 participants were randomly assigned to a treatment arm. Fourteen were excluded from analyses.
Participants by arm
| Arm | Count |
|---|---|
| Active Medication Escitalopram 10mg/day | 26 |
| Placebo Matched pill placebo | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Failure to show a conditioned response | 4 | 3 |
| Overall Study | Non-compliance with study procedures | 2 | 0 |
| Overall Study | Physiologic non-responsiveness | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Active Medication | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 25 Participants | 51 Participants |
| Age, Continuous | 30.46 years STANDARD_DEVIATION 11.46 | 34.04 years STANDARD_DEVIATION 11.56 | 32.25 years STANDARD_DEVIATION 11.54 |
| Region of Enrollment United States | 26 participants | 26 participants | 52 participants |
| Sex: Female, Male Female | 12 Participants | 14 Participants | 26 Participants |
| Sex: Female, Male Male | 14 Participants | 12 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 25 | 7 / 26 |
| serious Total, serious adverse events | 0 / 25 | 0 / 26 |
Outcome results
Primary
Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5
Three-way interaction between group (active vs. placebo), CS (+ vs. -), and trials (1 - 5). CS+ refers to the conditioned stimulus associated with the unconditioned stimulus (electric shock). Higher numbers reflect higher skin conductance response to the CS+ (conditioned stimulus). CS- refers to the stimulus not associated with the unconditioned stimulus. Higher numbers reflect higher skin conductance response to a CS-. Square-root transformed skin conductance conditioned response are reported for trials 1 to 5 of the Acquisition Phase.
Time frame: Baseline on Day 1 of Fear Conditioning Paradigm (14 to 17 days post medication initiation)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 4 | 0.231 micro-Siemens (square rooted) | Standard Error 0.086 |
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 2 | 0.419 micro-Siemens (square rooted) | Standard Error 0.122 |
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 5 | 0.281 micro-Siemens (square rooted) | Standard Error 0.071 |
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 3 | 0.230 micro-Siemens (square rooted) | Standard Error 0.119 |
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 1 | 0.634 micro-Siemens (square rooted) | Standard Error 0.093 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 3 | 0.685 micro-Siemens (square rooted) | Standard Error 0.104 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 4 | 0.626 micro-Siemens (square rooted) | Standard Error 0.102 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 5 | 0.543 micro-Siemens (square rooted) | Standard Error 0.118 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 2 | 0.870 micro-Siemens (square rooted) | Standard Error 0.113 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 1 | 0.574 micro-Siemens (square rooted) | Standard Error 0.111 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 3 | 0.331 micro-Siemens (square rooted) | Standard Error 0.112 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 1 | 0.532 micro-Siemens (square rooted) | Standard Error 0.088 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 2 | 0.428 micro-Siemens (square rooted) | Standard Error 0.116 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 4 | 0.181 micro-Siemens (square rooted) | Standard Error 0.082 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 5 | 0.144 micro-Siemens (square rooted) | Standard Error 0.067 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 2 | 0.817 micro-Siemens (square rooted) | Standard Error 0.107 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 4 | 0.677 micro-Siemens (square rooted) | Standard Error 0.096 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 1 | 0.634 micro-Siemens (square rooted) | Standard Error 0.105 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 3 | 0.856 micro-Siemens (square rooted) | Standard Error 0.099 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Acquisition Trials 1 to 5 | Trial 5 | 0.714 micro-Siemens (square rooted) | Standard Error 0.112 |
Primary
Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4
Three-way interaction between group (active vs. placebo), CS (+ vs. -), and trials (1 - 4). CS+ refers to the conditioned stimulus associated with the unconditioned stimulus (electric shock). Higher numbers reflect higher skin conductance response to the CS+ (conditioned stimulus). CS- refers to the stimulus not associated with the unconditioned stimulus. Higher numbers reflect higher skin conductance response to a CS-. Square-root transformed skin conductance conditioned response are reported for trials 1 to 4 of the Early Extinction Phase.
Time frame: Day 2 of Fear Conditioning Paradigm (15 to 18 days post medication initiation)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 1 | 0.745 micro-Siemens (square rooted) | Standard Error 0.13 |
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 2 | 0.496 micro-Siemens (square rooted) | Standard Error 0.103 |
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 3 | 0.544 micro-Siemens (square rooted) | Standard Error 0.111 |
| Active Medication CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 4 | 0.374 micro-Siemens (square rooted) | Standard Error 0.11 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 2 | 0.634 micro-Siemens (square rooted) | Standard Error 0.114 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 3 | 0.520 micro-Siemens (square rooted) | Standard Error 0.124 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 4 | 0.361 micro-Siemens (square rooted) | Standard Error 0.116 |
| Active Medication CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 1 | 0.853 micro-Siemens (square rooted) | Standard Error 0.853 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 3 | 0.438 micro-Siemens (square rooted) | Standard Error 0.105 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 2 | 0.386 micro-Siemens (square rooted) | Standard Error 0.097 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 4 | 0.309 micro-Siemens (square rooted) | Standard Error 0.104 |
| Placebo CS- | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 1 | 0.799 micro-Siemens (square rooted) | Standard Error 0.122 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 4 | 0.510 micro-Siemens (square rooted) | Standard Error 0.109 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 2 | 0.558 micro-Siemens (square rooted) | Standard Error 0.108 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 1 | 0.717 micro-Siemens (square rooted) | Standard Error 0.123 |
| Placebo CS+ | Physiological Reactivity as Measured by Square-root Transformed Skin Conductance Conditioned Response in Early Extinction Trials 1 to 4 | Trial 3 | 0.787 micro-Siemens (square rooted) | Standard Error 0.117 |