Antidepressant Activity in Healthy Volunteers
Conditions
Keywords
Citalopram, Escitalopram, Celexa, Lexapro, fMRI, antidepressant, healthy volunteers
Brief summary
Escitalopram (Lexapro) and citalopram (Celexa) are similar selective serotonin reuptake inhibitors that alter blood flow to the amygdala and other brain structures involved in regulating mood. Escitalopram consists of S-citalopram while citalopram contains both S-citalopram and R-citalopram (racemic citalopram). There is evidence that R-citalopram may block the effects of S-citalopram. The hypothesis being tested is that because of the antagonist effect of R-citalopram, S-citalopram will have a greater effect on the mood circuit than racemic citalopram when equal doses of S-citalopram are administered. The study design consists of a two week medication period followed by blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) while viewing affective visual stimuli.
Interventions
DRUGEscitalopram
One week of escitalopram taken orally at 10 mg followed by one week at 20 mg daily.
DRUGCitalopram
One week of citalopram taken orally at 20 mg followed by one week at 40 mg daily.
DRUGPlacebo
Two weeks of placebo taken orally.
Sponsors
Forest Laboratories
Michael Henry, MD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
21 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male aged 21 to 50 years. * Capable of providing informed consent. * Has an established residence and phone.
Exclusion criteria
* Meets DSM-IV criteria for an Axis I or II disorder. * History of substance dependence or abuse within the past month. * Use of NSAID's, beta blockers, calcium channel blockers, antidepressants, antipsychotic medications, lithium or other medication which in the opinion of the investigator would alter vascular responsivity. * Regular use of sedative hypnotic or narcotic medication, or other medication that might affect the individual's perception of visual stimuli. * History of cataracts or significant visual impairment. * A medical condition, which in the opinion of the investigator is likely to affect the individual's perception of the visual stimuli or vascular response. * Participation in a research protocol that included administration of medication within the past 3 months. * Cigarette smoking.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Happy and Fearful Faces Are Presented in a Rapid Covert Stimulus Presentation. | two weeks | Activation was measured using BOLD fMRI in response to happy and fearful faces presented in a rapid covert or masked presentation. The response following two weeks of escitalopram was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the left middle temporal gyrus. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Faces and a Fixation Stimulus Are Presented in an Overt Presentation. | 2 weeks | Activation was measured using BOLD fMRI in response to affective faces and a fixation stimulus presented in an overt or unmasked presentation. The response following two weeks of escitalopram was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the right insular cortex. |
| Number of Voxels Showing Greater Activation Following Citalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus. | 2 weeks | Activation was measured using BOLD fMRI in response to affective (happy and fearful) faces presented in a covert or masked presentation and contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of citalopram was compared to the response following two weeks of placebo. The cluster of differential activation was located in the right occipital fusiform gyrus. |
| Number of Voxels Showing Greater Activation Following Escitalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus. | 2 weeks | Activation was measured using BOLD fMRI in response to affective (happy and fearful) faces presented in a covert or masked presentation and contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of escitalopram was compared to the response following two weeks of placebo. The cluster of differential activation was located in the right inferior lateral occipital cortex. |
| Number of Voxels Showing Greater Activation Following Placebo Compared With Citalopram When Affective Words Are Contrasted With a Fixation Stimulus. | 2 weeks | Activation was measured using BOLD fMRI in response to affective words contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of placebo was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the right lingual gyrus and right superior lateral occipital cortex. |
| Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Affective Words Are Contrasted With a Fixation Stimulus. | 2 weeks | Activation was measured using BOLD fMRI in response to affective words contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of escitalopram was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the left primary visual cortex. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited by advertisement from April 2008 until January 2011.
Pre-assignment details
Participants had their serotonin transporter genotyped. Individuals with a genotype of SS or SLg were not randomized. A total of 85 potential participants were screened. Of those, 21 were excluded on the basis of genotype. Another 28 were determined to be ineligible for other reasons and 6 withdrew prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all randomized subjects regardless of order in which they received medications | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Medication Period (14 Days) | Adverse Event | 1 | 0 | 0 | 0 | 0 | 1 |
| First Medication Period (14 Days) | Physician Decision | 2 | 0 | 1 | 0 | 0 | 1 |
| Second Medication Period (14 Days) | Physician Decision | 1 | 0 | 0 | 2 | 0 | 0 |
| Second Medication Period (14 Days) | Protocol Violation | 1 | 0 | 0 | 0 | 1 | 0 |
| Third Medication Period (14 Days) | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
| Third Medication Period (14 Days) | poor data quality | 0 | 1 | 0 | 0 | 0 | 0 |
| Third Medication Period (14 Days) | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Age, Continuous | 30.1 years STANDARD_DEVIATION 7.9 |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 22 | 1 / 21 | 1 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 | 0 / 21 |
Outcome results
Primary
Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Happy and Fearful Faces Are Presented in a Rapid Covert Stimulus Presentation.
Activation was measured using BOLD fMRI in response to happy and fearful faces presented in a rapid covert or masked presentation. The response following two weeks of escitalopram was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the left middle temporal gyrus.
Time frame: two weeks
Population: Participants were only included in the analysis if they had complete data for all 3 fMRI scans and motion was within acceptable limits. Participants also had to have detectable plasma levels of R-citalopram and S-citalopram in order to be included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants With Complete Usable Data | Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Happy and Fearful Faces Are Presented in a Rapid Covert Stimulus Presentation. | 478 voxels |
Comparison: This analysis is a comparison between the escitalopram and citalopram medication periods.p-value: 0.000704Mixed Models Analysis
Secondary
Number of Voxels Showing Greater Activation Following Citalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus.
Activation was measured using BOLD fMRI in response to affective (happy and fearful) faces presented in a covert or masked presentation and contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of citalopram was compared to the response following two weeks of placebo. The cluster of differential activation was located in the right occipital fusiform gyrus.
Time frame: 2 weeks
Population: Participants were only included in the analysis if they had complete data for all 3 fMRI scans and motion was within acceptable limits. Participants also had to have detectable plasma levels of R-citalopram and S-citalopram in order to be included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants With Complete Usable Data | Number of Voxels Showing Greater Activation Following Citalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus. | 658 voxels |
Comparison: This analysis is a comparison between the citalopram and placebo medication periods.p-value: 0.00000936Mixed Models Analysis
Secondary
Number of Voxels Showing Greater Activation Following Citalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus.
Activation was measured using BOLD fMRI in response to affective (happy and fearful) faces presented in a covert or masked presentation and contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of citalopram was compared to the response following two weeks of placebo. The cluster of differential activation was located in the right lateral occipital cortex.
Time frame: 2 weeks
Population: Participants were only included in the analysis if they had complete data for all 3 fMRI scans and motion was within acceptable limits. Participants also had to have detectable plasma levels of R-citalopram and S-citalopram in order to be included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants With Complete Usable Data | Number of Voxels Showing Greater Activation Following Citalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus. | 253 voxels |
Comparison: This analysis is a comparison between the citalopram and placebo medication periods.p-value: 0.0279Mixed Models Analysis
Secondary
Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Affective Words Are Contrasted With a Fixation Stimulus.
Activation was measured using BOLD fMRI in response to affective words contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of escitalopram was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the left primary visual cortex.
Time frame: 2 weeks
Population: Participants were only included in the analysis if they had complete data for all 3 fMRI scans and motion was within acceptable limits. Participants also had to have detectable plasma levels of R-citalopram and S-citalopram in order to be included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants With Complete Usable Data | Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Affective Words Are Contrasted With a Fixation Stimulus. | 289 voxels |
Comparison: This analysis is a comparison between the escitalopram and citalopram medication periods.p-value: 0.0241Mixed Models Analysis
Secondary
Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Faces and a Fixation Stimulus Are Presented in an Overt Presentation.
Activation was measured using BOLD fMRI in response to affective faces and a fixation stimulus presented in an overt or unmasked presentation. The response following two weeks of escitalopram was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the right insular cortex.
Time frame: 2 weeks
Population: Participants were only included in the analysis if they had complete data for all 3 fMRI scans and motion was within acceptable limits. Participants also had to have detectable plasma levels of R-citalopram and S-citalopram in order to be included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants With Complete Usable Data | Number of Voxels Showing Greater Activation Following Escitalopram Compared With Citalopram When Faces and a Fixation Stimulus Are Presented in an Overt Presentation. | 735 voxels |
Comparison: This analysis is a comparison between the escitalopram and citalopram medication periods.p-value: 0.0000162Mixed Models Analysis
Secondary
Number of Voxels Showing Greater Activation Following Escitalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus.
Activation was measured using BOLD fMRI in response to affective (happy and fearful) faces presented in a covert or masked presentation and contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of escitalopram was compared to the response following two weeks of placebo. The cluster of differential activation was located in the right inferior lateral occipital cortex.
Time frame: 2 weeks
Population: Participants were only included in the analysis if they had complete data for all 3 fMRI scans and motion was within acceptable limits. Participants also had to have detectable plasma levels of R-citalopram and S-citalopram in order to be included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants With Complete Usable Data | Number of Voxels Showing Greater Activation Following Escitalopram Compared With Placebo When Affective Faces Are Presented in a Covert Stimulus Presentation and Contrasted With a Fixation Stimulus. | 396 voxels |
Comparison: This analysis is a comparison between the escitalopram and placebo medication periods.p-value: 0.00124Mixed Models Analysis
Secondary
Number of Voxels Showing Greater Activation Following Placebo Compared With Citalopram When Affective Words Are Contrasted With a Fixation Stimulus.
Activation was measured using BOLD fMRI in response to affective words contrasted with activation in response to a neutral fixation stimulus. The response following two weeks of placebo was compared to the response following two weeks of citalopram. The cluster of differential activation was located in the right lingual gyrus and right superior lateral occipital cortex.
Time frame: 2 weeks
Population: Participants were only included in the analysis if they had complete data for all 3 fMRI scans and motion was within acceptable limits. Participants also had to have detectable plasma levels of R-citalopram and S-citalopram in order to be included in the final analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants With Complete Usable Data | Number of Voxels Showing Greater Activation Following Placebo Compared With Citalopram When Affective Words Are Contrasted With a Fixation Stimulus. | 619 voxels |
Comparison: This analysis is a comparison between the placebo and citalopram medication periods.p-value: 0.0000633Mixed Models Analysis