Anxiety, Depression, Insomnia
Conditions
Keywords
Magnetic Resonance Spectroscopy, Glutamate, Glutamine, GABA, Lexapro, Lunesta, Escitalopram, Eszopiclone
Brief summary
The study examined the effects of adding the sleep aid eszopiclone to Lexapro on mood and levels of the neurotransmitters glutamate, glutamine, and GABA in women with depression, anxiety, and insomnia. Specifically, the objective was to determine the role of glutamate, glutamine, and GABA in mediating the response the to the combined treatment. The hypothesis was that levels of glutamine and glutamate will be increased in women receiving eszopiclone compared to those receiving placebo. The antidepressant effect of the medication combination and its effect on sleep status was also assessed.
Interventions
DRUGEszopiclone
Subjects receive 10 mg escitalopram daily for four weeks and 10 or 20 mg for an additional six weeks. Subjects also receive 3 mg eszopiclone.
DRUGPlacebo
Subjects receive 10 mg of escitalopram daily for four weeks followed by 10 or 20 mg for an additional six weeks. Subjects also receive placebo for eszopiclone.
Sponsors
Sumitomo Pharma America, Inc.
Steward St. Elizabeth's Medical Center of Boston, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Female aged 18 to 55 years and regularly menstruating. * Meets DSM-IV criteria for unipolar major depression. * Insomnia severity index score \> 10. * Hamilton Anxiety scale score \> 15. * Hamilton Depression scale score \> 17. * Capable of providing informed consent. * Has an established residence and phone.
Exclusion criteria
* Meets DSM-IV criteria for schizophrenia, schizoaffective disorder or other axis I or II diagnosis except co-morbid anxiety disorder and insomnia. * Actively abusing substances or alcohol; or has met DSM-IV criteria for substance dependence in the past month. * Pregnancy. * Use of benzodiazepines or other sedative-hypnotics, beta blockers, calcium channel blockers, antidepressants, antipsychotic medications, lithium or other medication which in the opinion of the investigator could alter glutamate or GABA activity in the brain. * A medical condition, which in the opinion of the investigator could possibly affect the individual's brain levels of Glu and GABA. * Participation in a research protocol that included administration of medication within the past 3 months. * Cigarette smoking. * Subject has known allergic sensitivity to any of the study to escitalopram, eszopiclone or zopiclone. * Clinically significant suicidal ideation or risk of suicide as evidenced by formulation of a plan or steps taken to act on those feelings. * History of clinically significant hepatic impairment. * Subject is taking a potent cytochrome p450 3A4 inhibitor medication (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) and is unwilling or it is clinically contraindicated to stop the medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Anterior Cingulate Cortex Glutamine From Baseline to Week 1. | baseline and 1 week | Glutamine levels were measured by single voxel magnetic resonance spectroscopy. In order to normalize the data, the glutamine values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly. |
| Change in Thalamic Glutamine From Baseline to Week 1 | baseline and 1 week | Glutamine levels were measured by single voxel magnetic resonance spectroscopy in the left thalamus. In order to normalize the data, the glutamine values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Anterior Cingulate Cortex GABA From Baseline to Week 1 | baseline and 1 week | GABA levels were measured in the anterior cingulate cortex using single voxel magnetic resonance spectroscopy. In order to normalize the data, the GABA values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly. |
| Change in Thalamic GABA From Baseline to Week 1 | baseline and 1 week | GABA levels were measured in the left thalamus using single voxel magnetic resonance spectroscopy. In order to normalize the data, the GABA values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly. |
| Change in Anterior Cingulate Cortex Glutamate From Baseline to Week 1 | baseline and 1 week | Glutamate levels were measured in the anterior cingulate cortex using single voxel magnetic resonance spectroscopy. In order to normalize the data, the glutamate values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly. |
| Change in Hamilton Anxiety Rating Scale Score From Baseline to Week 10 | baseline and 10 weeks | The Hamilton Anxiety Rating Scale is a 14 item ordinal scale that assesses symptoms of anxiety with ratings from 0-4. The score range is 0 to 56, with a higher score indicating higher levels of anxiety. A score of 15 was designated as the cut-off for enrollment in the study. |
| Change in Insomnia Severity Index Score From Baseline to Week 10 | baseline and 10 weeks | The Insomnia Severity Index is a 7 item scale that assesses difficulty sleeping and effect on quality of life with item scores from 0-4. The total score range is 0 to 28 with higher scores indicating higher levels of impairment and distress. |
| Change in Hamilton Depression Rating Scale Score From Baseline to Week 10 | baseline and 10 weeks | The Hamilton Depression Rating Scale is a 21 item scale that assesses symptoms of depression with items rated on a scale of 0-4 or 0-2. The total score range is 0 to 65. A score of 7 or lower is generally considered to be an absence of depressive symptoms. A score of 18 was considered to be the cut-off for enrollment in this study, as this indicates clinically significant depression. A higher score represents greater severity of depressive symptoms. |
| Change in Thalamic Glutamate From Baseline to Week 1 | baseline and 1 week | Glutamate levels were measured in the left thalamus using single voxel magnetic resonance spectroscopy. In order to normalize the data, the glutamate values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly. |
Countries
United States
Participant flow
Recruitment details
The recruitment period was from September 2008 until October 2010. Participants were recruited by advertising in the community.
Pre-assignment details
Enrolled participants were excluded before assignment to groups if they had another co-morbid psychiatric diagnosis, a medical condition that could affect glutamate or GABA levels, a clinical presentation that was not consistent with a diagnosis of major depressive disorder, or rating scale scores below the minimum for inclusion.
Participants by arm
| Arm | Count |
|---|---|
| Eszopiclone Lexapro for 10 weeks together with eszopiclone. | 14 |
| Placebo Escitalopram with placebo | 5 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Placebo | Eszopiclone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 14 Participants | 19 Participants |
| Age Continuous | 25.4 years STANDARD_DEVIATION 5 | 29.8 years STANDARD_DEVIATION 7.5 | 28.6 years STANDARD_DEVIATION 7.1 |
| Region of Enrollment United States | 5 participants | 14 participants | 19 participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 19 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 14 | 1 / 5 |
| serious Total, serious adverse events | 0 / 14 | 0 / 5 |
Outcome results
Primary
Change in Anterior Cingulate Cortex Glutamine From Baseline to Week 1.
Glutamine levels were measured by single voxel magnetic resonance spectroscopy. In order to normalize the data, the glutamine values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly.
Time frame: baseline and 1 week
Population: Participants who had usable MRS data from both the baseline and week 1 scans were included in the analysis. Participants whose data was considered unreliable were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Anterior Cingulate Cortex Glutamine From Baseline to Week 1. | 0.00059 ratio (glutamine to creatine) | Standard Deviation 0.096 |
| Placebo | Change in Anterior Cingulate Cortex Glutamine From Baseline to Week 1. | 0.00908 ratio (glutamine to creatine) | Standard Deviation 0.088 |
p-value: 0.8895% CI: [-0.139, 0.0122]t-test, 2 sided
Primary
Change in Thalamic Glutamine From Baseline to Week 1
Glutamine levels were measured by single voxel magnetic resonance spectroscopy in the left thalamus. In order to normalize the data, the glutamine values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly.
Time frame: baseline and 1 week
Population: Participants were included in the analysis if they had usable spectroscopy data from baseline and week 1 and were not considered to have any confounding issues such as an abnormal structural MRI.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Thalamic Glutamine From Baseline to Week 1 | -0.6639 ratio (glutamine to creatine) | Standard Deviation 0.292 |
| Placebo | Change in Thalamic Glutamine From Baseline to Week 1 | -0.3551 ratio (glutamine to creatine) | Standard Deviation 0.076 |
p-value: 0.7995% CI: [-0.286, 0.224]t-test, 2 sided
Secondary
Change in Anterior Cingulate Cortex GABA From Baseline to Week 1
GABA levels were measured in the anterior cingulate cortex using single voxel magnetic resonance spectroscopy. In order to normalize the data, the GABA values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly.
Time frame: baseline and 1 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Anterior Cingulate Cortex GABA From Baseline to Week 1 | 0.0013 ratio (GABA to creatine) | Standard Deviation 0.008 |
| Placebo | Change in Anterior Cingulate Cortex GABA From Baseline to Week 1 | -0.0036 ratio (GABA to creatine) | Standard Deviation 0.008 |
p-value: 0.3795% CI: [-0.0077, 0.0174]t-test, 2 sided
Secondary
Change in Anterior Cingulate Cortex Glutamate From Baseline to Week 1
Glutamate levels were measured in the anterior cingulate cortex using single voxel magnetic resonance spectroscopy. In order to normalize the data, the glutamate values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly.
Time frame: baseline and 1 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Anterior Cingulate Cortex Glutamate From Baseline to Week 1 | -0.0066 ratio (glutamate to creatine) | Standard Deviation 0.0148 |
| Placebo | Change in Anterior Cingulate Cortex Glutamate From Baseline to Week 1 | 0.215 ratio (glutamate to creatine) | Standard Deviation 0.0239 |
p-value: 0.1695% CI: [-0.58, 0.0136]t-test, 2 sided
Secondary
Change in Hamilton Anxiety Rating Scale Score From Baseline to Week 10
The Hamilton Anxiety Rating Scale is a 14 item ordinal scale that assesses symptoms of anxiety with ratings from 0-4. The score range is 0 to 56, with a higher score indicating higher levels of anxiety. A score of 15 was designated as the cut-off for enrollment in the study.
Time frame: baseline and 10 weeks
Population: Participants who completed 10 weeks and one participant who completed 6 weeks (using last observation carried forward) were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Hamilton Anxiety Rating Scale Score From Baseline to Week 10 | -11.4 scores on a scale | Standard Deviation 7.31 |
| Placebo | Change in Hamilton Anxiety Rating Scale Score From Baseline to Week 10 | -12 scores on a scale | Standard Deviation 6.68 |
p-value: 0.8995% CI: [-9.31, 10.51]t-test, 2 sided
Secondary
Change in Hamilton Depression Rating Scale Score From Baseline to Week 10
The Hamilton Depression Rating Scale is a 21 item scale that assesses symptoms of depression with items rated on a scale of 0-4 or 0-2. The total score range is 0 to 65. A score of 7 or lower is generally considered to be an absence of depressive symptoms. A score of 18 was considered to be the cut-off for enrollment in this study, as this indicates clinically significant depression. A higher score represents greater severity of depressive symptoms.
Time frame: baseline and 10 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Hamilton Depression Rating Scale Score From Baseline to Week 10 | -13.4 scores on a scale | Standard Deviation 8.26 |
| Placebo | Change in Hamilton Depression Rating Scale Score From Baseline to Week 10 | -20.75 scores on a scale | Standard Deviation 5.91 |
p-value: 0.195% CI: [-1.76, 16.46]t-test, 2 sided
Secondary
Change in Insomnia Severity Index Score From Baseline to Week 10
The Insomnia Severity Index is a 7 item scale that assesses difficulty sleeping and effect on quality of life with item scores from 0-4. The total score range is 0 to 28 with higher scores indicating higher levels of impairment and distress.
Time frame: baseline and 10 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Insomnia Severity Index Score From Baseline to Week 10 | -11.2 scores on a scale | Standard Deviation 8.3 |
| Placebo | Change in Insomnia Severity Index Score From Baseline to Week 10 | -9.5 scores on a scale | Standard Deviation 5.45 |
p-value: 0.6695% CI: [-10.31, 6.91]t-test, 2 sided
Secondary
Change in Thalamic GABA From Baseline to Week 1
GABA levels were measured in the left thalamus using single voxel magnetic resonance spectroscopy. In order to normalize the data, the GABA values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly.
Time frame: baseline and 1 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Thalamic GABA From Baseline to Week 1 | -0.0002 ratio (GABA to creatine) | Standard Deviation 0.0115 |
| Placebo | Change in Thalamic GABA From Baseline to Week 1 | -0.0058 ratio (GABA to creatine) | Standard Deviation 0.0033 |
p-value: 0.2195% CI: [-0.0037, 0.1481]t-test, 2 sided
Secondary
Change in Thalamic Glutamate From Baseline to Week 1
Glutamate levels were measured in the left thalamus using single voxel magnetic resonance spectroscopy. In order to normalize the data, the glutamate values were expressed as a ratio to levels of creatine, since creatine levels are not expected to vary significantly.
Time frame: baseline and 1 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eszopiclone | Change in Thalamic Glutamate From Baseline to Week 1 | -0.0016 ratio (glutamate to creatine) | Standard Deviation 0.287 |
| Placebo | Change in Thalamic Glutamate From Baseline to Week 1 | -0.7715 ratio (glutamate to creatine) | Standard Deviation 0.874 |
p-value: 0.2995% CI: [-1.35, 2.77]t-test, 2 sided