Glutamatergic and GABAergic Mediators of Antidepressant Response in Major Depression

Study Overview
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Brief Summary
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Primarily, this study seeks to evaluate whether citalopram treatment is associated with an increase in the Glutamine (Gln)/Glutamate (Glu) ratio in the anterior cingulate cortex (ACC) from baseline to day 3 of treatment. Additionally, this study would like to examine whether citalopram treatment is associated with an increase in the Gln/Glu ratio in the ACC from baseline to day 7 of treatment. In order to more fully examine baseline neurochemical and functional abnormalities in participants with MDD, we also seek to scan a group of age- and sex-matched non-depressed comparison individuals in order to perform between-group analyses of baseline neuroimaging measures.

Detailed Description
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Little is known about the acute effects of standard antidepressant treatments on brain glutamate and gamma-amino-butyric acid (GABA) levels, and their association with clinical response. In the current study, we used proton magnetic resonance spectroscopy (1H-MRS) to examine longitudinally the effects of citalopram on the glutamine/glutamate ratio and GABA levels in the pregenual anterior cingulate cortex (pgACC) - a region that has been repeatedly implicated in antidepressant response - of individuals with major depressive disorder (MDD). We acquired 1H-MRS scans at baseline and at days 3, 7, and 42 of citalopram treatment in nineteen unmedicated individuals with MDD. Ten age- and sex-matched non-depressed comparison individuals were scanned once and did not receive citalopram. The association between baseline metabolites and the change in metabolites from baseline to each time point and change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 42 was assessed by longitudinal regression analysis, adjusting for age, sex, and baseline MADRS, using generalized estimating equations.

Official Title
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Glutamatergic and GABAergic Mediators of Antidepressant Response in Major Depression

Conditions
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MDD, Citalopram, Major Depressive Disorder

Intervention / Treatment
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* Drug: citalopram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age ≥ 18 and ≤ 65 Meets DSM-IV criteria for MDD Current score of ≥ 18 on the 21-item Hamilton Depression Rating Scale (HAM-D). Exclusion Criteria: Unwillingness or inability to provide written informed consent. Current suicidal ideation Active psychotic symptoms Lifetime history of bipolar disorder, schizophrenia, or OCD Failed treatment with an adequate trial of ≥ 2 antidepressants during the current major depressive episode (failure will be defined as ≤ 50% subjective improvement, and an adequate trial will be defined as at least 4 weeks of treatment using at least the minimum dose of the antidepressant recommended by the manufacturer in product labeling) DSM-IV diagnosis of alcohol or substance dependence, with the exception of nicotine dependence, within three months prior to screening Any history of treatment with electroconvulsive therapy Positive urine toxicology screen for any drug of abuse or excluded medication at screening. Opiate pain medication being taken for a medical condition is exempt from needing a negative opiate screen. Clinically significant medical or neurologic disease, as judged by the principal investigator, which would increase the risk to the participant or interfere with interpretation of results Female participants with a positive urine pregnancy test at screening 12. Pregnancy. Females of childbearing potential must be using an effective contraceptive method (e.g., abstinence, prescription oral contraceptives, contraceptive injections, double-barrier method, male partner sterilization). 13. Any screening laboratory abnormality deemed clinically significant by the investigator 14. A QTc interval on screening ECG of ≥ 450 msec. 15. Use of any excluded medications (see Section 6.7 below) that cannot be discontinued during the screening phase 16. Previous failure to respond to treatment with citalopram that would, in the judgment of the investigator, constitute an adequate trial in MDD 17. Treatment with any investigational medications within 30 days prior to screening 18. Any contraindications to having an MRI scan, including cardiac pacemakers, metal vascular clips or stents, artificial heart valves, certain kinds of prostheses, brain stimulator devices, implanted drug pumps, ear implants, eye implants or known metal fragments in eyes, exposure to shrapnel or metal filings (wounded in military combat, sheetmetal workers, welders, and others), transdermal drug delivery systems, and certain tattoos with metallic ink 19. Left-handedness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label administration of citalopram to participants with major depressive disorder. MRI scans performed at baseline and days 3, 7, and 42. An age- and gender-matched group of healthy volunteers did not receive citalopram and received on MRI scan to perform between-group baseline analyses.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Major Depression<br>Participants with major depressive disorder received citalopram 20-40 mg daily for 6 weeks. MRI scans were acquired at baseline and days 3, 7, and 42. | Drug: citalopram<br>* citalopram 20-40 mg daily<br>* Other names: Celexa;|
| No Intervention: Healthy Volunteers<br>Healthy volunteer participants did not receive citalopram and performed one MRI scan. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Difference From Baseline to Day 3 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group | Estimated mean difference (day 3 minus baseline) in the glutamine/glutamate (Gln/Glu) ratio in the rostral anterior cingulate cortex as measured by proton magnetic resonance spectroscopy from baseline to day 3 of citalopram treatment within the depressed group. The change in metabolites from baseline to each time point was assessed by random regression analysis, adjusting for age and sex, using generalized estimating equations to account for the correlation of observations within individuals. | Change from Baseline to Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Difference From Baseline to Day 7 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group | Estimated mean difference (day 7 minus baseline) in the glutamine/glutamate (Gln/Glu) ratio in the rostral anterior cingulate cortex as measured by proton magnetic resonance spectroscopy from baseline to day 7 of citalopram treatment within the depressed group. The change in metabolites from baseline to each time point was assessed by random regression analysis, adjusting for age and sex, using generalized estimating equations to account for the correlation of observations within individuals. | Change from baseline to day 7 |