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Glutamatergic and GABAergic Mediators of Antidepressant Response in Major Depression

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01557946
First Posted: March 20, 2012
Last Update Posted: September 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Brian P. Brennan, MD, Mclean Hospital
  Purpose
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.

Condition Intervention Phase
MDD Citalopram Major Depressive Disorder Drug: citalopram Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Glutamatergic and GABAergic Mediators of Antidepressant Response in Major Depression

Resource links provided by NLM:


Further study details as provided by Brian P. Brennan, MD, Mclean Hospital:

Primary Outcome Measures:
  • Mean Difference From Baseline to Day 3 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group [ Time Frame: Change from Baseline to Day 3 ]
    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.


Secondary Outcome Measures:
  • Mean Difference From Baseline to Day 7 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group [ Time Frame: Change from baseline to day 7 ]
    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.


Enrollment: 32
Study Start Date: March 2012
Study Completion Date: September 2015
Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Major Depression
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
citalopram 20-40 mg daily
Other Name: Celexa
No Intervention: Healthy Volunteers
Healthy volunteer participants did not receive citalopram and performed one MRI scan.

Detailed Description:
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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female age ≥ 18 and ≤ 65
  2. Meets DSM-IV criteria for MDD
  3. Current score of ≥ 18 on the 21-item Hamilton Depression Rating Scale (HAM-D).

Exclusion Criteria:

  1. Unwillingness or inability to provide written informed consent.
  2. Current suicidal ideation
  3. Active psychotic symptoms
  4. Lifetime history of bipolar disorder, schizophrenia, or OCD
  5. 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)
  6. DSM-IV diagnosis of alcohol or substance dependence, with the exception of nicotine dependence, within three months prior to screening
  7. Any history of treatment with electroconvulsive therapy
  8. 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.
  9. 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
  10. 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

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01557946


Locations
United States, Massachusetts
McLean Hospital
Belmont, Massachusetts, United States, 02478
Sponsors and Collaborators
Mclean Hospital
Investigators
Principal Investigator: Brian P. Brennan, M.D. Mclean Hospital
  More Information

Responsible Party: Brian P. Brennan, MD, Associate Director of Translational Neuroscience Research, Mclean Hospital
ClinicalTrials.gov Identifier: NCT01557946     History of Changes
Other Study ID Numbers: 2011-P-001192
First Submitted: March 9, 2012
First Posted: March 20, 2012
Results First Submitted: January 20, 2017
Results First Posted: September 12, 2017
Last Update Posted: September 12, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Citalopram
Dexetimide
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents