Glutamatergic and GABAergic Mediators of Antidepressant Response in Major Depression

• Sponsor: Mclean Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01557946
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arms: 2
• Duration (Months): 42
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
MDD; Citalopram; Major Depressive Disorder	Drug: citalopram	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• 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.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
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Celexa
No Intervention: Healthy Volunteers Healthy volunteer participants did not receive citalopram and performed one MRI scan.

Outcome Measures

Primary Outcome Measures

1. Mean Difference From Baseline to Day 3 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group [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

1. Mean Difference From Baseline to Day 7 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

11. 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).

12. Any screening laboratory abnormality deemed clinically significant by the investigator

13. 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

Locations

	Site	City	State	Country	Postal Code
1	McLean Hospital	Belmont	Massachusetts	United States	02478

Sponsors and Collaborators

• Mclean Hospital

Investigators

• Principal Investigator: Brian P. Brennan, M.D., Mclean Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Brian P. Brennan, MD, Associate Director of Translational Neuroscience Research, Mclean Hospital
• ClinicalTrials.gov Identifier: NCT01557946
• Other Study ID Numbers: 2011-P-001192
• First Posted: Mar 20, 2012
• Last Update Posted: Sep 12, 2017
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Citalopram

Study Results

Participant Flow

Arm/Group Title	Citalopram 20 mg / 40 mg	Healthy Control
Arm/Group Description	Citalopram tablet taken once daily. Only applicable to MDD participants. Every subject began on 20 mg, and had the option to titrate up to 40 mg.	No citalopram tablet taken.
Period Title: Overall Study
STARTED	20	12
COMPLETED	17	12
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Citalopram 20/40 mg	Healthy Control	Total
Arm/Group Description	Citalopram tablet taken once daily.	No citalopram tablet taken.	Total of all reporting groups
Overall Participants	20	12	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	12 100%	32 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.5 (12.7)	38.2 (14.1)	39.0 (13.0)
Sex: Female, Male (Count of Participants)
Female	9 45%	7 58.3%	16 50%
Male	11 55%	5 41.7%	16 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10%	0 0%	2 6.3%
Not Hispanic or Latino	18 90%	12 100%	30 93.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 5%	1 8.3%	2 6.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 15%	4 33.3%	7 21.9%
White	16 80%	7 58.3%	23 71.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	20 100%	12 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Mean Difference From Baseline to Day 3 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group
Description	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.
Time Frame	Change from Baseline to Day 3

Outcome Measure Data

Analysis Population Description

One participant lacked a day 3 scan; one participant's day 3 scan was corrupted during data transfer and could not be recovered; and one participant's day 3 scan data was judged to be unusable due to poor spectral quality. Results are only presented for participants with depression as healthy control participants were only scanned once.

Arm/Group Title	Participants With Depression
Arm/Group Description	Participants with depression receiving citalopram
Measure Participants	16
Mean (Standard Error) [arbitrary units]	0.015 (0.032)

2. Secondary Outcome

Title	Mean Difference From Baseline to Day 7 in Glutamine/Glutamate (Gln/Glu) Ratio Within Depressed Group
Description	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.
Time Frame	Change from baseline to day 7

Outcome Measure Data

Analysis Population Description

One participant's day 7 scan was corrupted during data transfer and could not be recovered. Results are only presented for participants with depression as healthy control participants were only scanned once.

Arm/Group Title	Participants With Depression
Arm/Group Description	Participants with depression receiving citalopram
Measure Participants	18
Mean (Standard Error) [arbitrary units]	-0.0025 (0.031)

Adverse Events

Time Frame	Adverse events were collected during the duration of participant's participation in study (on average 8 weeks). Adverse events relate specifically to study medication.
Arm/Group Title	Citalopram 20 mg / 40 mg		Healthy Control
Arm/Group Description	Citalopram tablet taken once daily.		No citalopram tablet taken.
All Cause Mortality
	Citalopram 20 mg / 40 mg		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Citalopram 20 mg / 40 mg		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Citalopram 20 mg / 40 mg		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/19 (100%)		0/0 (NaN)
Gastrointestinal disorders
Abdominal Cramping	1/19 (5.3%)		0/0 (NaN)
Constipation	1/19 (5.3%)		0/0 (NaN)
Diarrhea	1/19 (5.3%)		0/0 (NaN)
General disorders
Headaches	9/19 (47.4%)		0/0 (NaN)
Insomnia	6/19 (31.6%)		0/0 (NaN)
Nausea	4/19 (21.1%)		0/0 (NaN)
Sedation	4/19 (21.1%)		0/0 (NaN)
Teeth Grinding	3/19 (15.8%)		0/0 (NaN)
Vivid Dreams	2/19 (10.5%)		0/0 (NaN)
Lethargy	3/19 (15.8%)		0/0 (NaN)
Dry Mouth	2/19 (10.5%)		0/0 (NaN)
Increased Sweating	2/19 (10.5%)		0/0 (NaN)
Jaw clenching	1/19 (5.3%)		0/0 (NaN)
Lightheadedness	1/19 (5.3%)		0/0 (NaN)
"Heaviness in Eyelids"	1/19 (5.3%)		0/0 (NaN)
"Spaciness"	1/19 (5.3%)		0/0 (NaN)
Dizziness	1/19 (5.3%)		0/0 (NaN)
Palpitations	1/19 (5.3%)		0/0 (NaN)
Right-Sided Jaw Pain	1/19 (5.3%)		0/0 (NaN)
Psychiatric disorders
"Emotional Dulling"	1/19 (5.3%)		0/0 (NaN)
Reproductive system and breast disorders
Anorgasmia	2/19 (10.5%)		0/0 (NaN)
Decreased Libido	1/19 (5.3%)		0/0 (NaN)

Limitations/Caveats

Modest sample size due to participant attrition and the cost and logistical challenges of the study design. Multiple comparisons, increasing the likelihood of type I errors. Open-label design which leaves open the possibility of a placebo effect.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.