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Bipolar Depression Before and After Lamotrigine Treatment (1HMRS-BP)

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ClinicalTrials.gov Identifier: NCT01042496
Recruitment Status : Completed
First Posted : January 5, 2010
Results First Posted : January 12, 2016
Last Update Posted : February 8, 2016
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Mark Frye, Mayo Clinic

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Bipolar Depression
Interventions Drug: Lamotrigine
Procedure: 1H-MR
Enrollment 72
Recruitment Details Subjects were recruited from the Mayo Clinic in Rochester, Minnesota.
Pre-assignment Details 39 subjects signed informed consent for the Bipolar Group, but 9 were screen failures, and one subject signed consent but did not start the study. 33 subjects signed informed consent for the Healthy Control group, and all of these subjects completed the study.
Arm/Group Title Bipolar Group Control Group
Hide Arm/Group Description

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks. Flexible titration for early response and/or side effects.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Period Title: Overall Study
Started 29 33
Completed 29 33
Not Completed 0 0
Arm/Group Title Bipolar Group Control Group Total
Hide Arm/Group Description

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks. Flexible titration for early response and/or side effects.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Total of all reporting groups
Overall Number of Baseline Participants 29 33 62
Hide Baseline Analysis Population Description
Only participants who took part in the study were included in the baseline analysis population.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 29 participants 33 participants 62 participants
36.10  (13.44) 35.18  (10.1) 35.61  (11.69)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 33 participants 62 participants
Female
17
  58.6%
15
  45.5%
32
  51.6%
Male
12
  41.4%
18
  54.5%
30
  48.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 29 participants 33 participants 62 participants
29 33 62
1.Primary Outcome
Title Mean Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Baseline for Both Groups, and After 12 Weeks of Lamotrigine Monotherapy for the Bipolar Group
Hide Description The MADRS is a 10-item observer rating scale assessing symptoms of depression. The score ranges from 0 (no depression) to 60 (very depressed). A score of less than 12 is considered clinical remission of depression.
Time Frame baseline, 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The control group only did the MADRS depression rating scale at baseline. 25 participants in the Bipolar group took the MADRS depression rating scale at 12 weeks.
Arm/Group Title Bipolar Group Control Group
Hide Arm/Group Description:

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks. Flexible titration for early response and/or side effects.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Overall Number of Participants Analyzed 29 33
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline 27.79  (5.80) 0.30  (0.64)
12 weeks 14.28  (11.67) NA [1]   (NA)
[1]
The control group only did the MADRS depression rating scale at baseline.
2.Secondary Outcome
Title Glutamate+Glutamine (GLX) Measured in Mid Anterior Cingulate Cortex (MACC) & Left Dorsal Lateral Prefrontal Cortex (LDLPC) Using Long TE PRESS MRS Technique at Baseline for Both Groups; After 12 Weeks of Lamotrigine Monotherapy for the Bipolar Group
Hide Description Two different MRS sequences were used to measure the brain chemicals in in anterior cingulate and left dorsal lateral prefrontal cortex : an intermediate echo-time PRESS sequence and a 2D J-resolved averaged PRESS sequence. (Note: The intermediate echo-time PRESS sequence was used for this outcome measure.) Spectroscopic data were inspected for quality; subjects whose data were contaminated by artifact were excluded from the study. Spectra were then processed using LCModel to quantify brain chemical levels. Regular brain MRI images were segmented, yielding a map of the amount of cerebrospinal fluid (CSF); the MRS voxel was overlaid onto the CSF map and the fraction of CSF was measured. This CSF corrected measurement was used for statistical analysis.
Time Frame baseline, after 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Sample sizes varied due to imaging results/scan viability. Excessive noise resulted in poor metabolite readings which in-turn were not used in the final analysis. Baseline: control group MACC n=7, LDLPC n=8, Bipolar group MACC n=18, LDLPC n=27. Bipolar group 12 weeks MACC n=12, LDLPC n=16. The control group did not do the procedure at 12 weeks.
Arm/Group Title Bipolar Group Control Group
Hide Arm/Group Description:

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks. Flexible titration for early response and/or side effects.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Overall Number of Participants Analyzed 28 8
Mean (Standard Deviation)
Unit of Measure: Institutional Units (IU)
Baseline GLX measured in MACC 15.08  (3.88) 11.98  (2.06)
12 Weeks GLX measured in MACC 12.69  (4.05) NA [1]   (NA)
Baseline GLX measured in LDLPC 14.0  (2.7) 12.9  (1.4)
12 Weeks GLX measured in LDLPC 14.1  (2.7) NA [1]   (NA)
[1]
The control group did not do the procedure at 12 weeks.
3.Secondary Outcome
Title N-acetylaspartic Acid (NAA) Measured in the MACC and LDLPC Using the Long TE (TE80) PRESS MRS Technique at Baseline for Both Groups, and After 12 Weeks of Lamotrigine Monotherapy for the Bipolar (BP) Group and BP Responders and Non-responders
Hide Description Two different MRS sequences were used to measure the brain chemicals in a single 2 x 2 x 2 cm cube located in the center of anterior cingulate cortex: an intermediate echo-time PRESS sequence and a 2D J-resolved averaged PRESS sequence. (Note: The intermediate echo-time PRESS sequence was used for this outcome measure.) Spectroscopic data were inspected for quality; subjects whose data were contaminated by artifact were excluded from the study. Spectra were then processed using LCModel to quantify brain chemical levels. Regular brain MRI images were segmented, yielding a map of the amount of CSF in the head. The MRS voxel was overlaid onto the CSF map and the fraction of CSF within the voxel measured. This CSF-corrected measurement was used for statistical analysis.
Time Frame baseline, 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Samples varied due to imaging results/scan viability. Baseline: control group MACC (M) and LDLPC (L) n=8, BP whole M n=28 (3 didn't complete), L n=27, BP Responders M n=13, L n=11, BP nonresponders M and L n=12; BP whole 12 weeks M and L n=16. BP Responders M and L n=10, BP nonresponders M and L n=6. Controls didn't do the procedure at 12 weeks.
Arm/Group Title Bipolar Lamotrigine Responders Group Control Group Bipolar Lamotrigine Non-Responders Group Bipolar Lamotrigine Group as Whole
Hide Arm/Group Description:

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks. Flexible titration for early response and/or side effects.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Non-responders were those bipolar participants who did not achieve remission (defined as a Montgomery Asberg Depression Rating Scale (MADRS) score <12 at week 12).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (DLPFC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (DLPFC).

Overall Number of Participants Analyzed 13 8 12 28
Mean (Standard Deviation)
Unit of Measure: Institutional Units (IU)
LDLPC Baseline NAA 19.5  (1.9) 20.1  (1.5) 21.0  (2.8) 20.0  (2.5)
LDLPC 12 weeks NAA 20.3  (2.1) NA [1]   (NA) 20.8  (2.9) 20.5  (2.4)
MACC Baseline NAA 15.7  (2.9) 17.51  (1.77) 15.2  (3.3) 15.4  (3.0)
MACC 12 weeks NAA 14.3  (3.2) NA [1]   (NA) 14.9  (3.8) 14.5  (3.4)
[1]
The control group did not do the procedure at 12 weeks.
4.Secondary Outcome
Title Mean Glutamate (GLU) Measured in the MACC and LDLPC Using the ProFit MRS Technique at Baseline for Both Groups, After 12 Weeks of Lamotrigine Monotherapy for the Bipolar Group
Hide Description Two different MRS sequences were used to measure the brain chemicals in a single 2 x 2 x 2 cm cube located in the center of anterior cingulate cortex: an intermediate echo-time PRESS sequence and a 2D J-resolved averaged PRESS sequence. (Note: The 2D J-resolved averaged PRESS sequence was used for this outcome measure.) Spectroscopic data were inspected for quality; subjects whose data were contaminated by artifact were excluded from the study. Spectra were then processed using LCModel to quantify brain chemical levels. Regular brain MRI images were segmented, yielding a map of the amount of CSF in the head. The MRS voxel was overlaid onto the CSF map and the fraction of CSF within the voxel measured. This CSF-corrected measurement was then used for statistical analysis.
Time Frame baseline, 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Sample sizes varied due to imaging results/scan viability. Excessive noise resulted in poor metabolite readings which in-turn were not used in the final analysis. Baseline: control group MACC n=8, LDLPC n=8, Bipolar group MACC n=13, LDLPC n=13. Bipolar group 12 weeks MACC n=8, LDLPC n=17. The control group did not do the procedure at 12 weeks.
Arm/Group Title Bipolar Group Control Group
Hide Arm/Group Description:

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks. Flexible titration for early response and/or side effects.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (DLPFC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (DLPFC).

Overall Number of Participants Analyzed 17 8
Mean (Standard Deviation)
Unit of Measure: Institutional Units (IU)
Baseline MACC 147.55  (32.57) 157.51  (36.17)
12 Weeks MACC 134  (13.5) NA [1]   (NA)
Baseline LDLPC 65.4  (15.5) 64.1  (12.6)
12 Weeks LDLPC 63.5  (11.6) NA [1]   (NA)
[1]
The control group did not do the procedure at 12 weeks.
5.Secondary Outcome
Title Glutamine/Glutamate Ratio Measured in the LDLPC at Baseline Using the ProFit Magnetic Resonance Spectroscopy (MRS) Technique
Hide Description Two different MRS sequences were used to measure the brain chemicals in a single 2 x 2 x 2 cm cube located in the center of anterior cingulate cortex: an intermediate echo-time PRESS sequence and a 2D J-resolved averaged PRESS sequence. (Note: The 2D J-resolved averaged PRESS sequence was used for this outcome measure.) Spectroscopic data were inspected for quality; subjects whose data were contaminated by artifact were excluded from the study. Spectra were then processed using LCModel to quantify brain chemical levels. Regular brain MRI images were segmented, yielding a map of the amount of CSF in the head. The MRS voxel was overlaid onto the CSF map and the fraction of CSF within the voxel measured. This CSF-corrected measurement was then used for statistical analysis.
Time Frame baseline
Hide Outcome Measure Data
Hide Analysis Population Description
Sample sizes varied between both scanning locations LDLPC and MACC and between metabolites due to imaging results/scan viability. Some subject scans yielded more viable information/ less noise during the scan process. Excessive noise resulted in poor metabolite readings which in-turn were not used in the final analysis.
Arm/Group Title Bipolar Group Control Group
Hide Arm/Group Description:

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks. Flexible titration for early response and/or side effects.

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (DLPFC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (DLPFC).

Overall Number of Participants Analyzed 6 0
Mean (Standard Deviation)
Unit of Measure: ratio
1.27  (.62)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Bipolar Group Control Group
Hide Arm/Group Description

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC) before and after treatment with Lamotrigine.

Lamotrigine: 12 week open trial: 25mg/day for 2 weeks, 50mg/day for 2 weeks, 100mg/day for 2 weeks, 200mg/day for 6 weeks

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

Subjects underwent proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

1H-MR: Proton magnetic resonance spectroscopy (1H-MR) evaluation of medial anterior cingulate cortex (MACC) and left dorsal lateral prefrontal cortex (LDLPC).

All-Cause Mortality
Bipolar Group Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Bipolar Group Control Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/29 (17.24%)      0/33 (0.00%)    
Psychiatric disorders     
Hospitalization due to progression of disease   1/29 (3.45%)  1 0/33 (0.00%)  0
Admitted to ER due to symptoms   1/29 (3.45%)  1 0/33 (0.00%)  0
Death   1/29 (3.45%)  1 0/33 (0.00%)  0
Worsening of bipolar symptoms   1/29 (3.45%)  1 0/33 (0.00%)  0
Withdrawal from study due to decrease in mood   1/29 (3.45%)  1 0/33 (0.00%)  0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Bipolar Group Control Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/29 (20.69%)      0/33 (0.00%)    
Blood and lymphatic system disorders     
Swollen lymph node   1/29 (3.45%)  1 0/33 (0.00%)  0
Abnormal high GGT level at study exit   1/29 (3.45%)  1 0/33 (0.00%)  0
Hepatobiliary disorders     
Abnormal high AST level at study exit   1/29 (3.45%)  1 0/33 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Paresthesia of Right Shoulder Blade   1/29 (3.45%)  1 0/33 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Pneumonia   1/29 (3.45%)  1 0/33 (0.00%)  0
Skin and subcutaneous tissue disorders     
Bruise on back of head near ossiput   1/29 (3.45%)  1 0/33 (0.00%)  0
Rash on left knee   1/29 (3.45%)  1 0/33 (0.00%)  0
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Mark A. Frye
Organization: Mayo Clinic
Phone: 507-284-6213
EMail: MFrye@mayo.edu
Layout table for additonal information
Responsible Party: Mark Frye, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01042496     History of Changes
Other Study ID Numbers: 09-004163
R01MH079261-01A2 ( U.S. NIH Grant/Contract )
First Submitted: January 4, 2010
First Posted: January 5, 2010
Results First Submitted: September 24, 2015
Results First Posted: January 12, 2016
Last Update Posted: February 8, 2016