Lamotrigine Therapy in Geriatric Bipolar Depression

• Sponsor: Mclean Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00720473
• Collaborator: (none)
• Enrollment: 69
• Location: 1
• Arms: 2
• Duration (Months): 68
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

We propose to study the efficacy and tolerability of lamotrigine in the treatment of older adults with bipolar depression and to compare measures of brain energy metabolism between older subjects with bipolar depression and healthy age-matched controls in order to better understand treatment response in geriatric bipolar depression.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Depression	Drug: Lamotrigine	N/A

Detailed Description

We will use MRI techniques and neuropsychological testing to investigate potential markers of treatment response in elderly bipolar depressed patients receiving lamotrigine and age-matched, non-depressed controls.

We intend to test these hypotheses:

1. At least 50% of older subjects with bipolar depression will respond treatment with lamotrigine as evidenced by a 50% reduction on the Montgomery Asberg Rating Scale (MADRS). In addition, treatment with lamotrigine will be safe and well tolerated as evidenced by a drop-out rate of less than 10% due to adverse effects.

2. Compared with healthy age-matched, non-demented, non-depressed controls, subjects with geriatric bipolar depression will demonstrate abnormalities in cerebral energy metabolism as assessed by elevated levels of glutamate and lactate, and decreased levels of NAA, using 1H MRS at 4T.

3. Successful treatment with lamotrigine in geriatric bipolar depression will result in decreases in lactate and glutamate, and elevations in NAA.

4. Baseline measures of executive functioning and information processing speed (measured by performance on the Wisconsin Card Sorting Test (WCST), Trails A and B and Stroop tests) will be impaired in subjects with geriatric bipolar depression compared with healthy controls. These measures will improve with successful treatment with lamotrigine and correlate with improvements in markers of cerebral energy metabolism (lactate, glutamate, NAA).

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Lamotrigine Therapy in the Treatment of Geriatric Bipolar Depression: An Evaluation of Markers of Cerebral Energy Metabolism
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Other: A: Other Open Label Study	Drug: Lamotrigine; Lamotrigine with dosage range from 25 mg to 200 mg per day.; Other Names: Lamictal
No Intervention: B: Healthy Controls

Outcome Measures

Primary Outcome Measures

1. Mean Glutamine to Creatine Ratio by Diagnosis at Baseline [Baseline]

2. Mean Glutamate to Creatine Ratio by Diagnosis at Baseline [Baseline]

3. Mean N-Acetyl Aspartate (NAA) to Creatine Ratio by Diagnosis at Baseline [Baseline]

4. Associations Between Depression Symptom Severity and Glutamate to Creatine Ratio at Baseline [Baseline]

   Estimated changes in least squares mean in the metabolite ratio per 10-point increase in MADRS score. The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.

5. Estimated Change in Least Squares Mean in Glutamate to Creatine Ratio Between Baseline and Follow-up [8 Weeks]

   Follow-up Least Squares Mean - Baseline Least Squares Mean

6. Estimated Change in Least Squares Mean in the Glutamine to Creatine Ratio Between Baseline and Follow-up [8 weeks]

   Follow-up Least Squares Mean - Baseline Least Squares Mean

7. Estimated Change in Least Squares Mean in the NAA to Creatine Ratio Between Baseline and Follow-up [8 weeks]

   Follow-up Least Squares Mean - Baseline Least Squares Mean

8. Association of MADRS Changes With Glutamate to Creatine Ratio Changes From Baseline to Follow-up [8 Weeks]

   Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. The MADRS minimum score is 0 and maximum is 60, with 60 being the most depressed score. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.

9. Associations of MADRS Changes With Glutamine to Creatine Ratio Changes From Baseline to Follow-up [8 weeks]

   Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.

10. Associations of MADRS Changes With NAA to Creatine Ratio Changes From Baseline to Follow-up [8 weeks]

    Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.

11. Mean Montgomery Asberg Depression Rating Scale (MADRS) Score at Baseline [Baseline]

    The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed.

12. Means of MADRS Scores at 8 Weeks [8 Weeks]

    The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria (for Bipolar Subjects):

• 60 years or older

• Meet DSM-IV diagnostic criteria for Bipolar Disorder, Current Episode Depressed

• First episode of mania before the age of 50 (early-onset bipolar disorder)

• Montgomery-Asberg Depression Rating Scale (MADRS) Score of greater or equal to 20.

• Young Mania Rating Scale (YMRS) of less than or equal to 6.

• Able to provide informed consent

• Must speak English

• Must be able to visit McLean Hospital for the screening visit and six study visits during the 8-week duration of the study.

• Subjects may be taking other medications for bipolar depression including antidepressants, mood stabilizers and antipsychotic mediations prior to lamotrigine therapy, but may not have any dosage adjustments of these medications in the week before lamotrigine is added.

Exclusion Criteria (for Bipolar Subjects):

• Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease.

• History of seizure disorder

• History or current diagnosis of the following psychiatric illnesses: any organic mental disorder (including dementia), schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorder not otherwise specified, unipolar major depressive disorder, patients with substance dependence disorders, including alcohol, active within the last 12 months.

• First episode of mania after the age of 50 (to exclude late-onset bipolar disorder)

• History of multiple adverse drug reactions or allergy to the study drugs.

• Use of medications that are excluded in this study (benzodiazepines, barbiturates; however, the use of non-benzodiazepine sedative hypnotics (such as zolpidem (Ambien)) may be used as needed except within 48 hours of the MRI scan)

• Any of the exclusion criteria mentioned in the MRI risks section below

Inclusion Criteria (for Controls):

• 60 years or older

• Able to provide informed consent

• Must speak English

• Women entering this study must be post-menopausal

Exclusion Criteria (for Controls):

• Same criteria for the Bipolar Depressed group with the exception of the "first episode of mania" which is not applicable.

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: Brent P Forester, MD, Mclean Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Brent Forester, Director, Mood Disorders Division, Geriatric Psychiatry Research Program, Mclean Hospital
• ClinicalTrials.gov Identifier: NCT00720473
• Other Study ID Numbers: 2005-P-002493
• First Posted: Jul 22, 2008
• Last Update Posted: Feb 1, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Brent Forester, Director, Mood Disorders Division, Geriatric Psychiatry Research Program, Mclean Hospital: Bipolar depression; Elderly; Lamotrigine; Brain energy metabolism
• Additional relevant MeSH terms: Depression; Depressive Disorder; Bipolar Disorder; Lamotrigine

Study Results

Participant Flow

Arm/Group Title	A: BPD Subjects	B: Healthy Control
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	No Intervention
Period Title: Overall Study
STARTED	45	24
COMPLETED	15	16
NOT COMPLETED	30	8

Baseline Characteristics

Arm/Group Title	BPD Subjects	Control Subjects	Total
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD	Total of all reporting groups
Overall Participants	23	14	37
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 73.9%	7 50%	24 64.9%
>=65 years	6 26.1%	7 50%	13 35.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.0 (5.9)	67.5 (8.8)	64.6 (7.4)
Sex: Female, Male (Count of Participants)
Female	9 39.1%	7 50%	16 43.2%
Male	14 60.9%	7 50%	21 56.8%
Region of Enrollment (participants) [Number]
United States	23 100%	14 100%	37 100%

Outcome Measures

1. Primary Outcome

Title	Mean Glutamine to Creatine Ratio by Diagnosis at Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Baseline scans were available for 37 participants. One participant was missing scan data.

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	22	14
Mean (Standard Deviation) [mean serum Glutamine to Creatine ratio]	.34 (.12)	.36 (.18)

2. Primary Outcome

Title	Mean Glutamate to Creatine Ratio by Diagnosis at Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Baseline scans were available for 37 participants. One participant was missing scan data.

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	22	14
Mean (Standard Deviation) [mean serum Glutamate to Creatine ratio]	.96 (.29)	.85 (.25)

3. Primary Outcome

Title	Mean N-Acetyl Aspartate (NAA) to Creatine Ratio by Diagnosis at Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Baseline scans were available for 37 participants. One participant was missing scan data.

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	22	14
Mean (Standard Deviation) [Mean NAA to creatine ratio]	0.97 (0.14)	0.84 (0.22)

4. Primary Outcome

Title	Associations Between Depression Symptom Severity and Glutamate to Creatine Ratio at Baseline
Description	Estimated changes in least squares mean in the metabolite ratio per 10-point increase in MADRS score. The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.

Arm/Group Title	A: Other
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.
Measure Participants	21
Least Squares Mean (95% Confidence Interval) [Glu:Cr/+10 MADRS]	0.18

5. Primary Outcome

Title	Estimated Change in Least Squares Mean in Glutamate to Creatine Ratio Between Baseline and Follow-up
Description	Follow-up Least Squares Mean - Baseline Least Squares Mean
Time Frame	8 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	13	11
Least Squares Mean (95% Confidence Interval) [serum Glutamate to Creatine ratio]	0.00	-0.12

6. Primary Outcome

Title	Estimated Change in Least Squares Mean in the Glutamine to Creatine Ratio Between Baseline and Follow-up
Description	Follow-up Least Squares Mean - Baseline Least Squares Mean
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	13	11
Least Squares Mean (95% Confidence Interval) [serum Glutamine to Creatine ratio]	0.02	0.08

7. Primary Outcome

Title	Estimated Change in Least Squares Mean in the NAA to Creatine Ratio Between Baseline and Follow-up
Description	Follow-up Least Squares Mean - Baseline Least Squares Mean
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	13	11
Least Squares Mean (95% Confidence Interval) [NAA to creatine ratio]	0.06	-0.03

8. Primary Outcome

Title	Association of MADRS Changes With Glutamate to Creatine Ratio Changes From Baseline to Follow-up
Description	Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. The MADRS minimum score is 0 and maximum is 60, with 60 being the most depressed score. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time Frame	8 Weeks

Outcome Measure Data

Analysis Population Description

Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.

Arm/Group Title	BPD Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.
Measure Participants	11
Least Squares Mean (95% Confidence Interval) [Glu:Cr/-10 MADRS]	-.007

9. Primary Outcome

Title	Associations of MADRS Changes With Glutamine to Creatine Ratio Changes From Baseline to Follow-up
Description	Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.

Arm/Group Title	BPD Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.
Measure Participants	11
Least Squares Mean (95% Confidence Interval) [Gln:Cr/-10 MADRS Score]	0.04

10. Primary Outcome

Title	Associations of MADRS Changes With NAA to Creatine Ratio Changes From Baseline to Follow-up
Description	Estimated least squares mean metabolite ratio changes with a 10-point decrease in MADRS score. MADRS minimum score is 0 and maximum is 60, with 60 being most depressed. Estimate was from linear regression models controlling for age and sex. The change is across regions, parieto-occipital and anterior cingulate cortex.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Association between depression symptom severity and metabolite ratios were only conducted in the depressed group, because there should be no change in MADRS score for non-depressed control subjects who received no treatment.

Arm/Group Title	BPD Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.
Measure Participants	11
Least Squares Mean (95% Confidence Interval) [NAA:Cr/-10 MADRS]	0.05

11. Primary Outcome

Title	Mean Montgomery Asberg Depression Rating Scale (MADRS) Score at Baseline
Description	The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

MADRS scores were available for 27 eligible bipolar subjects and 14 eligible controls.

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	27	14
Mean (Standard Deviation) [units on a scale]	24.78 (6.65)	1.03 (1.55)

12. Primary Outcome

Title	Means of MADRS Scores at 8 Weeks
Description	The minimum MADRS score is 0 and the maximum is 60, with 60 being the most depressed.
Time Frame	8 Weeks

Outcome Measure Data

Analysis Population Description

MADRS scores were available for 16 bipolar subjects who completed the protocol and 8 healthy controls.

Arm/Group Title	BPD Subjects	Control Subjects
Arm/Group Description	Open Label Study Lamotrigine : Lamotrigine with dosage range from 25 mg to 200 mg per day.	Age matched controls without BPD
Measure Participants	16	8
Mean (Standard Deviation) [units on a scale]	18.31 (9.41)	1.38 (1.51)

Adverse Events

Arm/Group Title	Control Subjects		BPD Subjects
Arm/Group Description	Age matched controls without BPD
All Cause Mortality
	Control Subjects		BPD Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Control Subjects		BPD Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		2/45 (4.4%)
Injury, poisoning and procedural complications
Loss of consciousness	0/24 (0%)	0	1/45 (2.2%)	1
Psychiatric disorders
Mania	0/24 (0%)	0	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Control Subjects		BPD Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		14/45 (31.1%)
Eye disorders
Blurry Vision	0/24 (0%)	0	1/45 (2.2%)	1
Gastrointestinal disorders
Stomach upset	0/24 (0%)	0	2/45 (4.4%)	2
General disorders
Decreased balance	0/24 (0%)	0	3/45 (6.7%)	3
Headache	0/24 (0%)	0	2/45 (4.4%)	2
Metabolism and nutrition disorders
Weight gain	0/24 (0%)	0	1/45 (2.2%)	1
Psychiatric disorders
mania	0/24 (0%)	0	1/45 (2.2%)	1
Insomnia	0/24 (0%)	0	4/45 (8.9%)	4
Irritability	0/24 (0%)	0	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Runny Nose	0/24 (0%)	0	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
Rash	0/24 (0%)	0	1/45 (2.2%)	1
Rash	0/24 (0%)	0	1/45 (2.2%)	1
Blister	0/24 (0%)	0	1/45 (2.2%)	1

Limitations/Caveats

Limited data was available for associating changes in MADRS scores with metabolite changes (22 regions from 11 participants with BPD).

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.