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

Primary Purpose

Bipolar Depression

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Lamotrigine

1H-MR

About this trial

This is an interventional treatment trial for Bipolar Depression focused on measuring Bipolar, depression

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Bipolar Group Inclusion Criteria:

Diagnosis of Bipolar Type I or II disorder depress phase (SCID confirmed)
Moderate depression as confirmed by Montgomery Asberg Depression Rating Scale greater than or equal to 20
Negative urine toxicology screen
Negative urine pregnancy test
No clinically significant lab abnormalities for complete blood count (CBC), Thyroid stimulating hormone (TSH), Sodium (Na+), Potassium (K+), Chlorine (Cl-), Carbon dioxide (CO2), creatinine (CREA), blood urea nitrogen (BUN), Glucose, hepatic panel.

Bipolar Group Exclusion Criteria:

Inability to provide informed consent
Any current Axis I diagnosis other than anxiety disorders needing concurrent antidepressant therapy
History of active substance abuse/dependence within the last 3 months
History of claustrophobia
History of adverse reaction to Lamotrigine
Fluoxetine and decanoate antipsychotic therapy
Unwilling or unable to taper current sub-optimal psychotropic medications other than a stable dosage of Lithium, Depakote, or an Atypical Antipsychotic approved by study personnel
Unstable active medical illness
Pregnancy or breast-feeding
Male/ Female not practicing a reliable form of birth control (condom, Intrauterine Device (IUD), depo injection)
Female wishing to commence oral contraceptive therapy within 3 months of enrollment date (stable oral contraceptive therapy exception)
Active suicidal ideation with plan
History of major head trauma with loss of consciousness > 5 minutes or skull fracture
History of previous neurological event (epilepsy, stroke, transient ischemic attack)
Implanted metal objects (i.e., pacemakers, aneurysm clips, metal prostheses, joints, rods)
Inability to speak English
Prominent Axis II disorder [This will be assessed by the principal investigator, who has >10 years clinical experience with this population. Hospital discharge summaries and outpatient medical records will be reviewed for evidence that Axis II pathology is the primary psychiatric disturbance (i.e., adequate trials of mood stabilizing treatments with minimal to no response, prominent self injurious behavior in the absence of significant mood symptomatology, or atypical cycle patterns)].

Healthy Control Group Inclusion Criteria:

Negative urine toxicology screen
Negative urine pregnancy test
Normal blood values for thyroid stimulating hormone (TSH)

Healthy Control Group Exclusion Criteria:

Inability to provide informed consent
Any current Axis I or II diagnosis
Known history of claustrophobia
Lifetime personal or family history (first-degree relative) of dementia, substance-related disorder (nicotine abuse or dependence exception), psychotic disorder, mood disorder (history of bereavement exception), anxiety disorder (specific phobia exception)
Unstable active medical illness
Pregnancy or breast-feeding
Male /Female not practicing a reliable form of birth control (condom, IUD, depo injection)
History of major head trauma with loss of consciousness > 5 minutes or skull fracture
History of previous neurological event (epilepsy, stroke, transient ischemic attack)
Implanted metal objects (i.e., pacemakers, aneurysm clips, metal prostheses, joints)
Inability to speak English
On current medications known to affect glutamate (i.e., Riluzole).
Any medically remarkable impairment due to a medical condition or brain injury resulting in significant impairment in cognitive functioning based on neuropsychological test battery and/or MRS scan results.

Sites / Locations

Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Bipolar Group

Control Group

Arm 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.

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

Outcomes

Primary Outcome Measures

Mean Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Baseline for Both Groups, and After 12 Weeks of Lamotrigine Monotherapy for the Bipolar Group

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.

Secondary Outcome Measures

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

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.

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

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.

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

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.

Glutamine/Glutamate Ratio Measured in the LDLPC at Baseline Using the ProFit Magnetic Resonance Spectroscopy (MRS) Technique

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.

Full Information

NCT ID

NCT01042496

First Posted

January 4, 2010

Last Updated

January 12, 2016

Sponsor

Mayo Clinic

Collaborators

National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT01042496

Brief Title

Bipolar Depression Before and After Lamotrigine Treatment

Acronym

1HMRS-BP

Official Title

1H-MR Spectroscopy of Bipolar Depression Before and After Lamotrigine Treatment

Study Type

Interventional

2. Study Status

Record Verification Date

January 2016

Overall Recruitment Status

Completed

Study Start Date

December 2009 (undefined)

Primary Completion Date

September 2014 (Actual)

Study Completion Date

October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Mayo Clinic

Collaborators

National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study compared glutamate and other neurometabolites measured by proton magnetic resonance spectroscopy (1H-MRS) in bipolar I and II patients currently depressed with age-matched healthy controls. The study will also compare 1H-MRS of bipolar I and II patients before and after taking a 12-week course of lamotrigine. The goal of this study was to better understand the neurobiology of bipolar depression and how lamotrigine may therapeutically impact brain function and mood response. The hypothesis was that in comparison to non-remission participants, bipolar participants who achieve remission (defined as a Montgomery Asberg Depression Rating Scale (MADRS) score <12 at week 12) associated with lamotrigine monotherapy will exhibit a greater decrease in glutamate (Glu) and an increase in N-acetyl aspartate (NAA), reported as a cerebrospinal fluid (CSF)-corrected absolute concentration percent change from baseline to endpoint in anterior cingulate (AC) and dorsolateral prefrontal cortex (DLPFC).

Detailed Description

Depression is the predominant prevailing mood state in bipolar disorder and bipolar depression is associated with substantial morbidity and mortality. However, in comparison to acute mania, bipolar depression is understudied both from the standpoint of its pathophysiology as well as clinical trials which include FDA-approved treatments. Given this lack of evidence to base guidelines, clinicians and patients are limited as to how best to treat the depressive phase of the illness. Proton magnetic resonance spectroscopy (1H-MRS) is a valuable, non-invasive method to study in-vivo brain biochemistry. Of the novel imaging paradigms, MRS is uniquely positioned to investigate biochemical mechanism of drug action that is objectively measurable and clinically relevant. As there is increasing interest in glutamatergic dysregulation in mood disorders, this project will utilize 1H-MRS to study glutamate and glutamine levels in brain regions implicated in bipolar disorder (anterior cingulate and dorsolateral prefrontal cortex). This was a 5-year single-site study of bipolar depression utilizing 1H-MR spectroscopy before and after treatment with lamotrigine. At baseline bipolar depressed subjects and age-matched controls underwent a 1H-MRS at Mayo Clinic in Rochester, Minnesota. The bipolar depressed subjects were then be placed on 12-week, open evaluation of lamotrigine monotherapy. After 12 weeks, the bipolar subjects underwent a second 1H-MRS scan. 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. 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 cube was overlaid onto the CSF map and the fraction of CSF within the cube measured. This measurement was used to "remove" the CSF from the MRS cube giving brain chemical concentrations. The concentrations were then used for statistical analysis. Note: All of the spectroscopy data are expressed in Institutional Units (IU).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Bipolar Depression

Keywords

Bipolar, depression

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

72 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bipolar Group

Arm Type

Active Comparator

Arm Description

Arm Title

Control Group

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Lamotrigine

Other Intervention Name(s)

Lamictal®

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

1H-MR

Intervention Description

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

Primary Outcome Measure Information:

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

Description

Time Frame

baseline, 12 weeks

Secondary Outcome Measure Information:

Title

Description

Time Frame

baseline, after 12 weeks

Title

Description

Time Frame

baseline, 12 weeks

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

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

Title

Glutamine/Glutamate Ratio Measured in the LDLPC at Baseline Using the ProFit Magnetic Resonance Spectroscopy (MRS) Technique

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Bipolar Group Inclusion Criteria: Diagnosis of Bipolar Type I or II disorder depress phase (SCID confirmed) Moderate depression as confirmed by Montgomery Asberg Depression Rating Scale greater than or equal to 20 Negative urine toxicology screen Negative urine pregnancy test No clinically significant lab abnormalities for complete blood count (CBC), Thyroid stimulating hormone (TSH), Sodium (Na+), Potassium (K+), Chlorine (Cl-), Carbon dioxide (CO2), creatinine (CREA), blood urea nitrogen (BUN), Glucose, hepatic panel. Bipolar Group Exclusion Criteria: Inability to provide informed consent Any current Axis I diagnosis other than anxiety disorders needing concurrent antidepressant therapy History of active substance abuse/dependence within the last 3 months History of claustrophobia History of adverse reaction to Lamotrigine Fluoxetine and decanoate antipsychotic therapy Unwilling or unable to taper current sub-optimal psychotropic medications other than a stable dosage of Lithium, Depakote, or an Atypical Antipsychotic approved by study personnel Unstable active medical illness Pregnancy or breast-feeding Male/ Female not practicing a reliable form of birth control (condom, Intrauterine Device (IUD), depo injection) Female wishing to commence oral contraceptive therapy within 3 months of enrollment date (stable oral contraceptive therapy exception) Active suicidal ideation with plan History of major head trauma with loss of consciousness > 5 minutes or skull fracture History of previous neurological event (epilepsy, stroke, transient ischemic attack) Implanted metal objects (i.e., pacemakers, aneurysm clips, metal prostheses, joints, rods) Inability to speak English Prominent Axis II disorder [This will be assessed by the principal investigator, who has >10 years clinical experience with this population. Hospital discharge summaries and outpatient medical records will be reviewed for evidence that Axis II pathology is the primary psychiatric disturbance (i.e., adequate trials of mood stabilizing treatments with minimal to no response, prominent self injurious behavior in the absence of significant mood symptomatology, or atypical cycle patterns)]. Healthy Control Group Inclusion Criteria: Negative urine toxicology screen Negative urine pregnancy test Normal blood values for thyroid stimulating hormone (TSH) Healthy Control Group Exclusion Criteria: Inability to provide informed consent Any current Axis I or II diagnosis Known history of claustrophobia Lifetime personal or family history (first-degree relative) of dementia, substance-related disorder (nicotine abuse or dependence exception), psychotic disorder, mood disorder (history of bereavement exception), anxiety disorder (specific phobia exception) Unstable active medical illness Pregnancy or breast-feeding Male /Female not practicing a reliable form of birth control (condom, IUD, depo injection) History of major head trauma with loss of consciousness > 5 minutes or skull fracture History of previous neurological event (epilepsy, stroke, transient ischemic attack) Implanted metal objects (i.e., pacemakers, aneurysm clips, metal prostheses, joints) Inability to speak English On current medications known to affect glutamate (i.e., Riluzole). Any medically remarkable impairment due to a medical condition or brain injury resulting in significant impairment in cognitive functioning based on neuropsychological test battery and/or MRS scan results.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark Frye, MD

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Rochester

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

12. IPD Sharing Statement

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Bipolar Depression Before and After Lamotrigine Treatment

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