Clinical trial NCT01042496: Bipolar Depression Before and After Lamotrigine Treatment
Official title: 1H-MR Spectroscopy of Bipolar Depression Before and After Lamotrigine Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bipolar Depression
Keywords: Bipolar
depression
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2010-01-05
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Mean Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Baseline for Both Groups, and After 12 Weeks of Lamotrigine Monotherapy for the Bipolar Group
timeFrame: baseline, 12 weeks
Secondary outcomes:
measure: 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
timeFrame: baseline, after 12 weeks
measure: 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
timeFrame: baseline, 12 weeks
measure: 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
timeFrame: baseline, 12 weeks
measure: Glutamine/Glutamate Ratio Measured in the LDLPC at Baseline Using the ProFit Magnetic Resonance Spectroscopy (MRS) Technique
timeFrame: baseline
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Mark Frye, MD
role: PRINCIPAL_INVESTIGATOR
References: