Bipolar Depression Before and After Lamotrigine Treatment

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).

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.