Depression is the predominant prevailing pole in bipolar disorder and it 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 and FDA-approved treatments. With little guidance, clinicians and patients are limited as to what evidence-based treatment is available for bipolar depression. 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 at 3T to study glutamate and glutamine levels in brain regions implicated in bipolar disorder [anterior cingulate (Brodmann's areas 24a/b and 32) and dorsolateral prefrontal cortex (Brodmann's 9/46)]. The goal of this project is to evaluate whether anterior cingulate and prefrontal cortex glutamine, quantified as a CSF-corrected absolute concentration percent change from baseline, is associated with clinical remission (MADRS=12) to the anti-glutamatergic mood stabilizer lamotrigine. At baseline, approximately 80 bipolar depressed subjects and 30 age-matched controls will undergo 1H- MRS of the anterior cingulate and left dorsolateral prefrontal cortex on a GE 3.0 Tesla LX MRI system located in the Charlton North Imaging Facility on the Mayo Clinic campus. The bipolar depressed subjects will then enter a 12-week evaluation of lamotrigine monotherapy. After 12 weeks the bipolar subjects will undergo a second 1H-MRS scan.

Public Health Relevance

This study will evaluate what biochemical changes are associated with effective lamotrigine treatment, a drug which has been shown to be helpful for many patients with bipolar depression. A better understanding as to how the drug is effective may enable more specific individualized treatment (i.e. identifying the particular patient who should receive lamotrigine based on a MR spectroscopy biochemical picture of the brain). By doing so, we may be able to increase the likelihood of treatment response and decrease the number of ineffective treatments and/or serious side effects for patients with bipolar depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079261-05
Application #
8468209
Study Section
Interventions Committee for Adult Mood and Anxiety Disorders (ITMA)
Program Officer
Muehrer, Peter R
Project Start
2009-07-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$284,896
Indirect Cost
$94,816
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Croarkin, Paul E; Nakonezny, Paul A; Wall, Christopher A et al. (2016) Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents. Psychiatry Res 247:25-33
Frye, Mark A; Doederlein, Allen; Koenig, Barbara et al. (2015) National survey and community advisory board development for a bipolar disorder biobank. Bipolar Disord 17:598-605
Cuellar-Barboza, Alfredo B; Frye, Mark A; Grothe, Karen et al. (2015) Change in consumption patterns for treatment-seeking patients with alcohol use disorder post-bariatric surgery. J Psychosom Res 78:199-204
Croarkin, Paul E; Thomas, M Albert; Port, John D et al. (2015) N-acetylaspartate normalization in bipolar depression after lamotrigine treatment. Bipolar Disord 17:450-7
Winham, Stacey J; Cuellar-Barboza, Alfredo B; McElroy, Susan L et al. (2014) Bipolar disorder with comorbid binge eating history: a genome-wide association study implicates APOB. J Affect Disord 165:151-8
Chung, Sun Ju; Armasu, Sebastian M; Biernacka, Joanna M et al. (2011) Variants in estrogen-related genes and risk of Parkinson's disease. Mov Disord 26:1234-42
Post, Robert M; Altshuler, Lori L; Frye, Mark A et al. (2010) Complexity of pharmacologic treatment required for sustained improvement in outpatients with bipolar disorder. J Clin Psychiatry 71:1176-86; quiz 1252-3
Calabrese, Joseph R; Ketter, Terence A; Youakim, James M et al. (2010) Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry 71:1363-70
Whitwell, J L; Avula, R; Senjem, M L et al. (2010) Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia. Neurology 74:1279-87