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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Interventions Committee for Adult Mood and Anxiety Disorders (ITMA)
Program Officer
Muehrer, Peter R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Croarkin, Paul E; Luby, Joan L; Cercy, Kelly et al. (2017) Genetic Risk Score Analysis in Early-Onset Bipolar Disorder. J Clin Psychiatry 78:1337-1343
Nassan, Malik; Li, Qingqin; Croarkin, Paul E et al. (2017) A genome wide association study suggests the association of muskelin with early onset bipolar disorder: Implications for a GABAergic epileptogenic neurogenesis model. J Affect Disord 208:120-129
Scola, Gustavo; McNamara, Robert K; Croarkin, Paul E et al. (2016) Lipid peroxidation biomarkers in adolescents with or at high-risk for bipolar disorder. J Affect Disord 192:176-83
Croarkin, Paul E; Nakonezny, Paul A; Wall, Christopher A et al. (2016) Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents. Psychiatry Res Neuroimaging 247:25-33
Nassan, Malik; Nicholson, Wayne T; Elliott, Michelle A et al. (2016) Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine. Mayo Clin Proc 91:897-907
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
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
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
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

Showing the most recent 10 out of 16 publications