The overall aims of this proposal are to 1) prepare and store lymphoblastoid cells (LCLs) and plasma from 480 clinically ill bipolar patients for future experiments and 2) use the LCLs to characterize calcium activity in the LCLs to a) predict treatment outcomes, b) provide information to aid psychiatrists in selecting a treatment regimen most likely to be effective for an individual bipolar patient and c) contribute to more reliable an valid diagnosis of bipolar disorder. The research will result in more personalized and overall effective treatments and outcomes of bipolar disorder (BD). To accomplish these aims, we propose an additional blood draw from patients participating in the Bipolar CHOICE Trial. The 10 site Bipolar CHOICE Network is conducting between December 2010 and 2013 the largest prospective randomized comparative effectiveness study in BD to date. Eighty healthy control subjects will also be tested to aid in differentiating the threshold values of the calcium measurements that may be diagnostically associated with bipolar disorder or predictive of treatment responses from levels that occur naturally in persons without bipolar disorder. The studies will test whether evidence based biomarkers (calcium laboratory tests conducted when stimulated by chemicals similar to ones occurring naturally in human brain function) in cell lines established from a blood sample predict the likelihood of response to the two mood stabilizers (lithium and quetiapine) being compared in the Bipolar CHOICE study. The calcium test results will also be studied to determine their utility as an additional criterion in establishing a valid diagnosis of bipolar disorder and in explaining the principal disturbed symptoms that characterize bipolar disorders (e.g., impulsivity, rapidly shifting moods, sleep disturbances). Each of these objectives serves our pragmatic goal of developing more personalized treatments for bipolar disorder. A unique strength of this proposed adjunctive calcium signaling investigation resides in using the Bipolar CHOICE sample in the NIMH Agency for Healthcare Research and Quality funded study, which will provide a full spectrum of participants and of outcomes, insuring that the results will be generalizable to actual clinical care. Only the costs o conducting the biomarker calcium signaling studies will be additionally required;the AHRQ award fully funds the 480 patient, randomized, 6 month duration comparative effectiveness study. To enhance recruitment, minimize selection and volunteer bias, and maximize retention, in addition to randomized medications, each group will have adjunctive personalized treatment to manage specific mood states and comorbid conditions. BD is a lifelong, chronic and highly recurrent mood disorder characterized by episodes of mania or hypomania as well as episodes of depression. The full spectrum of bipolar disorder has a lifetime prevalence of approximately 4.5% with half of patients reporting their onset by age 14 and heritability estimated to be 80%. This high degree of human suffering and chronic burden has placed bipolar disorder among the top 10 causes of disability worldwide, with direct and indirect costs estimated to be $70.6 billion per year in 2008 dollars in the United States. The Bipolar CHOICE study of quetiapine vs. lithium meets all pertinent criteria for testing biomarkers of treatment effectiveness. These criteria include evidence that patients can be clearly differentiated by the biomarker, an evidence base linking the biomarker both to the disease and treatment studied and prediction of benefit for one group. Understanding biological differences at the molecular level could transform our ability to use and develop medical technologies more effectively, targeting interventions at more defined groups of individuals with greater precision. This potential, sometimes referred to as personalized medicine, has strong bearing on comparative effectiveness research.

Public Health Relevance

The goals of this calcium biomarker study conducted as part of a comparative effectiveness study of over 400 clinically ill bipolar patients are to improve prediction of treatment outcomes, aid psychiatrists in selecting a treatment regimen most likely to be effective for an individual bipolar patient and improve the validity of diagnosis of bipolar disorder. The research will result in more personalized and overall effective treatments and outcomes of bipolar disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Meinecke, Douglas L
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
United States
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Fries, Gabriel R; Colpo, Gabriela D; Monroy-Jaramillo, Nancy et al. (2017) Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder. Eur Neuropsychopharmacol 27:1110-1119