Browsing by Subject "lithium"

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    Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study
    (Wiley, 2021) Lin, Yian; Maihofer, Adam X.; Stapp, Emma; Ritchey, Megan; Alliey‐Rodriguez, Ney; Anand, Amit; Balaraman, Yokesh; Berrettini, Wade H.; Bertram, Holli; Bhattacharjee, Abesh; Calkin, Cynthia V.; Conroy, Carla; Coryell, William; D'Arcangelo, Nicole; DeModena, Anna; Biernacka, Joanna M.; Fisher, Carrie; Frazier, Nicole; Frye, Mark; Gao, Keming; Garnham, Julie; Gershon, Elliot; Glazer, Kara; Goes, Fernando S.; Goto, Toyomi; Karberg, Elizabeth; Harrington, Gloria; Jakobsen, Petter; Kamali, Masoud; Kelly, Marisa; Leckband, Susan G.; Lohoff, Falk W.; Stautland, Andrea; McCarthy, Michael J.; McInnis, Melvin G.; Mondimore, Francis; Morken, Gunnar; Nurnberger, John I.; Oedegaard, Ketil J.; Syrstad, Vigdis Elin Giever; Ryan, Kelly; Schinagle, Martha; Schoeyen, Helle; Andreassen, Ole A.; Shaw, Marth; Shilling, Paul D.; Slaney, Claire; Tarwater, Bruce; Calabrese, Joseph R.; Alda, Martin; Nievergelt, Caroline M.; Zandi, Peter P.; Kelsoe, John R.; Psychiatry, School of Medicine
    Background Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.
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    Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.
    (NPG, 2015-11-05) Mertens, Jerome; Wang, Qiu-Wen; Kim, Yongsung; Yu, Diana X.; Pham, Son; Yang, Bo; Zheng, Yi; Diffenderfer, Kenneth E.; Zhang, Jian; Soltani, Sheila; Eames, Tameji; Schafer, Simon T.; Boyer, Leah; Marchetto, Maria C.; Nurnberger, John I.; Calabrese, Joseph R.; Oedegaard, Ketil J.; McCarthy, Michael J.; Zandi, Peter P.; Alda, Martin; Nievergelt, Caroline M.; Mi, Shuangli; Brennand, Kristen J.; Kelsoe, John R.; Gage, Fred H.; Yao, Jun; Department of Psychiatry, IU School of Medicine
    Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.