Major depressive episodes contribute substantially to morbidity and mortality in bipolar disorder. While multiple medications have demonstrated efficacy for treating these episodes, a majority of patients do not reach complete symptomatic remission or have difficulty tolerating these medications. Studies of the mechanism of action of treatments known to be effective in bipolar may provide new treatment targets. Work by our group and others strongly implicates Wnt/GSK3 signaling in the mechanism of action of lithium, which remains a first-line treatment for bipolar depression as well as prevention of recurrence. We therefore have utilized high-throughput cell-based screening in neuronal cells to identify compounds that showed potential additivity or synergy with lithium in terms of effects on Wnt/GSK3 signaling. Among the active F.D.A.-approved drugs with safety profiles compatible with long-term use, we identified multiple statins that acted synergistically with Wnt3a treatment and show further additivity with lithium treatment, including simvastatin, one of the most potent statins known to be capable of crossing the blood-brain barrier. We have validated 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase as the relevant target. Statins have not been directly examined in the treatment of bipolar disorder. A recent rodent study found evidence that a statin augmented the antidepressant-like effects with fluoxetine. Intriguingly, multiple population-based studies also suggest that statins may be associated with a statistically significant decrease in depressive symptoms, and a decrease in the likelihood of adverse psychiatric outcomes. Another study examining statin treatment of dementia indicated a decrease in depressive symptoms compared to placebo. We now propose to conduct a randomized, double-blind, placebo-controlled, proof-of-concept investigation of simvastatin as add-on treatment to lithium in outpatients with bipolar I disorder in a major depressive episode. In parallel, we will collect fibroblasts and derive induced pluripotent stem cells (iPSCs) and neuronal progenitor (NP) cells. The function of the Wnt signaling pathway in patient-specific iPSC-derived NP cells will then be quantified in cell-based assays, with and without treatment with lithium and simvastatin, to enable examination of the association between Wnt/GSK3 signalling and magnitude of improvement in depressive symptoms. These experiments are expected to serve as a crucial first step in the development of new bipolar pharmacotherapies. By predicting the benefit of an adjunctive therapy for bipolar disorder based upon its effects on Wnt/GSK3 signaling pathway and attempting to correlate these responses using patient-specific neuronal cell models, our proposed study will provide a critical test of the importance of Wnt/GSK3 signaling in regulating neuroplasticity in bipolar disorder and depression. At a minimum, these studies will also provide a well-phenotyped, patient-derived cellular resource for future investigation of lithium response and bipolar disorder that can be applied in future studies toward high-throughput screening for lithium-like drugs.

Public Health Relevance

Bipolar depression is frequently chronic and disabling, and the need for new treatments is acute. The proposed investigation will investigate the potential efficacy of a novel treatment with well-established safety. At the same time, it will help to validate a cell-based model useful for identification of future bipolar depression treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH093958-02
Application #
8444420
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Hillefors, MI
Project Start
2012-03-15
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$214,664
Indirect Cost
$91,090
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Tobe, Brian T D; Crain, Andrew M; Winquist, Alicia M et al. (2017) Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci U S A 114:E4462-E4471
Bavamian, S; Mellios, N; Lalonde, J et al. (2015) Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder. Mol Psychiatry 20:573-84
Madison, J M; Zhou, F; Nigam, A et al. (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20:703-17
Haggarty, Stephen J; Perlis, Roy H (2014) Translation: screening for novel therapeutics with disease-relevant cell types derived from human stem cell models. Biol Psychiatry 75:952-60
Wang, J L; Shamah, S M; Sun, A X et al. (2014) Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness. Transl Psychiatry 4:e428
Uher, Rudolf; Tansey, Katherine E; Malki, Karim et al. (2012) Biomarkers predicting treatment outcome in depression: what is clinically significant? Pharmacogenomics 13:233-40
Perlis, Roy H; Smoller, Jordan W; Mysore, Jayalakshmi et al. (2010) Prevalence of incompletely penetrant Huntington's disease alleles among individuals with major depressive disorder. Am J Psychiatry 167:574-9
Perlis, Roy H; Ostacher, Michael J; Uher, Rudolf et al. (2009) Stability of symptoms across major depressive episodes in bipolar disorder. Bipolar Disord 11:867-75
Perlis, R H; Fava, M; Trivedi, M H et al. (2009) Irritability is associated with anxiety and greater severity, but not bipolar spectrum features, in major depressive disorder. Acta Psychiatr Scand 119:282-9
Perlis, Roy H; Patrick, Amanda; Smoller, Jordan W et al. (2009) When is pharmacogenetic testing for antidepressant response ready for the clinic? A cost-effectiveness analysis based on data from the STAR*D study. Neuropsychopharmacology 34:2227-36