The McCarthy laboratory is focused on the molecular genetics of mood disorders. Research areas covered include genetic, molecular, and cellular mechanisms underlying bipolar disorder, major depression, and comorbid conditions like substance abuse and metabolic disease. The laboratory has three main research areas that are currently active.
1. Circadian mechanisms in cellular models of bipolar disorder
We are using cells from human subjects (fibroblasts and iPSC derived neurons) to identify disturbances in circadian rhythms in gene expression. By understanding how the clock oscillator and/or clock outputs are affected in bipolar disorder, we hope to identify mechanisms by which neurons either malfunction, or benefit from pharmacotherapeutic interventions like lithium.
2. Circadian mechanisms of antipsychotic induced metabolic disorders
Antipsychotic drugs have important uses as mood stabilizers and as augmentation of antidepressants. However, their long-term use is associated with weight gain and metabolic disorders like type 2 diabetes. Using pancreatic islet cells, we are measuring circadian rhythms, and examining how dopamine and antipsychotic drugs may disturb circadian rhythms to alter the temporal pattern of insulin release.
3. Identifying biomarkers of treatment response in human subjects
Outcomes in mood disorders are commonly sub-optimal. At the VA San Diego Mood Disorder Clinic, we run a series of human clinical trials using pharmacogenetic testing, functional neuroimaging and peripheral biomarkers to efficiently select optimal drugs to manage mood symptoms and/or predict pharmacotherapeutic outcomes.
McCarthy MJ, Wei H, Landgraf D, Le Roux MJ, Welsh DK. Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients. European Neuropsychopharmacology 2016 PMID: 27216486
McCarthy MJ, Le Roux MJ, Wei H, Beesley S, Kelsoe JR, Welsh DK. Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms. Neuropharmacology 2016 101:439-48. PMID: 26476274.
McCarthy MJ, Wei H, Marnoy Z , Darvish R , McPhie D, Cohen B, and Welsh DK. Genetic and clinical factors predict lithium’s effects on PER2 gene expression rhythms in cells from bipolar disorder patients. Translational Psychiatry 2013, 3: e318. PMID: 24150227.
Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y1, Diffenderfer KE, Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI, Calabrese JR, Ødegaard KJ, McCarthy MJ, Zandi PP, Alba M, Nievergelt CM; Pharmacogenomics of Bipolar Disorder Study, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 2015 527: 95-9. PMID: 26524527. PMCID: PMC4742055
Freyberg Z and McCarthy MJ. Dopamine D2 Receptors and the Circadian Clock Reciprocally Mediate Antipsychotic Drug Metabolic Disturbances. NPJ Schizophrenia 2017. 3:17 PMID: 28560263.
Stein M, McCarthy MJ, Chen CY, Jain S, Gelernter J, He F, Heeringa S, Kessler R, Nock M, Ripke S, Sun X, Wynn G, Smoller J, and Ursano R. Genome-wide Analysis of Insomnia Disorder. Molecular Psychiatry 2018.[Epub ahead of print] PMID: 29520036