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Advances toward precision medicine for bipolar disorder: mechanisms & molecules

Abstract

Given its chronicity, contribution to disability and morbidity, and prevalence of more than 2%, the effective treatment, and prevention of bipolar disorder represents an area of significant unmet medical need. While more than half a century has passed since the introduction of lithium into widespread use at the birth of modern psychopharmacology, that medication remains a mainstay for the acute treatment and prevention of recurrent mania/hypomania and depression that characterize bipolar disorder. However, the continued limited understanding of how lithium modulates affective behavior and lack of validated cellular and animal models have resulted in obstacles to discovering more effective mood stabilizers with fewer adverse side effects. In particular, while there has been progress in developing new pharmacotherapy for mania, developing effective treatments for acute bipolar depression remain inadequate. Recent large-scale human genetic studies have confirmed the complex, polygenic nature of the risk architecture of bipolar disorder, and its overlap with other major neuropsychiatric disorders. Such discoveries have begun to shed light on the pathophysiology of bipolar disorder. Coupled with broader advances in human neurobiology, neuropharmacology, noninvasive neuromodulation, and clinical trial design, we can envision novel therapeutic strategies informed by defined molecular mechanisms and neural circuits and targeted to the root cause of the pathophysiology. Here, we review recent advances toward the goal of better treatments for bipolar disorder, and we outline major challenges for the field of translational neuroscience that necessitate continued focus on fundamental research and discovery.

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Acknowledgements

We would like to acknowledge helpful discussion and feedback from members of the Haggarty, Perlis, and Karmacharya laboratories, along with members of the Dauten Family Center for Bipolar Treatment Innovation at Massachusetts General Hospital. This work was supported through funding from the Stuart & Suzanne Steele MGH Research Scholars Program, NIH R01MH120227, NIH R01AT009144, NIH R01MH113858. This manuscript is dedicated to the compassionate staff of the Rockyview General Hospital and Foothills Medical Center.

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SJH was or is a member of the scientific advisory board of Rodin Therapeutics, Psy Therapeutics, Frequency Therapeutics, and Souvien Therapeutics, none of whom were involved in the present study. SJH has also received speaking or consulting fees from Amgen, AstraZeneca, Biogen, Merck, Regenacy Pharmaceuticals, Syros Pharmaceuticals, Juvenescence, as well as sponsored research or gift funding from AstraZeneca, JW Pharmaceuticals, and Vesigen unrelated to the content of this manuscript. RHP is a member of the scientific advisory board of Psy Therapeutics, Outermost Therapeutics, and Genomind, and reports consulting fees from Genomind, RID Ventures, Takeda, and Burrage Capital. He holds equity in Psy Therapeutics and Outermost Therapeutics. All of these are unrelated to the content of this manuscript. RK: None.

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Haggarty, S.J., Karmacharya, R. & Perlis, R.H. Advances toward precision medicine for bipolar disorder: mechanisms & molecules. Mol Psychiatry 26, 168–185 (2021). https://doi.org/10.1038/s41380-020-0831-4

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