Potential Novel Treatments in Bipolar Depression

  • Rodrigo Machado-VieiraEmail author
  • Ioline D. Henter
  • Husseini K. Manji
  • Carlos A. ZarateJr.
Part of the Milestones in Drug Therapy book series (MDT)


Currently available therapeutics for bipolar disorder (BD)—and bipolar depression in particular—are scarce and often ineffective. This is particularly troubling because the long-term course of bipolar depression comprises recurrent depressive episodes and persistent residual symptoms. Glutamate and its cognate receptors have consistently been implicated in the pathophysiology of mood disorders, as well as in the development of novel therapeutics for these disorders. Since the rapid and robust antidepressant effects of the glutamatergic modulator ketamine were first observed, similar agents have been studied in both major depressive disorder (MDD) and BD. This chapter reviews the clinical and preclinical evidence supporting the use of novel glutamate receptor modulators for the treatment of bipolar depression. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the melatonergic system, the glucocorticoid system, the arachidonic acid (AA) cascade, and oxidative stress and bioenergetics. The chapter discusses several specific agents, including N-acetyl cysteine (NAC), scopolamine, biperiden, agomelatine, riluzole, ketamine, memantine, creatine, metyrapone, ketoconazole, mifepristone, and celecoxib. Non-pharmacological somatic treatments are not reviewed.


Antidepressant Bipolar disorder Cholinergic Depression Dopamine Glutamate Melatonin Oxidative stress Treatment 



Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health and National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927). A patent for the use of ketamine in depression has been awarded that lists Drs. Zarate and Manji among the inventors. Dr. Zarate has assigned his rights on the patent to the US government, but will share a percentage of any royalties that may be received by the government. Dr. Manji has also assigned his rights on the patent to the US government, and has waived his personal rights to this patent and will not receive any direct financial benefit therefrom. Dr. Manji is a full-time employee of Janssen Research & Development, LLC. The remaining authors have no conflicts of interest to disclose, financial or otherwise.


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Copyright information

© Springer International Publishing Switzerland (outside the USA)  2016

Authors and Affiliations

  • Rodrigo Machado-Vieira
    • 1
    Email author
  • Ioline D. Henter
    • 1
  • Husseini K. Manji
    • 2
  • Carlos A. ZarateJr.
    • 3
  1. 1.Experimental Therapeutics and Pathophysiology BranchBethesdaUSA
  2. 2.Janssen Pharmaceuticals of Johnson and Johnson, Janssen Research and DevelopmentTitusvilleUSA
  3. 3.Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of HealthBethesdaUSA

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