Molecule of the Month

J. Phillip Kennedy; Craig W. Lindsley

doi:10.2174/156802607780960438

Abstract

New FDA Approval of Cymbalta™ for Generalized Anxiety Disorder. Major depressive disorder is the 4th leading cause of disability worldwide and projected to rise significantly by 2020 [1]. In response, Eli Lilly and others developed Selective Serotonin Reuptake Inhibitors (SSRIs), such as Prozac™, as a first generation approach to combat this debilitating disorder [2]. However, serotonin reuptake monotherapy with SSRIs affords remission of symptoms for only one third of patients in clinical trials. This data drove researchers at Eli Lilly to develop a second generation of antidepressives that would be more clinically effective by targeting the reuptake of both serotonin (5-HT) and norepinephrine (NE). The result of their research was Cymbalta™, a potent, dual inhibitor of serotonin (5-HT, Ki = 4.6 nM) and norepinephrine (NE, Ki = 16 nM) that represented a new class of drugs referred to as a serotonin and norepinephrine reuptake inhibitors (SNRIs) [3,4]. Moreover, Cymbalta™ was a 10-fold more potent SSRI than Prozac™ (5-HT, Ki = 48 nM). Subsequent clinical trials with Cymbalta™ demonstrated that enhancing both serotonergic and noradrenergic neurotransmission results in improved antidepressant efficacy. Shortly thereafter, Cymbalta™ was approved by the FDA, and over 4.5 million patients have taken Cymbalta™ for the treatment of major depressive disorder or diabetic peripheral neuropathic pain [3-5]. In February of 2007, the FDA approved Cymbalta™ for the treatment of generalized anxiety disorder (GAD), a condition that affects over 6.5 million adults in America. GAD is a complex disorder characterized by exaggerated worry, chronic anxiety,irritability, sleep disturbances and fatigue which last for at least six months and cycle through periods of exacerbation and remission. In three randomized, double-blind, placebo-controlled GAD clinical studies, Cymbalta™ provided patients with a 46% improvement in anxiety symptoms compared to 32% with placebo, as evaluated by the Hamilton Anxiety Scale. In addition, patients taking Cymbalta™ experienced a 46% improvement in function compared to 26% with placebo, as measured by the Sheehan Disability Scale. In these trials, the dose range of Cymbalta™ was 60-120 mg/day, with the 120 mg dose provided the greatest efficacy [5]. REFERENCES [1] Murray, C.J.L.; Lopez, A.D., Eds. ‘The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020’ Cambridge, MA: Harvard University Press, 1996. [2] Wong, D.T.; Perry, K.W.; Bymaster, F.P. ‘Case History: The Discovery of Fluoxetine Hydrochloride ( Prozac )’ Nat. Rev. Drug Discov. 2005, 49, 764-774. [3] Bymaster, F.P.; Beedle, E.E.; Findlay, J.; Gallagher, P.T.; Krushinski, J.H.; Mitchell, S.; Robertson, D.W.; Thompson, D.C.; Wallace, L.; Wong, D.T. ‘Duloxetine (Cymbalta™), a Dual Inhibitor of Serotonin and Norepinephrine Reuptake’ Bioorg. Med. Chem. Lett. 2003, 13, 4477-4480. [4] Bymaster, F.P.; Lee, T.C.; Knadler, M.P.; Detke, M.J.; Iyengar, S. ‘The Dual Transporter Inhibitor Duloxetine: A Review of its Preclinical Pharmacology, Pharmacokinetic Profile, and Clinical Results in Depression’ Curr. Pharm. Design 2005, 11, 1475-1493. [5] For information on the FDA approval of Cymbalta™ for GAD see: www.lilly.com.

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