Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder.
LY354740, a potent and selective mGlu (metabotropic glutamate receptor)2/3 agonist, has shown efficacy in the treatment of generalized anxiety disorder (GAD). LY544344 is a LY354740 prodrug that increases LY354740 bioavailability. This 8-week study was designed to evaluate the efficacy, safety, and tolerability of LY544344 in the treatment of GAD. Participants had a diagnoses of GAD, baseline Hospital Anxiety and Depression Scale anxiety subscale scores > or = 10, and moderate illness severity. Patients were randomized to double-blind treatment with LY544344 16 mg b.i.d. (n = 28), LY544344 8 mg b.i.d. (n = 36), or placebo (n = 44). LY544344 16 mg b.i.d.-treated patients showed significantly greater improvement from baseline in Hamilton Anxiety and Clinical Global Impression-Improvement scores, as well as response and remission rates compared with placebo-treated patients. LY544344 was well tolerated and there were no significant differences in the incidence of treatment-emergent adverse events among the three treatment groups. However, the trial was discontinued early based on findings of convulsions in preclinical studies. In conclusion, the findings of this study support the potential efficacy of mGlu2/3 receptor agonist agents in the treatment of GAD. Additional studies will be needed to further assess the toxicological and clinical profile of LY354740/LY544344.
Dunayevich
Eduardo
E
Orexigen Therapeutics, San Diego, CA 92130, USA. edunayevich@orexigen.com
Erickson
Janelle
J
Levine
Louise
L
Landbloom
Ronald
R
Schoepp
Darryle D
DD
Tollefson
Gary D
GD
D000328:Adult; D000409:Alanine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D000704:Analysis of Variance; D001008:Anxiety Disorders / Q000097:blood / Q000188:drug therapy*; D001643:Bridged Bicyclo Compounds / Q000097:blood / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004341:Drug Evaluation / Q000379:methods*; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome
C503966:2-((2'-amino)propionyl)aminobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D000409:Alanine; C104753:eglumetad