title: A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia.
abstract: The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Kinon
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Brian A
authors.initials: BA
authors.lastname: Millen
authors.forename: Olawale O
authors.initials: OO
authors.lastname: Osuntokun
authors.forename: Judy E
authors.initials: JE
authors.lastname: Williams
authors.forename: Sara
authors.initials: S
authors.lastname: Kollack-Walker
authors.forename: Kimberley
authors.initials: K
authors.lastname: Jackson
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kryzhanovskaya
authors.forename: Natalia
authors.initials: N
authors.lastname: Jarkova
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007297:Inpatients; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011355:Prodrugs / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D012559:Schizophrenia / Q000188:drug therapy*; D016903:Drug Monitoring
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; C534551:LY 2140023; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D001569:Benzodiazepines; D000077152:Olanzapine