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.

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

“…The efficacy of heterotropic agonists in this PCP model was observed in mGluR3 but not mGluR2 knock-out mice, consistent with their activation of mGluR2 in vitro (31)(32)(33)(34). Although mGluR2/3 agonists and mGluR2-positive allosteric modulators represent a potentially efficacious mGluR2-targeted antipsychotic therapy (35,36), data from animal models of schizophrenia suggest that NAAG peptidase inhibition represents a related but distinctly different pharmacotherapy based on activation of mGluR3 (12,26). The present study was initiated to test the hypothesis that, consistent with the glutamate theory of this disorder, NAAG peptidase inhibitors also block the PCP-induced increase in glutamate release in the mPFC and NAc, brain regions associated with the behavioral and neurochemical effects of PCP and schizophrenia (1,(37)(38)(39)(40).…”

Clozapine, a Fast-Off-D2 Antipsychotic

“…A four-week trial had little or no efficacy against positive symptoms or negative signs when compared with olanzapine. 34,35 While there does not at present appear to be a significant role for glutamate receptors in the antipsychotic treatment of schizophrenia, these are only limited studies, and much remains to be learned about the possible benefit of this approach. Table 1, this high value for clozapine and a similar high value for quetiapine immediately indicated that these two drugs had K i values higher than any of the other antipsychotics and likely had a unique mechanism of interaction with the D2 receptor, namely, "loose binding to the D2 receptor".…”

Novel Treatments of Psychosis

“…These agonists have a more favorable safety profile. Unlike current treatments, pomaglumetad was well tolerated and had a low incidence of extrapyramidal symptoms (EPS), hyperprolactinemia, and weight gain [24,25,27,28].…”

“…The trial did not achieve interpretable results, however, as both pomaglumetad and the active control, olanzapine, failed to separate from placebo due to an unusually high placebo response [25]. An additional phase II trial examined pomaglumetad as a monotherapy in acute psychotic exacerbations in schizophrenia.…”