Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison

Abstract

We tested the hypothesis that long-term treatment with pomaglumetad methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either pomaglumetad methionil (n = 516) or aripiprazole (n = 162). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The pomaglumetad methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group (−2.8 ± 0.4 versus 0.4 ± 0.6; P < 0.001). However, change in Positive and Negative Syndrome Scale (PANSS) total scores for aripiprazole was significantly greater than for pomaglumetad methionil (−15.58 ± 1.58 versus −12.03 ± 0.99; P = 0.045). The incidences of SAEs (8.2% versus 3.1%; P = 0.032) and discontinuation due to AEs (16.2% versus 8.7%; P = 0.020) were significantly higher for pomaglumetad methionil compared with aripiprazole. No statistically significant differences in the incidence of TEAEs, EPS, or suicidal ideation or behavior were noted between treatment groups. In conclusion, long-term treatment with pomaglumetad methionil resulted in significantly less weight gain than aripiprazole. This trial is registered with ClinicalTrials.gov NCT01328093.

mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions

“…1,2 Although initial trials with mGluR2/3 agonists have had mixed results, [3][4][5][6][7] data increasingly indicate that changes in mGluR3 are associated with schizophrenia and aging, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] encouraging this treatment strategy. Clinical trials were originally based on data from rodent models.…”

“…20 mGluR2/3 agonists have been a focus of drug development for schizophrenia, based on findings that NMDAR antagonists increase, whereas mGluR2/3 agonists decrease, glutamate release in rodent medial PFC. 23,27,49 However, the results of clinical trials have been mixed, [3][4][5][6][7] emphasizing the need for understanding mGluR2/3 actions in primate dlPFC. Here we examined mGluR2/3 mechanisms in the dlPFC of rhesus macaque monkeys.…”

Role of calcium, glutamate and NMDA in major depression and therapeutic application

“…The activation of mGlu2 and mGlu3 receptors on presynaptic nerve terminals inhibits presynaptic glutamate release, modulating synaptic plasticity and LTP. Highly selective mGluR2-positive allosteric modulators (PAMs), inhibiting presynaptic glutamate release, are more promising than mixed mGluR2/3 agonists in clinical studies (Adams et al, 2013(Adams et al, , 2014Hopkins, 2013;Trabanco and Cid, 2013).…”

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].…”