Min Ma1, Qian Ren1, Yuko Fujita1, Chun Yang1, Chao Dong1, Yuta Ohgi2, Takashi Futamura2, Kenji Hashimoto3. 1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan. 2. Department of CNS Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. 3. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
Abstract
RATIONALE: Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression. OBJECTIVES: The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission. METHODS: The tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine. RESULTS: A single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex. CONCLUSIONS: These results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.
RATIONALE: Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression. OBJECTIVES: The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission. METHODS: The tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine. RESULTS: A single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex. CONCLUSIONS: These results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.
Authors: George I Papakostas; Maurizio Fava; Lee Baer; Michaela B Swee; Adrienne Jaeger; William V Bobo; Richard C Shelton Journal: Am J Psychiatry Date: 2015-06-18 Impact factor: 18.112
Authors: Panos Zanos; Ruin Moaddel; Patrick J Morris; Lace M Riggs; Jaclyn N Highland; Polymnia Georgiou; Edna F R Pereira; Edson X Albuquerque; Craig J Thomas; Carlos A Zarate; Todd D Gould Journal: Pharmacol Rev Date: 2018-07 Impact factor: 25.468