The efficacy of currently available medications for depression is unsatisfactory, and that has spurred the development of novel antidepressants based on a hypothesis other than the monoamine hypothesis. Recent studies have revealed the importance of the glutamatergic system as a drug target for depression, and the validity of this hypothesis has been underpinned by the discovery of the...
(R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant...
Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts robust antidepressant effects in patients with treatment-resistant depression. The precise mechanisms underlying ketamine's antidepressant actions remain unclear, although previous research suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation plays a role. We investigated whether...
(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the...
Background: Although previous reports suggest sex-specific differences in the antidepressant actions of (R,S)-ketamine, these differences in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. Methods: Saline or (R)-ketamine was administered 23 hours post lipopolysaccharide administration to adult male or female mice. Subsequently, antidepressant...
Historically, identification of active metabolites has contributed to drug discovery for psychiatric disorders. It has led to the identification of new medications such as desipramine (a metabolite of imipramine) and paliperidone (a metabolite of risperidone). (R,S)-Ketamine, which has been regarded as the greatest breakthrough in depression research, is rapidly and stereoselectively...
Major depressive disorder (MDD) affects approximately 10% to 20% of the US population (Kessler et al. , 2005); thus, the economic burden of MDD is immense. Currently, selective serotonin reuptake inhibitors and serotonin- and noradrenaline-reuptake inhibitors are widely prescribed for patients with MDD as first-line treatments. However, these medications have several drawbacks; approximately...
Based on the discovery of the robust antidepressant effects of ketamine in patients with depression, including those with treatment-resistant depression, agents acting on the glutamatergic system have drawn much attention as potential novel antidepressants. Among the agents acting on the glutamatergic system, preclinical data have indicated that the group II metabotropic glutamate (mGlu)...
BACKGROUND: Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice. METHODS: Therefore, development of...
Background: Similar to the N-methyl-D-aspartate receptor antagonist ketamine, the metabotropic glutamate 2/3 receptor antagonist, MGS0039, shows antidepressant effects. However, there are no reports comparing these 2 compounds in the social defeat stress model of depression. Methods: We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible...