Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors

Maeng, Sungho; Zarate, Carlos A.; Du, Jing; Schloesser, Robert J.; McCammon, Joseph; Chen, Guang; Manji, Husseini K.

doi:10.1016/j.biopsych.2007.05.028

Cited by 1,027 publications

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“…While antidepressant effects occurred with these agents, they were not as sustained as those of ketamine [116] . Recent studies have found that the NMDAR agonist GLYX-13 has effects similar to ketamine but without the adverse effects, such as the psychotomimetic consequences and impaired cognition that limit its clinical use [120] .…”

Section: Targeting Nmdarsmentioning

confidence: 89%

“…Ketamine rapidly increases the expression of synaptic proteins and the number of excitatory spine synapses in the PFC [50,114,115] . In the FST, ketamine reduces immobility (a behavioral endophenotype reversible by antidepressants) concomitant with a rapid increase in glutamate release, activation of AMPARs, and increased hippocampal BDNF concentration [116,117] . From this evidence, a glu tamatergic hypothesis of depression is proposed in which the glutamatergic system is the primary mediator of depression and serves as a final pathway in antidepressant therapy.…”

Section: Ketamine Has Rapid-onset Antidepressant Effi Cacymentioning

confidence: 99%

“…Moreover, the onset of ketamine effects requires AMPARs, as the antidepressant-like behaviors are attenuated by pre-treatment with the AMPAR antagonist NBQX in mouse models of depression [116] .…”

Section: Targeting Amparsmentioning

confidence: 99%

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Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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Section: Targeting Nmdarsmentioning

confidence: 89%

Section: Ketamine Has Rapid-onset Antidepressant Effi Cacymentioning

confidence: 99%

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Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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“…Supporting interest in mixed NMDA agents/SRIs, the open channel blocker ketamine exerts rapid antidepressant properties in patients. [153][154][155] Although the risk of cognitive impairment and psychosis tempers interest in channel blockers as a therapeutic strategy, 34,146,156 the anti-Alzheimer agent memantine has only a low risk of psychosis, because of its marked voltage-dependency and rapid kinetics 156 -158 ; its potential antidepressant actions are under investigation, although clinical data are as yet ambivalent. 159 -161 In fact, memantine interacts with several other sites 156 (Table 2), supporting the notion that NMDA receptor blockers could serve as a template for generating well-tolerated multitarget antidepressants of accelerated onset of action.…”

Section: Glutamatergic Receptors As Targets: Ionotropic and Metabotromentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

180

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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“…These results are consistent with previous studies [12,13], in which (R)-ketamine appeared to be a more potent, long-lasting, and safe antidepressant than (S)-ketamine. MK-801, another NMDAR antagonist, also has rapid antidepressant effects but they are not maintained [14,15]. These findings raise doubts about the NMDAR-dependent antidepressant responses to ketamine.…”

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confidence: 99%

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

et al. 2016

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Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors

Cited by 1,027 publications

References 18 publications

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

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