Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy.
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ABSTRACT:
SUBMITTER: Stuart SA
PROVIDER: S-EPMC4487826 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.
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Project description:Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this hypothesis and potential mechanistic underpinnings we compared the effects of ketamine and CP-101,606 on neurophysiological biomarkers in rats immediately after drug administration and after the drugs had been eliminated. Local field and auditory-evoked potentials (AEPs) were recorded from primary auditory cortex and hippocampus in freely moving rats. Effects of different doses of ketamine or CP-101,606 were evaluated on amplitude of AEPs, auditory gating, and absolute power of delta and gamma oscillations 5-30 min (drug-on) and 5-6 h (drug-off) after systemic administration. Both ketamine and CP-101,606 significantly enhanced AEPs in cortex and hippocampus in the drug-off phase. In contrast, ketamine but not CP-101,606 disrupted auditory gating and increased gamma-band power during the drug-on period. Although both drugs affected delta power, these changes did not correlate with increase in AEPs in the drug-off phase. Our findings show that both ketamine and CP-101,606 augment AEPs after drug elimination, consistent with synaptic potentiation as a mechanism for antidepressant efficacy. However, these drugs had different acute effects on neurophysiological parameters. These results have implications for understanding the underlying mechanisms for the rapid-onset antidepressant effects of NMDA receptor inhibition and for the use of electrophysiological measures as translatable biomarkers.
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