“We … discuss our hypothesis that the therapeutic effects of monoaminergic antidepressants and ketamine may be mediated by increased AMPA-to-NMDA glutamate receptor throughput in critical neuronal circuits. We hypothesize that ketamine directly mediates this throughput, whereas monoaminergic antidepressants work indirectly and gradually; this may explain, in part, the lag of onset of several weeks to months that is observed with traditional antidepressants."
PMID: 18221626 [PubMed - indexed for MEDLINE]
“Although most antidepressants exert their initial effects by increasing the intrasynaptic levels of serotonin and/or norepinephrine, the resolution of core depressive symptoms becomes manifest only after weeks of administration. This suggests that alterations in downstream signaling cascades likely are the relevant targets ultimately responsible for their therapeutic effects. These observations have led to the appreciation that whereas dysfunction within the monoaminergic neurotransmitter system is likely to have an important role in mediating some aspects of mood disorders’ pathophysiology, it likely represents the consequences of other more key abnormalities [5,6].
…Contemporary theories about the neurobiologic underpinnings of mood disorders posit that neuroplasticity deficiency and cellular resilience may lie behind their pathophysiology and that antidepressants exert major effects on signaling pathways that regulate neuroplasticity and cell survival.
… [Rapid improvement resulting from ketamine] are posited to be due to an increase in AMPA relative to NMDA glutamatergic throughput, which results in increased synaptic potentiation. … early neuroplastic changes most likely explain the sustained effect of a single dose of ketamine.
…The NMDA/NR2B receptor subtype also seems to be relevant to the mechanism of antidepressant action and a reasonable target to pursue to develop the next generation of antidepressants. We recently found that Ro 25-6981, a selective NR2B subunit antagonist, has antidepressant-like properties in rodents and that these effects, similar to ketamine, appear in part to be largely mediated through AMPA receptors."
