Novel Molecular Targets for Mood Disorders and Psychosis Proceedings of a Workshop (2021) / Chapter Skim
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3 Targeting Glutamate Receptors for Treatment-Resistant Depression
3 Targeting Glutamate Receptors for Treatment-Resistant Depression
Pages 13-24
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From page 13... ...
. • Ketamine delivered intravenously and esketamine delivered intranasally provide rapid, robust antidepressant effects (Canuso)
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From page 14... ...
Tremendous progress in understanding the key role glutamate receptors play in regulating synaptic plasticity has fueled the development of novel, rapidly acting antidepressants -- ketamine and esketamine -- that have shown effectiveness against treatment-resistant depression, said Husseini Manji. Moreover, he said, the therapeutic effects of these medications appear to persist even when the drug has cleared from the body, allowing for intermittent administration.
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From page 15... ...
, were also similar across clinical trials, said Canuso. CLINICAL AND PATIENT EXPERIENCES WITH INTRANASAL ESKETAMINE Canuso leads the team at Janssen Research & Development, LLC that developed intranasal esketamine (Spravato®)
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From page 16... ...
, Canuso's team was particularly interested in studying intranasal esketamine in patients with acute suicidal ideation, when quickly bringing symptoms under control is essential. She noted that patients who are acutely suicidal are typically excluded from clinical treat ment trials of antidepressants, in part because these patients often receive extensive clinical care that can confound study outcomes.
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From page 17... ...
Therefore, he said, the underlying mechanisms relevant to ketamine's antidepressant effects are most likely molecular targets that are engaged within a 2- to 4-fold range from the target antidepressant plasma level. The molecular targets engaged at higher doses are probably not relevant to the anti depressant effects of ketamine, although they may play a role in mediating its anesthetic effects.
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From page 18... ...
Later, beginning at about 6 hours after ketamine administration, there is an increased expression of genes associated with new synapses, including genes expressed by axon terminals, such as synapsin 1 and SV2A, and genes that are expressed by the postsynaptic dendritic spine, such as PSD95 and GluR1, said Krystal. Yale scientists Ronald Duman and George Aghajanian demonstrated that ketamine triggers the rapid regrowth of dendritic spines that had previously undergone pruning, he continued.
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From page 19... ...
This triggers a shuttling of intracellular AMPA receptors to the cell sur face, thus increasing the efficacy of synaptic communication and increasing neuroplasticity. Meanwhile, the stimulation of TrkB receptors activates the Akt/mTOR pathway, resulting in increased protein synthesis and the recre ation of pruned dendritic spines, he said.
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From page 20... ...
The work of Weill Cornell Medicine scientist Conor Liston highlighted that there might be different mechanisms underlying the initiation and maintenance of ketamine's antidepressant effects, with initiation caused by enhanced AMPA receptor function and trafficking to the cell surface and maintenance caused by newly regrown dendritic spines, said Krystal. If interfering with the maintenance of recreated dendritic spines shortens the therapeutic effect of ketamine, he said it raises the question of whether it is possible to increase the duration of the antidepressant effects by increasing the duration of the newly restored dendritic spines.
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From page 21... ...
Clinicians and researchers have explored different strategies for extend ing the antidepressant effect of ketamine, said Carlos Zarate, chief of the Section on Neurobiology and Treatment of Mood Disorders and Section of Experimental Therapeutics and Pathophysiology Branch at NIMH and clinical professor of psychiatry at The George Washington University. These include adjunctive drugs such as glutamatergic modulators; psycho therapies such as cognitive-behavioral therapy or motivation enhancement therapy; non-invasive neurostimulation; repeated racemic ketamine2 infusions; and continued use of intranasal esketamine, said Zarate.
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From page 22... ...
For example, Abdallah and colleagues used functional magnetic resonance imaging to show that ketamine treatment normalizes prefrontal global brain connectivity in patients with treatment-resistant depression (Abdallah et al., 2017) , explained Zarate.
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From page 23... ...
Krystal added that there are a number of molecular mechanisms that are engaged in the presynaptic and postsynaptic models of ketamine efficacy discussed earlier, and some of these may be targets to potentiate the antidepressant effect of ketamine. These include muscarinic antagonists, psychedelic agents, 5-HT2A agonists, GABA-A receptor partial inverse agonists, AMPAkines, metabotropic glutamate receptor-2 antagonists, and ketamine metabolites.
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