Novel Molecular Targets for Mood Disorders and Psychosis Proceedings of a Workshop (2021) / Chapter Skim
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5 Emerging Drug Targets
5 Emerging Drug Targets
Pages 31-40
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From page 31... ...
. • Preclinical and Phase 1 clinical studies suggest that the first in-class mTORC1 activator NV-5138 activates key synaptic proteins in brain regions implicated in depression and may relieve symptoms of depression (Saiah)
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From page 32... ...
The search for novel antidepressants appears to be converging on a final common pathway -- the glutamate receptor (NMDA/AMPA) to mTOR pathway -- which modulates cellular activity in the prefrontal cortex, said Robert Davis, senior vice president and chief scientific officer at I ntracellular Therapeutics.
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From page 33... ...
The mTOR pathway regulates cellular growth and the cellular response to nutrients through the activity of two protein complexes called mTORC1 and mTORC2, said Eddine Saiah, chief scientific officer at Navitor Pharmaceuticals. mTORC1 plays an especially important role in brain and mood disorders by regulating synaptogenesis via protein synthesis, axon elongation, and dendritic branching, said Saiah.
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SOURCE: Presented by Eddine Saiah, March 9, 2021. 5-HT2A agonists also include a class of drugs called psychedelics or classic serotonergic hallucinogens, such as LSD, psilocybin, and mescaline, said Gabriella Gobbi, professor of psychiatry at McGill University.
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The next question, said Gobbi, is whether low doses of LSD can be effective clinically for patients with depression, social anxiety, and/or autism spectrum. TAAR1/5-HT1AR AGONISTS IN SCHIZOPHRENIA TREATMENT Kenneth Koblan, chief scientific officer at Sunovion Pharmaceuticals, described a recently developed antipsychotic drug that, unlike many conventional medications for psychosis, does not antagonize monoamine receptors.
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From page 36... ...
"We believe that it modulates presynaptic dopamine synthesis capacity," Koblan said regarding its hypothesized mechanism of action. A global, 4-week Phase 2 clinical study in acutely psychotic patients showed that across all geographies and subgroups, participants randomized to SEP-856 rather than placebo improved significantly on the Positive and Negative Syndrome Scale (PANSS)
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A recently published Phase 2 study demonstrated that this combined therapy improved the patients' PANSS total score, with similar improvements observed in clinical subscales that assessed the drug's impact on positive and negative psychosis symptoms (Brannan et al., 2021)
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From page 38... ...
. With neither of these two different and well-characterized proof-of-concept clinical trials achieving their target endpoints for alleviating negative symptoms, Murthy suggested that, "we should exercise extreme caution in pursuing NMDA modulators for these effects, and also potentially consider a different regimen." Although luvadaxistat was not found to improve negative symptoms, the drug developer for this compound reported that signals of improved cognitive performance were observed in some schizophrenia patients (Neurocrine Biosciences, 2021)
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From page 39... ...
Paul suggested that both M1 and M4 receptor targeting may be important -- M1 more for treating the precognitive effects and negative symptoms and M4 more for treating psychosis. In Roth's lab and others, researchers are leveraging computational approaches to construct roadmaps for developing drugs that interact with multiple molecular targets.
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