NMDA receptor modulator

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NMDA receptor modulators (glutamate modulators) are a new form of antipsychotic that are in Phase II FDA studies. The first compound studied was glycine which was hypothesized by Daniel Javitt after observation that people with phencyclidine(PCP)-induced psychosis were lacking in glutamate transmission. [1] (PCP is an NMDA receptor antagonist that blocks glutamate.) In giving glycine to people with PCP-induced psychosis a recovery rate was noted. From there, it was hypothesized that people with psychosis from schizophrenia would benefit from increased glutamate transmission and glycine was added with strong recovery rates noted especially in the area of negative and cognitive symptoms. Glycine, however, sporadic results aside (dose 60 g/day or 0.8 g/kg, [2] [3] approximately the amount in 300 g of gelatin powder or two kilograms of sunflower seeds [4] ) remains an adjunct antipsychotic and an unworkable compound. However, the Eli Lilly and Company study drug LY-2140023 is being studied as a primary antipsychotic and is showing strong recovery rates, especially in the area of negative and cognitive symptoms of schizophrenia. Tardive dyskinesia, diabetes and other standard complications have not been noted:

Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P = 0.001 at week 4). Notably, patients treated with LY-2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia. [5]

Other NMDA receptor modulators are being studied and this modality of treatment may once approved as antipsychotic medications gradually replace the current (dopaminergic) antipsychotics.

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<span class="mw-page-title-main">Haloperidol</span> Typical antipsychotic medication

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<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

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<span class="mw-page-title-main">Risperidone</span> Antipsychotic medication

Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection. The injectable versions are long-acting and last for 2–4 weeks.

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<span class="mw-page-title-main">Bitopertin</span> Chemical compound

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Ulotaront is an investigational antipsychotic that is undergoing clinical trials for the treatment of schizophrenia and Parkinson's disease psychosis. The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube. Ulotaront is in Phase III of clinical development.

<span class="mw-page-title-main">Iclepertin</span> Chemical compound

Iclepertin is an investigational nootropic to enhance the cognition and functional capacity in schizophrenia developed by Boehringer Ingelheim. As of May 2020, it is in phase III of clinical trial under the code name CONNEX-3. BI 425809 is an inhibitor of glycine transporter 1 (Gly-T1) that in phase II improved cognition after 12 weeks in patients with schizophrenia. Doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. Schizophrenia is characterized by abnormalities in glutamatergic pathways related to NMDA receptor hypofunction. Inhibition of GlyT1 on the presynaptic membrane or astrocytes is hypothesized to increase glycine levels within the synapse. The NMDA receptor function may be enhanced by increasing levels of its co-agonist, glycine, within the synaptic cleft, which may lead to improvements in cognitive function.

References

  1. ↑ "Essential Science Indicators".
  2. ↑ Heresco-Levy, Uriel; Javitt, Daniel C.; Ermilov, Marina; Mordel, Clara; Silipo, Gail; Lichtenstein, Michael (1999). "Efficacy of High-Dose Glycine in the Treatment of Enduring Negative Symptoms of Schizophrenia". Archives of General Psychiatry. 56 (1): 29–36. doi:10.1001/archpsyc.56.1.29. PMID   9892253.
  3. ↑ Evins, A. E.; Fitzgerald, S. M.; Wine, L.; Rosselli, R.; Goff, D. C. (2000). "Placebo-Controlled Trial of Glycine Added to Clozapine in Schizophrenia". American Journal of Psychiatry. 157 (5): 826–828. doi:10.1176/appi.ajp.157.5.826. PMID   10784481. S2CID   26013829.
  4. ↑ "Amino Acid Glycine". Archived from the original on 2011-08-11. Retrieved 2010-05-31.
  5. ↑ Patil, Sandeep T; Lu Zhang; Ferenc Martenyi; Stephen L. Lowe; Kimberley A. Jackson; Boris V. Andreev; Alla S. Avedisova; Leonid M. Bardenstein; Issak Y. Gurovich; Margarita A. Morozova; Sergey N. Mosolov; Nikolai G. Neznanov; Alexander M. Reznik; Anatoly B. Smulevich; Vladimir A. Tochilov; Bryan G. Johnson; James A. Monn; Darryle D. Schoepp (September 2007). "Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial" (PDF). Nature Medicine. Nature Publishing Group. 13 (9): 1102–1107. doi:10.1038/nm1632. PMID   17767166. S2CID   6417333 . Retrieved 2009-02-01.


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