Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Hot Topics
  • Published:

Potentiation of AMPA receptors for rapid therapeutic gain in psychiatry has reached a new level of excitement

Neuropsychopharmacology volume 49, pages 339–340 (2024)Cite this article

Subjects

A new age of antidepressants arose in 2006 with the publication of data describing the rapid-acting antidepressant effects of ketamine and scopolamine. These clinical findings led to the approval of (S)-ketamine for treatment-resistant depression in 2019 and a dextromethorphan/bupropion combination in 2022. The 2006 report of spirituality-evoking effects of psilocybin led to subsequent striking observations of rapid and enduring antidepressant effects of psyilocybin and other psychedelic drugs and the launch of numerous biotech companies. Clinical trial listings for ongoing studies with numerous other potential rapid-acting medicines (e.g., (R)-ketamine, esmethadone, zuranolone, psychedelics, mGlu2/3 receptor antagonists and NMDA receptor modulators) are prevalent [1].

AMPA receptors (AMPARs) are pivotal to the transduction of the antidepressant effects of conventional and rapid-acting antidepressants but have yet to be successfully utilized to generate a rapid-acting medication [2]. Potentiation of AMPARs by small molecules (AMPAkines) has raised neurotoxicity concerns, tolerability issues, and difficulties in identifying a potentiator with the optimal ability to energize (but not over-energize) excitatory neurotransmission. Although a Phase 1b study showed both mood and executive function improvements with the AMPAkine Org 26576, the development of this compound did not proceed. Clinical investigation of the AMPAkine TAK-653 in depressed patients is currently undergoing patient enrollment. TAK-653 has been studied in healthy volunteers where it demonstrated good tolerability and biological and antidepressant-associated biological activation [3]. There are also two Phase 2-ready AMPAkines under clinical development for sleep apnea, opioid-induced respiratory depression, and spinal cord injury (http://respirerx.com/product-pipeline/).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Witkin JM, Golani LK, Smith JL. Clinical pharmacological innovation in the treatment of depression. Expert Rev Clin Pharmacol. 2023;16:349–62. https://doi.org/10.1080/17512433.2023.2198703.

    Article  CAS  PubMed  Google Scholar 

  2. Alt A, Nisenbaum ES, Bleakman D, Witkin JM. A role for AMPA receptors in mood disorders. Biochem Pharmacol. 2006;71:1273–88. https://doi.org/10.1016/j.bcp.2005.12.022.

    Article  CAS  PubMed  Google Scholar 

  3. Dijkstra F, O’Donnell P, Klaassen E, Buhl D, Asgharnejad M, Rosen L, et al. Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers. Transl Psychiatry. 2022;12:408. https://doi.org/10.1038/s41398-022-02148-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kato AS, Burris KD, Gardinier KM, Gernert DL, Porter WJ, Reel J, et al. Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism. Nat Med. 2016;22:1496–501. https://doi.org/10.1038/nm.4221.

    Article  CAS  PubMed  Google Scholar 

  5. Radin DP, Li YX, Rogers G, Purcell R, Lippa A. Tarps differentially affect the pharmacology of ampakines. Biochem Pharmacol. 2018;154:446–51. https://doi.org/10.1016/j.bcp.2018.06.013.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang D, Lape R, Shaikh SA, Kohegyi BK, Watson JF, Cais O, et al. Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics. Nat Commun. 2023;14:1659. https://doi.org/10.1038/s41467-023-37259-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. RespireRx Pharmaceuticals Inc, Glen Rock, NJ, USA

    Jeffrey M. Witkin & Arnold Lippa

Authors
  1. Jeffrey M. Witkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arnold Lippa
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JMW conceptualized the paper and both AL and JMW wrote and edited the manuscript.

Corresponding author

Correspondence to Jeffrey M. Witkin.

Ethics declarations

Competing interests

The authors declare no competing interests. Both JMW and AL are employees of RespireRx Pharmaceuticals Inc. None of the compounds from this company are in clinical development for major depressive disorder.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Witkin, J.M., Lippa, A. Potentiation of AMPA receptors for rapid therapeutic gain in psychiatry has reached a new level of excitement. Neuropsychopharmacol. 49, 339–340 (2024). https://doi.org/10.1038/s41386-023-01651-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-023-01651-y

This article is cited by

Search

Advanced search

Quick links