Novel drug developmental strategies for treatment-resistant depression

Éva Borbély, Mária Simon, Eberhard Fuchs, Ove Wiborg, Boldizsár Czéh, Zsuzsanna Helyes*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

22 Citations (Scopus)
161 Downloads (Pure)


Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment-resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I–III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu 5 receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S-ketamine, but add-on therapies with second-generation antipsychotics, certain nutritive, anti-inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large-scale, high-throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies.

Original languageEnglish
JournalBritish Journal of Pharmacology
Issue number6
Pages (from-to)1146-1186
Number of pages41
Publication statusPublished - Mar 2022

Bibliographical note

© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.


  • antidepressant
  • glutamate
  • monoamine
  • neuroimaging
  • neuroinflammation
  • neuroplasticity
  • opioid


Dive into the research topics of 'Novel drug developmental strategies for treatment-resistant depression'. Together they form a unique fingerprint.

Cite this