Novel drug developmental strategies for treatment‐resistant depression
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...
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| Published in | British journal of pharmacology Vol. 179; no. 6; pp. 1146 - 1186 |
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| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Blackwell Publishing Ltd
01.03.2022
John Wiley and Sons Inc |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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 mGlu5 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. |
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| AbstractList | 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 mGlu5 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. 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 mGlu5 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.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 mGlu5 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. 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. 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 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. 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. |
| Author | Borbély, Éva Fuchs, Eberhard Czéh, Boldizsár Wiborg, Ove Helyes, Zsuzsanna Simon, Mária |
| AuthorAffiliation | 2 Molecular Pharmacology Research Group, Szentágothai János Research Centre University of Pécs Pécs Hungary 6 Neurobiology of Stress Research Group, Szentágothai János Research Centre University of Pécs Pécs Hungary 4 German Primate Center Leibniz Institute for Primate Research Göttingen Germany 7 Department of Laboratory Medicine, Medical School University of Pécs Pécs Hungary 5 Department of Health Science and Technology Aalborg University Aalborg Denmark 3 Department of Psychiatry and Psychotherapy, Clinical Centre, Medical School University of Pécs Pécs Hungary 1 Department of Pharmacology and Pharmacotherapy, Medical School University of Pécs Pécs Hungary |
| AuthorAffiliation_xml | – name: 4 German Primate Center Leibniz Institute for Primate Research Göttingen Germany – name: 5 Department of Health Science and Technology Aalborg University Aalborg Denmark – name: 1 Department of Pharmacology and Pharmacotherapy, Medical School University of Pécs Pécs Hungary – name: 7 Department of Laboratory Medicine, Medical School University of Pécs Pécs Hungary – name: 3 Department of Psychiatry and Psychotherapy, Clinical Centre, Medical School University of Pécs Pécs Hungary – name: 2 Molecular Pharmacology Research Group, Szentágothai János Research Centre University of Pécs Pécs Hungary – name: 6 Neurobiology of Stress Research Group, Szentágothai János Research Centre University of Pécs Pécs Hungary |
| Author_xml | – sequence: 1 givenname: Éva surname: Borbély fullname: Borbély, Éva organization: University of Pécs – sequence: 2 givenname: Mária surname: Simon fullname: Simon, Mária organization: University of Pécs – sequence: 3 givenname: Eberhard surname: Fuchs fullname: Fuchs, Eberhard organization: Leibniz Institute for Primate Research – sequence: 4 givenname: Ove surname: Wiborg fullname: Wiborg, Ove organization: Aalborg University – sequence: 5 givenname: Boldizsár surname: Czéh fullname: Czéh, Boldizsár organization: University of Pécs – sequence: 6 givenname: Zsuzsanna surname: Helyes fullname: Helyes, Zsuzsanna email: zsuzsanna.helyes@aok.pte.hu organization: University of Pécs |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34822719$$D View this record in MEDLINE/PubMed |
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| ISSN | 0007-1188 1476-5381 |
| IngestDate | Thu Aug 21 18:17:06 EDT 2025 Thu Jul 10 18:12:16 EDT 2025 Sat Aug 23 13:24:21 EDT 2025 Mon Jul 21 05:59:54 EDT 2025 Sun Jul 06 05:07:54 EDT 2025 Thu Apr 24 22:50:34 EDT 2025 Wed Jan 22 16:27:29 EST 2025 |
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| Issue | 6 |
| Keywords | neuroinflammation monoamine antidepressant opioid glutamate neuroimaging neuroplasticity |
| Language | English |
| License | Attribution-NonCommercial 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
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| Notes | Funding information János Bolyai Research Scholarship of the Hungarian Academy of Sciences, Grant/Award Number: BO/00592/19/5; EU Social Fund, Grant/Award Number: EFOP‐3.6.1‐16‐2016‐00004 EFOP‐3.6.2‐16‐2017‐00008; Hungarian Brain Research Program, Grant/Award Number: 2017‐1.2.1‐NKP‐2017‐00002; Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Grant/Award Numbers: TKP2020‐IKA‐08, 2020‐4.1.1‐TKP2020, OTKA FK137951, OTKA K138046, ÚNKP‐21‐5‐PTE‐998; Pécsi Tudományegyetem (Szolcsányi János Research Fund) ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 Funding information János Bolyai Research Scholarship of the Hungarian Academy of Sciences, Grant/Award Number: BO/00592/19/5; EU Social Fund, Grant/Award Number: EFOP‐3.6.1‐16‐2016‐00004 EFOP‐3.6.2‐16‐2017‐00008; Hungarian Brain Research Program, Grant/Award Number: 2017‐1.2.1‐NKP‐2017‐00002; Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Grant/Award Numbers: TKP2020‐IKA‐08, 2020‐4.1.1‐TKP2020, OTKA FK137951, OTKA K138046, ÚNKP‐21‐5‐PTE‐998; Pécsi Tudományegyetem (Szolcsányi János Research Fund) |
| OpenAccessLink | https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fbph.15753 |
| PMID | 34822719 |
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| PageCount | 41 |
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| PublicationCentury | 2000 |
| PublicationDate | March 2022 |
| PublicationDateYYYYMMDD | 2022-03-01 |
| PublicationDate_xml | – month: 03 year: 2022 text: March 2022 |
| PublicationDecade | 2020 |
| PublicationPlace | England |
| PublicationPlace_xml | – name: England – name: London – name: Hoboken |
| PublicationTitle | British journal of pharmacology |
| PublicationTitleAlternate | Br J Pharmacol |
| PublicationYear | 2022 |
| Publisher | Blackwell Publishing Ltd John Wiley and Sons Inc |
| Publisher_xml | – name: Blackwell Publishing Ltd – name: John Wiley and Sons Inc |
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| SubjectTerms | Animal models Animals antidepressant Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Antipsychotics Clinical trials Depression - drug therapy Depressive Disorder, Major - drug therapy Depressive Disorder, Treatment-Resistant - drug therapy Drug Development glutamate Glutamatergic transmission Glutamic acid receptors (ionotropic) Glutamic acid receptors (metabotropic) Humans Inflammation Ketamine Mental depression Molecular modelling monoamine N-Methyl-D-aspartic acid receptors Neuroimaging neuroinflammation neuroplasticity Neuroprotection Neuroprotective agents Neurotransmission opioid Review Therapeutic targets Treatment resistance Tryptamine |
| Title | Novel drug developmental strategies for treatment‐resistant depression |
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