Novel drug developmental strategies for treatment‐resistant depression

• Published in: British journal of pharmacology Vol. 179; no. 6; pp. 1146 - 1186
• Main Authors: Borbély, Éva, Simon, Mária, Fuchs, Eberhard, Wiborg, Ove, Czéh, Boldizsár, Helyes, Zsuzsanna
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2022; John Wiley and Sons Inc
• Subjects: 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; neuroinflammation; monoamine; antidepressant; opioid; glutamate; neuroimaging; neuroplasticity
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.15753

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.