Novel drug developmental strategies for treatment‐resistant depression
British Journal of Pharmacology – November 25, 2021
Source: OpenAlex
Summary
Major depressive disorder is a leading global disability, with many patients resistant to conventional medicine. Novel pharmacology is crucial for effective treatment of major depression. Promising drug candidates, currently in Phase I-III clinical trials, target specific brain neurotransmitter receptors. These neuroscience-based approaches modulate brain chemistry, inhibiting certain signaling pathways or influencing opioid systems. Hallucinogenic tryptamine derivates, a drug class related to tryptophan and brain disorders, also show potential. S-ketamine, an NMDA receptor antagonist, is the only registered drug for treatment-resistant depression, profoundly influencing behavior. Add-on therapies also improve outcomes.
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 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.