Novel drug developmental strategies for treatment‐resistant depression

Major depressive disorder is a leading cause of disability worldwide, and conventional therapies fail many patients, especially those with treatment-resistant depression (TRD). This review examines novel drug targets and candidates in Phase I–III clinical trials. The most promising approaches include blocking glutamatergic neurotransmission with NMDA and mGlu5 receptor antagonists, modulating the opioidergic system with κ receptor antagonists, and using hallucinogenic tryptamine derivatives. The only registered drug for TRD is the NMDA receptor antagonist S-ketamine, but add-on therapies with second-generation antipsychotics, nutritive, anti-inflammatory, and neuroprotective agents also appear effective. Ongoing large-scale omics and neuroimaging studies may reveal new molecular mechanisms and therapeutic strategies.

Study at a glance

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.