Novel drug developmental strategies for treatment-resistant depression

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.

Keywords: antidepressant; glutamate; monoamine; neuroimaging; neuroinflammation; neuroplasticity; opioid.

FIGURE 1

Synaptic targets for the drug candidates investigated in Phase I–III studies. Panel (a) represents the excitatory ionotropic and G protein coupled receptors (GPCRs), as well as the ion channels serving as targets for novel compounds for TRD treatment. Panel (b) represents the postsynaptic inhibitory receptors and presynaptic targets on which the new drug candidates exert their effects. Colour boxes indicate the mechanisms of action for the representative members of the different drug groups. ↓ denotes activation, ┴ denotes inhibition, double arrowhead denotes partial agonism. D₂ receptor, D₂ dopamine receptor; mGlu, metabotropic glutamate receptor; κ receptor, κ opioid receptor; μ receptor, μ opioid receptor

FIGURE 2

Other mechanisms leading to antidepressant effects in TRD patients. Anti‐inflammatory and immunomodulatory effects can be achieved by several different mechanisms. Activation of rapamycin complex 1 (mTORC1) by NV‐5138, inhibition of JAK by tofacitinib, COX by aspirin and HMG‐CoA‐reductase by simvastatin lead to beneficial effects. Drugs promoting neuroprotection, neurogenesis and neuroendocrine interactions can also improve the patient's symptoms, although the precise mechanism of action is unknown in most cases. Inducing electrocortical quiescence by isoflurane, influencing the membrane fluidity or neurotransmitter formation by S‐adenosyl‐l‐methionine and affecting the energy production, storage and utilization, by creatine monohydrate, can also be effective mechanisms. HPA axis, hypothalamic–pituitary–adrenal axis, ATP, adenosine triphosphate

FIGURE 3

Summary of the published clinical studies with positive outcomes. Pie charts demonstrate compounds listed on https://clinicaltrials.gov or https://www.clinicaltrialsregister.eu/, which were studied in randomized, controlled, blinded or open‐label trials and published with positive results in TRD patients (the number of trials is shown in brackets)