NK1 receptor antagonists for depression: Why a validated concept was abandoned

Area of Science:

• Neuroscience
• Psychiatry
• Pharmacology

Background:

• NK1 receptor antagonists demonstrated antidepressant efficacy in clinical trials.
• A Phase III trial failure with aprepitant in Major Depression led to a loss of confidence in this drug class.
• This review critically examines the dose selection process for aprepitant using Positron Emission Tomography (PET) receptor occupancy.

Purpose of the Study:

• To evaluate the role of PET receptor occupancy in selecting doses for NK1 receptor antagonist development.
• To investigate potential reasons for the failure of aprepitant in Phase III clinical trials for Major Depression.
• To provide recommendations for future drug development in neuropsychiatry.

Main Methods:

• Searched PubMed, Google Scholar, and FDA databases for relevant studies.
• Focused on NK1 receptor antagonists, human PET receptor occupancy, and clinical trials in Major Depression.
• Reviewed data on dose selection and receptor occupancy levels for aprepitant.

Main Results:

• Initial studies showed antidepressant efficacy for NK1 receptor antagonists.
• PET studies indicated that 80-160mg of nanoparticle aprepitant achieved ~90% NK1 receptor occupancy.
• No antidepressant effect was observed at these doses, contrasting with earlier formulations requiring 300mg.
• Subsequent research suggests 100% NK1 receptor occupancy may be necessary for efficacy.

Conclusions:

• Aprepitant's Phase III failure may stem from an insufficient understanding of the exposure-occupancy-response relationship.
• The potential of NK1 antagonists for treating depression and other psychiatric disorders may have been prematurely dismissed.
• Caution is advised in using PET occupancy data for dose selection; establishing the link between exposure, occupancy, and clinical response is vital.