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

BACKGROUND

NK1 receptor antagonists were abandoned despite antidepressant efficacy in five randomized clinical trials. The loss of confidence may be attributed to the failure of a Phase III clinical program with the NK1 receptor antagonist aprepitant in Major Depression. This review examines how PET receptor occupancy was used to select doses for aprepitant and that these may not have achieved adequate exposure.

METHODS

PubMed, Google Scholar, and FDA databases were searched for articles concerning NK1 receptor antagonists, human PET receptor occupancy and clinical trials in Major Depression.

RESULTS

Antidepressant efficacy was initially demonstrated with three NK1 receptor antagonists, including aprepitant. A nanoparticle formulation of aprepitant was then developed to improve oral bioavailability. In PET studies, doses of 80 and 160mg achieved a high level (~ 90%) of occupancy of NK1 receptors in the human brain and were selected for Phase III. The efficacy of these doses of the nanoparticle formulation may not have been established in depressed patients prior to Phase III, and previous formulations required a dose of 300mg of aprepitant for efficacy. No antidepressant effect of 80 or 160mg of aprepitant was found, and it was concluded that the NK1 antagonist concept was flawed. However, subsequent studies with other compounds showed that a higher level of NK1 receptor occupancy (100%) was required for antidepressant efficacy.

LIMITATIONS

Key data concerning the bioequivalence of different formulations of aprepitant have not been published. The importance of NK1 antagonists for pharmacotherapy of depression and other psychiatric disorders has not been established in clinical practice.

CONCLUSION

Aprepitant may have failed in Phase III because of an inadequate understanding of the relationship between brain NK1 receptor occupancy and clinical response. A validated and novel mechanistic approach to treat depression has been misperceived as ineffective and abandoned. Caution should be exercised in the appropriate use of PET occupancy data to select doses for drug development programs in neuropsychiatry. The relationship between exposure, receptor occupancy and clinical response should be established. A crisis of confidence has followed the failure of this and other programs in neuropsychiatry, with a far reaching and detrimental impact on pharmaceutical research.