A randomized controlled trial of intranasal Neuropeptide Y in patients with major depressive disorder

Background: Since about one-third of patients with major depressive disorder (MDD) do not respond adequately to available antidepressants, there is a need for treatments based on novel mechanisms of action. Neuropeptide Y (NPY), a normal brain constituent, is reduced in cerebrospinal fluid of patients with MDD and post-traumatic stress disorder and in corresponding rodent models. Moreover, NPY administered centrally or intranasally rescues pathophysiology in these models. Consequently, we conducted the first, to our knowledge, controlled trial of NPY as a treatment for MDD. Methods: Thirty MDD patients on a stable dose of a conventional antidepressant insufflated 6.8 mg NPY (n = 12) or placebo (n = 18) in a double blind randomized fashion. Effects were assessed at baseline, +1 hour, +5 hours, +24 hours, and +48 hours. The primary outcome was change in depression severity measured with the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: NPY was superior to placebo at +24 hours (change −10.3 [95% CI: −13.8; −6.8]) vs −5.6 (95% CI: −8.4; −2.7); group*time F = 3.26, DF = (1,28), P =.04; Cohen’s d = 0.67). At +5 hours MADRS decreased −7.1 ([95% CI: −10.0; −4.2] vs −3.5 [95% CI: −5.8; −1.2]; group*time F = 2.69, DF = (1,28), P =.05; Cohen’s d = 0.61). MADRS reduction at +48 hours was not significant. Conclusions: Since no results regarding the trajectory of NPY effects existed prior to this study we extrapolated from the known NPY biology and predicted the effects will occur 5–48 hours post insufflation. We chose +48 hours as the primary endpoint and +1, +5, and +24 hours as secondary endpoints. The results, the first of their kind, indicate that insufflated NPY is antidepressant, despite not meeting the primary outcome, and call for dose ranging and repeated NPY insufflation trials.