A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder

Sehrish Sayed, Nicholas T Van Dam, Sarah R Horn, Marin M Kautz, Michael Parides, Sara Costi, Katherine A Collins, Brian Iacoviello, Dan V Iosifescu, Aleksander A Mathé, Steven M Southwick, Adriana Feder, Dennis S Charney, James W Murrough, Sehrish Sayed, Nicholas T Van Dam, Sarah R Horn, Marin M Kautz, Michael Parides, Sara Costi, Katherine A Collins, Brian Iacoviello, Dan V Iosifescu, Aleksander A Mathé, Steven M Southwick, Adriana Feder, Dennis S Charney, James W Murrough

Abstract

Background: Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder.

Methods: Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes.

Results: Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score.

Conclusions: Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: https://ichgcp.net/clinical-trials-registry/NCT01533519" title="See in ClinicalTrials.gov">NCT01533519).

Keywords: anxiety; neuropeptide Y; posttraumatic stress disorder; resilience; stress; trauma.

© The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Study flow diagram. (A) Overview of randomized crossover study design. (B) Study procedure timeline occurring on each of 2 treatment days (V2 and V5). NPY, neuropeptide Y; VS, vital signs.
Figure 2.
Figure 2.
Effect of neuropeptide Y (NPY) treatment and dose on anxiety following symptom provocation in patients with posttraumatic stress disorder (PTSD). Figure displays observed values for anxiety measures before and immediately following a symptom provocation procedure (+32-minute time point) in subjects under NPY and placebo conditions (left column). Mean differences between NPY and placebo in change in symptom measure with associated SEs for each dose of NPY are also displayed (right column). In the case of summarized change scores depicted in the right column, the change in symptom severity (post minus baseline) is compared between NPY and placebo (PBO) as a difference score (NPY minus PBO). Therefore, larger numbers represent greater symptom severity, and negative difference scores indicate less anxiety symptoms under NPY relative to PBO. The dose-response effect was tested using an interaction term from a linear mixed model that adjusted for treatment order and baseline severity. (A) Beck Anxiety Inventory (BAI). (B) State-Trait Anxiety Inventory-State Form (STAI-State). (C) Impact of Events Scale-Revised (IES-R).

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