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The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study

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Abstract

Rationale

Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin’s role in the regulation of anxiety and fear in humans.

Objectives

Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat).

Methods

Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5–7-day wash-out period. Threat consisted of unpleasant electric shocks. The “NPU” threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle).

Results

As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle.

Conclusions

As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

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Fig. 1
Fig. 2

adapted from Schmitz and Grillon 2012). b Participants were asked to rate their online subjective anxiety on a scale of 1–10 by pressing arrows on the keyboard throughout the NPU threat test. During the N condition, the display read “No Shocks at Anytime” at the top of the screen; during the P condition, the display read “Shocks Only During Cue”; and during the U condition, the display read “Shocks at Anytime.” The visual threat cues consisted of colored shapes that were displayed intermittently throughout each condition. Startle probes are represented by yellow bursts, and shocks are represented by red lightning

Fig. 3

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Acknowledgements

We would like to thank Dr. Carlos Zarate, Jr. and Dr. Peixiong Yuan for assistance with plasma sample storage and shipping. We would like to thank NIMH nurses for their assistance with clinical coverage. We would like to thank Dr. Deborah Roberts for her assistance with protocol management.

Funding

This study was supported by the Intramural Research Program of the National Institute of Mental Health (grant number ZIAMH002798), Protocol 17-M-0046, NCT03036397 (clinicaltrials.gov). Azevan Pharmaceuticals Inc. provided SRX246 and placebo without charge and funded analysis of plasma samples for drug content. No NIH investigator involved in this study received any payment or other benefits from Azevan Pharmaceuticals Inc. T.L., E.P., E.B., A.M., A.B., C.R., N.B., E.D., S.P., M.E., and C.G. have nothing to disclose. M.B. and N.S. serve as officers at Azevan Pharmaceuticals and hold equity in the Company.

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Authors and Affiliations

  1. National Institute of Mental Health, Bethesda, MD, USA

    Tiffany R. Lago, Emily Page, Emily Beydler, Adrienne Manbeck, Alexis Beale, Camille Roberts, Nicholas Balderston, Monique Ernst & Christian Grillon

  2. VA Boston Healthcare System, Boston, MA, USA

    Tiffany R. Lago

  3. Boston University School of Medicine, Boston, MA, USA

    Tiffany R. Lago & Suzanne L. Pineles

  4. Azevan Pharmaceuticals Inc, Bethlehem, PA, USA

    Michael J. Brownstein, Eve Damiano & Neal Simon

  5. University of Pennsylvania, Philadelphia, PA, USA

    Nicholas Balderston

  6. National Center, PTSD At VA Boston Healthcare System, Boston, MA, USA

    Suzanne L. Pineles

  7. Lehigh University, Bethelhem, PA, USA

    Neal Simon

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  1. Tiffany R. Lago
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  2. Michael J. Brownstein
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Corresponding author

Correspondence to Tiffany R. Lago.

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Conflict of interest

T.L., E.P., E.B., A.M., A.B., C.R., N.B., E.D., S.P., M.E., and C.G. have nothing to disclose. M.B. and N.S. serve as officers at Azevan Pharmaceuticals Inc. and hold equity in the Company. Azevan Pharmaceuticals Inc. provided SRX246 and placebo without charge and funded analysis of plasma samples for drug content. T.L., E.P., E.B., A.M., A.B., C.R., N.B., S.P., M.E., and C.G. did not receive any payment or other benefits from Azevan Pharmaceuticals Inc.

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Lago, T.R., Brownstein, M.J., Page, E. et al. The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study. Psychopharmacology 238, 2393–2403 (2021). https://doi.org/10.1007/s00213-021-05861-4

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