Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment
Condition: Alcoholism
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Double-blind, placebo-controlled, cross-over design study examining the effects of a
      norepinephrine alpha1 receptor antagonist (prazosin) on stress reactivity in a laboratory
      stressor task.
    

Detailed description: 
      OBJECTIVES

      The first objective of the current study is to examine norepinephrine alpha1 (NE-alpha1)
      receptor involvement in reactivity to unpredictable stressors in humans, by using the NPU
      stress task in conjunction with an alpha1-blocker, prazosin. The second objective of the
      study is to provide preliminary evidence that prazosin is effective at reducing
      stress-reactivity in alcoholics in early abstinence.

      PARTICIPANTS

      Sixty-four healthy adult participants and sixty-four participants with an Alcohol Use
      Disorder in early abstinence.

      STUDY OVERVIEW

      Sixty-four healthy adult participants (32 males & 32 females) will be recruited to
      participate in a double-blind, placebo-controlled, cross-over design study examining the
      effects of a NE-alpha1 antagonist (prazosin) on the defensive (physiological and self-report
      affect) response to stressors using a well-validated animal-human translational stressor
      task. Participants will complete two overnight study visits where 2 mg prazosin and placebo
      are administered on separate visits separated by approximately 7 days. Drug order is randomly
      assigned and counterbalanced across participants (double-blind; study visits 1-2). On each of
      these two study visits, participants will complete the No Shock, Predictable Shock,
      Unpredictable Shock (NPU) task 90 minutes after drug administration. The NPU task is designed
      to examine stress reactivity to predictable and unpredictable stressors (i.e., electric
      shock). These two visits provide for a within-subject evaluation of the effect of acute
      antagonism of alpha1-NE receptors (via prazosin) to investigate the role of this NE mechanism
      in unpredictable (vs. predictable) stressor response.

      After the full healthy adult/control sample has completed the study, the investigators will
      conduct preliminary data analysis to evaluate the first study hypothesis. These analyses are
      used to evaluate the sensitivity of the NPU task to NE-alpha1 mechanisms and its potential
      utility as an early surrogate endpoint for stress-related relapse mechanisms in alcoholism.
      The investigators will only recruit the sample of sixty-four alcoholic participants to
      complete the study if the first hypothesis is initially supported with healthy controls.
      These participants will meet Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5)
      criteria for Alcohol Use Disorder (at least moderate severity) and be in early abstinence
      (1-8 weeks). All other study procedures will be identical for this sample.

      OUTCOME MEASURES

      The primary outcome is startle potentiation during the NPU task and the secondary outcome is
      self-reported retrospective fear/anxiety during the NPU task.

      HYPOTHESES

        1. Prazosin (2mg vs. placebo) will reduce stress reactivity to unpredictable (vs.
           predictable) stressors measured via startle potentiation and self-report.

        2. Abstinent alcoholics (vs. controls) will display elevated stress reactivity to
           unpredictable (vs. predictable) stressors measured via startle potentiation and
           self-report.

        3. The predicted effects of prazosin on reducing stress reactivity to unpredictable (vs.
           predictable) stressors (Hypothesis 1) measured via startle potentiation and self-report
           will be moderated by alcoholism, such that the effects of prazosin will be larger in
           abstinent alcoholics than control participants.
    

Intervention name(s): Prazosin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 2mg Prazosin; Placebo
Intervention MeSH terms: Prazosin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Screening
Keywords: Alcoholism; Prazosin; Startle Potentiation; Norepinephrine; Anxiety; Fear; Stress