The Role of Orexin in Human Panic Disorder
Condition: Panic Disorder
MeSH terms: Panic Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to provide some information (pilot data) about whether the study
      drug, suvorexant, (1) affects levels of orexin in people with panic disorder, and (2) is
      associated with decreased panic symptoms in response to a carbon dioxide (CO2) challenge.
    

Detailed description: 
      Orexins

      Hypocretins (orexins), a more recently identified class of pro-arousal neuropeptides, are
      synthesized by neurons in the lateral and posterior hypothalamus The main described orexins,
      orexin A (ORX A) and orexin B (ORX B), are both cleaved from a common precursor peptide,
      prepro-orexin. Orexin A, a 33 amino-acid residue peptide, appears to be conserved across many
      mammalian species. Orexin B contains 28 amino acids. Orexins promote a variety of behaviors
      including alertness, vigilance, locomotion, fight-flight responses, and feeding. The
      physiological effects of the orexins are mediated via 2 G-protein coupled receptors, ORX1 and
      ORX2. Orexin A binds with greater affinity to the ORX1 receptor, while orexin A and B bind
      with similar affinity to the ORX2 receptor.

      Orexins and Animal Fear Models

      Orexins have been implicated in anxiogenesis in some animal fear models. For example, central
      (icv) injection of orexin A in mice induced anxiety-like responses in the light-dark
      exploration test and elevated plus maze.

      Using an established, γ-aminobutyric acid (GABA)-deficit, rodent model of
      panic-vulnerability, the investigators' Indiana University preclinical anxiety collaborators
      provoked a panic-like response in rodents with an anxiogenic sodium lactate (NaLac) infusion,
      which response was blunted following either site-specific orexin (ORX) gene silencing or
      systemic pretreatment with an ORX1 antagonist.

      In addition, ORX neurons (peptidergic neurons in the lateral hypothalamus) were shown, in
      turn, to stimulate discrete efferent sites within an emotional network (e.g., bed nucleus of
      the stria terminalis) to elicit specific behavioral components of the panic-response
      following sodium lactate. Taken together, these results support the concept that ORX
      hypersecretion or ORX neuronal overactivity could also be present in human panic disorder
      (PD).

      Orexins' Emerging Role in Human Anxiogenesis / Panicogenesis

      Similar to the NaLac model animals, humans with PD have been reported to have cortical and
      subcortical GABA deficits. If these GABA deficits also extend to impairment of GABAergic
      inhibition of dorsomedial hypothalamus (DMH) ORX neurons in PD patients, as predicted by the
      NaLac animal model, they may result in ORX hypersecretion, increased sympathetic activation,
      and panicogenesis.

      There have been few clinical studies of ORX metabolism or function in human anxiety
      populations. However, recently generated human pilot data in the principal investigator's
      (PI's) lab, studying the effects of a well-documented anxiogenic stimulus (35% CO2
      inhalation) on behavioral, physiological, and biochemical (plasma ORX A; assayed by a
      standard radioimmunoassays [RIA] kit) measures, in 1 PD patient and 2 healthy volunteers. In
      this paradigm, the PD patient had a mild panic episode associated with marked early
      elevations in plasma ORX levels, relative to the volunteers who had minimal anxiety,
      consistent with a role for ORX in the initiation or elaboration of the human panic response.

      It was also demonstrated that, in contrast to human subjects without any axis I psychiatric
      disorder or with depression alone without panic, only subjects who had high panic scores but
      no depression had significantly elevated ORX levels in the cerebrospinal fluid (CSF).

      The ORX hyperactivity hypothesis of panic that has been evinced from this work is highly
      innovative, and promises to broaden the understanding of the neurobiology of human panic
      disorder, as well as provide new treatment directions.

      While there are limitations with using plasma ORX A as a measure of central nervous system
      (CNS) ORX function, one research group has recently published human data indicating that
      resting state CSF and plasma ORX A levels are highly correlated.

      Accordingly, the central hypothesis of this translational human pilot project, and a more
      definitive project based on it, is as follows: PD is a human anxiety disorder associated with
      specific cortical and subcortical GABA deficits that result in disruption of normal
      inhibitory regulation of pro-arousal ORX neurons. This disruption promotes excessive ORX
      release, sympathetic activation, and vulnerability to spontaneous or chemically induced
      panic. Pretreatment with an ORX1 receptor antagonist prior to chemical challenge is therefore
      expected to block the evoked panic response.

      Rationale for the Use of CO2 Inhalation

      The 35% CO2 challenge is well documented in the literature as being reliable, safe, and easy
      to administer. The procedure has acceptable test-retest reliability, and may be used to
      monitor improvement in clinical status following the administration of antipanic medications.

      Approximately 70% of PD patients will have a panic attack in response to this challenge,
      which closely resembles a real-life panic. Therefore, in addition to resting/baseline
      measurement of plasma ORX A, CO2-evoked levels of plasma ORX A in PD patients will also be
      examined, and these responses will be correlated with other behavioral and physiological
      parameters recorded during the CO2 test. The PI has had considerable experience using PD
      challenge paradigms in clinical research contexts, and he is very familiar with the
      application of the 35% CO2 challenge.

      Project Aims and Expected Results

      The project is a study that gathers pilot data relating to the role of orexin in human panic
      disorder. The effect sizes generated from this pilot work will permit planning and powering
      of a larger-scale study. It is anticipated that the study will be completed over the course
      of one year.

      Specific Aim 1 will be to provide a preliminary demonstration that acute administration of
      the first-in-class, FDA-approved insomnia agent, suvorexant, a mixed ORX1/2 receptor
      antagonist, will block 35% CO2-induced panic symptoms in PD patients, via amelioration of
      central ORX neuronal hyperactivity (as reflected in blunted plasma ORX responses to CO2
      challenge).

      To address Specific Aim 1, a prospective, parallel-group, repeated-measures design will be
      used to compare behavioral, physiological, and biochemical (plasma ORX) responses in 2
      independent, unmedicated groups of PD outpatients (n=6 in each group) at baseline/resting
      state and after panic provocation due to brief (1 minute) inhalation of a 35% CO2 / 65% O2
      gas mixture. PD patients will be randomized, in a double-blind manner, to receive either a
      single, oral dose of the mixed ORX1/2 receptor antagonist, suvorexant (10 mg dose), or
      identical placebo, 120 minutes before CO2 challenge.

      Expected results: It is expected that, compared to placebo, suvorexant pretreatment will
      blunt behavioral, physiological, and biochemical (plasma ORX) responses to 35% CO2 in PD, due
      to suppression of CNS ORX hyperactivity. The effect sizes generated from the pilot work will
      permit planning and powering of a larger-scale study, to definitively address Specific Aim 1.
    

Intervention name(s): suvorexant; placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Suvorexant
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science