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The Role of Orexin in Human Panic Disorder

Sponsor
University of California, San Francisco (Other)
Overall Status
Completed
CT.gov ID
NCT02593682
Collaborator
(none)
3
Enrollment
1
Location
2
Arms
46.4
Actual Duration (Months)
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 4

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
3 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Basic Science
Official Title:
The Role of Orexin in Human Panic Disorder
Actual Study Start Date :
May 1, 2016
Actual Primary Completion Date :
Mar 13, 2020
Actual Study Completion Date :
Mar 13, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Suvorexant Group

In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge.

Drug: suvorexant
Placebo Comparator: Placebo Group

In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge.

Drug: placebo

Outcome Measures

Primary Outcome Measures

  1. Change in Orexin Levels (Blood) +1 Minute [Baseline and +1 minute post-CO2 challenge]

    Change in orexin levels from baseline to +1 min post-CO2 challenge

  2. Change in Orexin Levels (Blood) +5 Minutes [Baseline and +5 minutes post-CO2 challenge]

    Change in orexin levels from baseline to +5 min post-CO2 challenge

  3. Change in Orexin Levels (Blood) +15 Minutes [Baseline and +15 minutes post-CO2 challenge]

    Change in orexin levels from baseline to +15 min post-CO2 challenge

  4. Change in Orexin Levels (Blood) +60 Minutes [Baseline and +60 minutes post-CO2 challenge]

    Change in orexin levels from baseline to +60 min post-CO2 challenge

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  • They must be in stable physical health as determined by a medical evaluation, including physical examination, electrocardiogram, laboratory findings (comprehensive metabolic panel, complete blood count [CBC], free T4, urine pregnancy test, urinalysis), urine toxicology screen, and a negative urine pregnancy test in women of child-bearing potential.

  • They must satisfy the new clinical criteria in the Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5) for a current principal diagnosis of PD as confirmed by a semi-structured, diagnostic interview, the Mini International Neuropsychiatric Interview (MINI), administered by the PI.

  • Since clinical depression (MDD) is associated with CSF ORX abnormalities, only patients with a current PD without MDD will be enrolled. They will also be required to have a current Montgomery-Asberg Depression Rating Scale (MADRS) total score <12.

  • They will be off all regular psychiatric medications and avoid drinking grapefruit juice for at least 2 weeks prior to the 35% CO2 test.

  • They must not be pregnant or breastfeeding a baby; and women of childbearing potential must be using birth control while on this study.

Exclusion Criteria:

  • any history of a psychotic disorder, bipolar disorder, MDD, depression not otherwise specified (NOS), obsessive compulsive disorder, an eating disorder, post-traumatic stress disorder, or generalized anxiety disorder

  • medical conditions for which suvorexant could be contraindicated, such as narcolepsy

  • any other sleep disorder

  • a substance use disorder, as defined by the DSM-5, within 6 months of the screening visit

  • ongoing use of psychiatric medications in the 2 weeks prior to the 35% CO2 test

  • current use of certain drugs, including

  • strong cytochrome P450 3A (CYP3A) inhibitors (such as ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan);

  • moderate CYP3A inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil);

  • strong CYP3A inducers (such as rifampin, carbamazepine and phenytoin);

  • digoxin

  • history of any neurological disorder affecting the CNS

  • history of uncontrolled or serious medical illness

  • a history of hypersensitivity or allergy to suvorexant

  • pregnancy or lactation status, or unwillingness to use birth control while on this study, for women of child-bearing potential

  • compromised lung function (e.g., chronic obstructive pulmonary disease [COPD], emphysema, idiopathic pulmonary fibrosis, lung cancer)

  • inability to fast the required amount of time prior to study visit 2

  • a positive test for cannabinoids, opiates, benzodiazepines, amphetamines, cocaine and metabolites

  • out-of-range lab values

  • an abnormal EKG

  • a score > 12 on the Montgomery-Asberg Depression Rating Scale (MADRS)

  • inability or unwillingness to avoid drinking grapefruit juice for two weeks prior to the 35% CO2 challenge test

  • a history of sudden onset of muscle weakness (cataplexy)

Contacts and Locations

Locations

Site City State Country Postal Code
1 UCSF Fresno Medical Education Program Fresno California United States 93701

Sponsors and Collaborators

  • University of California, San Francisco

Investigators

  • Principal Investigator: Andrew Goddard, MD, University of California, San Francisco

Study Documents (Full-Text)

More Information

Publications

Responsible Party:
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT02593682
Other Study ID Numbers:
  • 2015078
First Posted:
Nov 1, 2015
Last Update Posted:
Jul 2, 2021
Last Verified:
Jun 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Additional relevant MeSH terms:
Panic Disorder
Suvorexant

Study Results

Participant Flow

Recruitment Details Per IRB records, 3 participants enrolled and 2 completed the study. PI left institution and all efforts to locate data have been exhausted.
Pre-assignment Detail
Arm/Group Title Suvorexant Group Placebo Group
Arm/Group Description In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge. suvorexant In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge. placebo
Period Title: Overall Study
STARTED 0 0
COMPLETED 0 0
NOT COMPLETED 0 0

Baseline Characteristics

Arm/Group Title Suvorexant Group Placebo Group Total
Arm/Group Description In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge. suvorexant In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge. placebo Total of all reporting groups
Overall Participants 0 0 0
Age () []
<=18 years
Between 18 and 65 years
>=65 years
Sex: Female, Male () []
Female
Male
Race (NIH/OMB) () []
American Indian or Alaska Native
Asian
Native Hawaiian or Other Pacific Islander
Black or African American
White
More than one race
Unknown or Not Reported
Region of Enrollment (participants) []

Outcome Measures

1. Primary Outcome
Title Change in Orexin Levels (Blood) +1 Minute
Description Change in orexin levels from baseline to +1 min post-CO2 challenge
Time Frame Baseline and +1 minute post-CO2 challenge

Outcome Measure Data

Analysis Population Description
PI left institution and all efforts to locate data have been exhausted.
Arm/Group Title Suvorexant Group Placebo Group
Arm/Group Description In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge. suvorexant In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge. placebo
Measure Participants 0 0
2. Primary Outcome
Title Change in Orexin Levels (Blood) +5 Minutes
Description Change in orexin levels from baseline to +5 min post-CO2 challenge
Time Frame Baseline and +5 minutes post-CO2 challenge

Outcome Measure Data

Analysis Population Description
PI left institution and all efforts to locate data have been exhausted.
Arm/Group Title Suvorexant Group Placebo Group
Arm/Group Description In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge. suvorexant In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge. placebo
Measure Participants 0 0
3. Primary Outcome
Title Change in Orexin Levels (Blood) +15 Minutes
Description Change in orexin levels from baseline to +15 min post-CO2 challenge
Time Frame Baseline and +15 minutes post-CO2 challenge

Outcome Measure Data

Analysis Population Description
PI left institution and all efforts to locate data have been exhausted.
Arm/Group Title Suvorexant Group Placebo Group
Arm/Group Description In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge. suvorexant In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge. placebo
Measure Participants 0 0
4. Primary Outcome
Title Change in Orexin Levels (Blood) +60 Minutes
Description Change in orexin levels from baseline to +60 min post-CO2 challenge
Time Frame Baseline and +60 minutes post-CO2 challenge

Outcome Measure Data

Analysis Population Description
PI left institution and all efforts to locate data have been exhausted.
Arm/Group Title Suvorexant Group Placebo Group
Arm/Group Description In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge. suvorexant In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge. placebo
Measure Participants 0 0

Adverse Events

Time Frame PI left institution and all efforts to locate data have been exhausted.
Adverse Event Reporting Description PI left institution and all efforts to locate data have been exhausted.
Arm/Group Title Suvorexant Group Placebo Group
Arm/Group Description In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge. suvorexant In this arm, subjects will receive a placebo, compounded to look identical to the study drug, 2 hours before a one-minute 35% CO2 challenge. placebo
All Cause Mortality
Suvorexant Group Placebo Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/0 (NaN) 0/0 (NaN)
Serious Adverse Events
Suvorexant Group Placebo Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/0 (NaN) 0/0 (NaN)
Other (Not Including Serious) Adverse Events
Suvorexant Group Placebo Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/0 (NaN) 0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Dr. Andrew Goddard
Organization University of California, San Francisco
Phone (317) 274-3960
Email agoddard@fresno.ucsf.edu
Responsible Party:
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT02593682
Other Study ID Numbers:
  • 2015078
First Posted:
Nov 1, 2015
Last Update Posted:
Jul 2, 2021
Last Verified:
Jun 1, 2021