- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02593682
The Role of Orexin in Human Panic Disorder
Study Overview
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 Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
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California
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Fresno, California, United States, 93701
- UCSF Fresno Medical Education Program
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Suvorexant Group
In this arm, subjects will receive 10 mg suvorexant 2 hours before a one-minute 35% CO2 challenge.
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Orexin Levels (Blood) +1 Minute
Time Frame: Baseline and +1 minute post-CO2 challenge
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Change in orexin levels from baseline to +1 min post-CO2 challenge
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Baseline and +1 minute post-CO2 challenge
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Change in Orexin Levels (Blood) +5 Minutes
Time Frame: Baseline and +5 minutes post-CO2 challenge
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Change in orexin levels from baseline to +5 min post-CO2 challenge
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Baseline and +5 minutes post-CO2 challenge
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Change in Orexin Levels (Blood) +15 Minutes
Time Frame: Baseline and +15 minutes post-CO2 challenge
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Change in orexin levels from baseline to +15 min post-CO2 challenge
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Baseline and +15 minutes post-CO2 challenge
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Change in Orexin Levels (Blood) +60 Minutes
Time Frame: Baseline and +60 minutes post-CO2 challenge
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Change in orexin levels from baseline to +60 min post-CO2 challenge
|
Baseline and +60 minutes post-CO2 challenge
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Collaborators and Investigators
Investigators
- Principal Investigator: Andrew Goddard, MD, University of California, San Francisco
Publications and helpful links
General Publications
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- Strawn JR, Pyne-Geithman GJ, Ekhator NN, Horn PS, Uhde TW, Shutter LA, Baker DG, Geracioti TD Jr. Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. 2010 Aug;35(7):1001-7. doi: 10.1016/j.psyneuen.2010.01.001. Epub 2010 Feb 8. Erratum In: Psychoneuroendocrinology. 2016 Jan;63:410.
- Goddard AW, Ball SG, Martinez J, Robinson MJ, Yang CR, Russell JM, Shekhar A. Current perspectives of the roles of the central norepinephrine system in anxiety and depression. Depress Anxiety. 2010 Apr;27(4):339-50. doi: 10.1002/da.20642.
- Bonaventure P, Yun S, Johnson PL, Shekhar A, Fitz SD, Shireman BT, Lebold TP, Nepomuceno D, Lord B, Wennerholm M, Shelton J, Carruthers N, Lovenberg T, Dugovic C. A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther. 2015 Mar;352(3):590-601. doi: 10.1124/jpet.114.220392. Epub 2015 Jan 12.
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- Coryell W, Arndt S. The 35% CO2 inhalation procedure: test-retest reliability. Biol Psychiatry. 1999 Apr 1;45(7):923-7. doi: 10.1016/s0006-3223(98)00241-8.
- Bertani A, Caldirola D, Bussi R, Bellodi L, Perna G. The 35% CO2 hyperreactivity and clinical symptomatology in patients with panic disorder after 1 week of treatment with citalopram: an open study. J Clin Psychopharmacol. 2001 Jun;21(3):262-7. doi: 10.1097/00004714-200106000-00003.
- van Beek N, Griez E. Reactivity to a 35% CO2 challenge in healthy first-degree relatives of patients with panic disorder. Biol Psychiatry. 2000 May 1;47(9):830-5. doi: 10.1016/s0006-3223(99)00265-6.
- Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ. LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress. 2003 Sep;6(3):189-97. doi: 10.1080/1025389031000146773.
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- Salomon RM, Ripley B, Kennedy JS, Johnson B, Schmidt D, Zeitzer JM, Nishino S, Mignot E. Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry. 2003 Jul 15;54(2):96-104. doi: 10.1016/s0006-3223(02)01740-7.
- Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam EG, Lee CK, Lellouch J, Lepine JP, Newman SC, Oakley-Browne MA, Rubio-Stipec M, Wells JE, Wickramaratne PJ, Wittchen HU, Yeh EK. The cross-national epidemiology of panic disorder. Arch Gen Psychiatry. 1997 Apr;54(4):305-9. doi: 10.1001/archpsyc.1997.01830160021003.
- Pollack MH, Otto MW, Rosenbaum JF, Sachs GS, O'Neil C, Asher R, Meltzer-Brody S. Longitudinal course of panic disorder: findings from the Massachusetts General Hospital Naturalistic Study. J Clin Psychiatry. 1990 Dec;51 Suppl A:12-6.
- Keller MB, Hanks DL. Course and outcome in panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 1993 Jul;17(4):551-70. doi: 10.1016/0278-5846(93)90005-d.
- Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J Psychiatry. 2000 Mar;176:229-35. doi: 10.1192/bjp.176.3.229.
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- Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, Ma J, Yee KL, Ermlich S, Mangin E, Lines C, Rosen L, Chodakewitz J, Murphy GM. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep. 2013 Feb 1;36(2):259-67. doi: 10.5665/sleep.2386.
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- Johnson PL, Samuels BC, Fitz SD, Lightman SL, Lowry CA, Shekhar A. Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia. Neuropsychopharmacology. 2012 Jul;37(8):1911-22. doi: 10.1038/npp.2012.38. Epub 2012 Mar 28.
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- Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D. Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10685-90. doi: 10.1073/pnas.0702676104. Epub 2007 Jun 11.
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Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2015078
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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